CAP Profiles

Bio

Bio

C.F. Rehnborg Chair in Disease Prevention at Stanford University, Professor of Medicine, Professor of Health Research and Policy, and Professor (by courtesy) of Biomedical Data Science at the School of Medicine; Professor (by courtesy) of Statistics at the School of Humanities and Sciences; co-Director, Meta-Research Innovation Center at Stanford; Director of the PhD program in Epidemiology and Clinical Research.
Born in New York City in 1965 and raised in Athens, Greece. Valedictorian (1984) at Athens College; National Award of the Greek Mathematical Society (1984); MD (top rank of medical school class) from the National University of Athens in 1990; also received DSc in biopathology from the same institution. Trained at Harvard and Tufts (internal medicine and infectious diseases), then held positions at NIH, Johns Hopkins and Tufts. Chaired the Department of Hygiene and Epidemiology, University of Ioannina Medical School in 1999-2010 (tenured professor since 2003) while also holding adjunct professor positions at Harvard School of Public Health, Tufts, and Imperial College. Senior Advisor on Knowledge Integration at NCI/NIH (2012-6). Served as President, Society for Research Synthesis Methodology, and editorial board member of many leading journals (including PLoS Medicine, Lancet, Annals of Internal Medicine, JNCI, Science Translational Medicine, Clinical Chemistry, Molecular and Cellular Proteomics, AIDS, IJE, JCE, Clinical Trials, and PLoS ONE, among others) and as Editor-in-Chief of the European Journal of Clinical Investigation (2010-now). Delivered ~500 invited and honorary lectures. Recipient of many awards (e.g. European Award for Excellence in Clinical Science [2007], Medal for Distinguished Service, Teachers College, Columbia University [2015], Chanchlani Global Health Award [2017], Epiphany Science Courage Award [2018]). Inducted in the Association of American Physicians (2009), European Academy of Cancer Sciences (2010) American Epidemiological Society (2015), European Academy of Sciences and Arts (2015). Honorary titles from FORTH (2014) and Ioannina (2015) and honorary doctorates from Rotterdam (2015) and Athens (2017). Multiple honorary lectureships/visiting professorships (Caltech, Oxford, LSHTM, Yale, U Utah, U Conn, UC Davis, U Penn among others). The PLoS Medicine paper on “Why most published research findings are false” has been the most-accessed article in the history of Public Library of Science (>2.5 million hits). Author of 7 literary books in Greek, two of which (“Toccata for the Girl with the Burnt Face” (Kedros 2012) and “Variations on the Art of the Fugue and a Desperate Ricercar” (Kedros 2014)) were shortlisted for best book of the year Anagnostis awards. Brave Thinker scientist for 2010 according to Atlantic, “may be one of the most influential scientists alive”. Author of ~1000 papers in peer-reviewed journals, 67% of papers as single/first/last author. Highly Cited Researcher according to Thomson Reuters in both Clinical Medicine and in Social Sciences. Citation indices: h=167, m=7 per Google Scholar (h=136 per WoS and Scopus). Current citation rates: >3,000 new citations per month per Google Scholar, >1,500 new citations per month per Scopus or Web of Knowledge.
Current citation rates suggest that I am among the 10 scientists worldwide who are currently the most commonly cited, perhaps also the currently most-cited physician. This probably only proves that citation metrics are highly unreliable, since I estimate that I have been rejected over 1,000 times in my life. Regardless, I consider myself privileged to have learned and to continue to learn from interactions with students and young scientists (of all ages) from all over the world and I love to be constantly reminded that I know next to nothing.

Academic Appointments

Administrative Appointments

  • Editor-in-chief, European Journal of Clinical Investigation (2010 - Present)
  • Member, Stanford Cardiovascular Institute (2010 - Present)
  • Member, Stanford Cancer Center (2010 - Present)
  • Affiliate, Stanford Center on Longevity (2012 - Present)
  • Affiliated faculty, Woods Institute for the Environment (2011 - Present)
  • Professor of Statistics (by courtesy), Stanford University School of Humanities and Sciences (2011 - Present)
  • Professor of Health Research and Policy, Stanford University School of Medicine (2011 - Present)
  • Professor of Medicine, Stanford University School of Medicine (2010 - Present)
  • Co-Director, Meta-Research Innovation Center at Stanford (METRICS) (2013 - Present)
  • Professor of Biomedical Data Science (by courtesy), Stanford University School of Medicine (2016 - Present)
  • C.F. Rehnborg Professor in Disease Prevention and Director, Stanford Prevention Research Center (2010 - Present)

Honors & Awards

  • Epiphany Science Courage Award, Novim (inaugural award) (2018)
  • Elected Councilor, Association of American Physicians (2017-2022)
  • Elected member, Association of American Physicians (2009-)
  • President, Society for Research Synthesis Methodology (2009-2010)
  • Elected fellow, European Academy of Cancer Sciences (2010-)
  • Elected member, American Epidemiological Society (2015-)
  • Elected member, European Academy of Sciences and Arts (2015-)
  • European Award for Excellence in Clinical Science, European Society for Clinical Investigation (2007)
  • Chanchlani Award for Global Health, McMaster University (2017)
  • David-Sackett-Preis, Deutsche Netzwerk Evidenzbasierte Medizin (2017)
  • Lifetime Achievement Award, Hellenic Society for Pharmacological Science (2016)
  • Medal for Distinguished Service, Teachers College, Columbia University (2015)
  • Honorary PhD, Erasmus University Rotterdam (2015)
  • Honorary PhD (health sciences), University of Athens (2017)
  • Litchfield Lectureship, Oxford University (2015)
  • Levine lectureship, Yale (2016)
  • Harris lectureship in science and civilization, Caltech (2016)
  • Snyder Lectureship, University of Utah (2016)
  • Anatomy Lesson lecturer, University of Amsterdam and Academic Medical Center (2016)
  • Annual Distinguished Investigator, University of Connecticut School of Medicine and Health Center (2017)
  • Snively visiting professorship, UC Davis (2017)
  • Gonatas memorial lectureship, University of Pennsylvania (2018)
  • Honorary member, FORTH (2014)
  • Honorary professor (omotimos), University of Ioannina (2014)
  • Executive board member and center director, Human Genome Epidemiology Network (2004-)

Boards, Advisory Committees, Professional Organizations

  • Chair, Scientific Advisory Board, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh (2015 - Present)
  • Faculty Fellow, Stanford Center for Innovation on Global Health (2015 - Present)
  • Member, Scientific Advisory Board, Berkeley Initiative for Transparency in Social Sciences (2014 - Present)
  • Member, Scientific Advisory Board, Center for Open Science (2013 - Present)
  • Member, Scientific Advisory Board, International Epidemiology Institute (2012 - Present)
  • Member, Scientific Advisory Board, Reproducibility Initiative (2012 - Present)
  • Senior Advisor for Knowledge Integration, NCI, NIH (2012 - 2016)
  • Member, Methodology Committee, PCORI (2011 - 2013)
  • Vice President, Board of Directors, Hellenic Center for Infectious Disease Control (2000 - 2001)

Professional Education

  • Fellowship, New England Medical Center, Tufts University School of Medicine, Infectious Diseases (1996)
  • Residency, New England Deaconess Hospital, Harvard Medical School, Internal Medicine (1993)
  • DSc, University of Athens School of Medicine, Athens, Greece, Biopathology (1996)
  • MD, University of Athens School of Medicine, Athens, Greece, Medicine (1990)

Contact

Links

Research & Scholarship

Current Research and Scholarly Interests

I have worked in the fields of evidence-based medicine, clinical investigation, clinical and molecular epidemiology, clinical research methodology, empirical research methods, statistics, and genomics. I have a strong interest in meta-research and in large-scale evidence (in particular randomized trials and meta-analyses) and in appraisal and control of diverse biases in biomedical research. I am interested in developing and applying new research methods, and in the interdisciplinary enhancement of existing research methods for study design and analysis in biomedicine. Some of my most influential papers in terms of citations are those addressing issues of replication validity of genetic association studies, biases in biomedical research, research synthesis methods, extensions of meta-analysis, genome-wide association studies and agnostic evaluation of associations, and validity of randomized trials and observational research. I have also designed, steered and participated in influential randomized trials (in particular, the major trials that changed decisively the management and outcome of HIV infection, but also trials in nephrology, and in antibiotic use in the community), and large international consortia that have helped transform the efficiency of research in diverse fields of genomic, molecular and clinical epidemiology. I enjoy working with a diverse array of colleagues from very diverse disciplines and to have an opportunity to learn from both senior and junior investigators, and particularly students at all levels.

Clinical Trials

  • Personal Genomics for Preventive Cardiology Not Recruiting

    The purpose of this study is to see if providing information to a person on their inherited (genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their diet, lifestyle or medication regimen to alter their risk.

    Stanford is currently not accepting patients for this trial. For more information, please contact Josh Knowles, 650-804-2526.

    View full details

Teaching

2017-18 Courses

Stanford Advisees

Publications

All Publications

  • The Proposal to Lower P Value Thresholds to .005 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Loannidis, J. A. 2018; 319 (14): 1429–30

    View details for DOI 10.1001/jama.2018.1536

    View details for Web of Science ID 000429590200008

    View details for PubMedID 29566133

  • Meta-research: Why research on research matters PLOS BIOLOGY Ioannidis, J. A. 2018; 16 (3): e2005468

    Abstract

    Meta-research is the study of research itself: its methods, reporting, reproducibility, evaluation, and incentives. Given that science is the key driver of human progress, improving the efficiency of scientific investigation and yielding more credible and more useful research results can translate to major benefits. The research enterprise grows very fast. Both new opportunities for knowledge and innovation and new threats to validity and scientific integrity emerge. Old biases abound, and new ones continuously appear as novel disciplines emerge with different standards and challenges. Meta-research uses an interdisciplinary approach to study, promote, and defend robust science. Major disruptions are likely to happen in the way we pursue scientific investigation, and it is important to ensure that these disruptions are evidence based.

    View details for DOI 10.1371/journal.pbio.2005468

    View details for Web of Science ID 000428987600023

    View details for PubMedID 29534060

    View details for PubMedCentralID PMC5865753

  • Defending Biomedical Science in an Era of Threatened Funding JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 317 (24): 2483–84

    View details for DOI 10.1001/jama.2017.5811

    View details for Web of Science ID 000404106600014

    View details for PubMedID 28459974

  • Meta-assessment of bias in science PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Costas, R., Ioannidis, J. P. 2017; 114 (14): 3714-3719

    Abstract

    Numerous biases are believed to affect the scientific literature, but their actual prevalence across disciplines is unknown. To gain a comprehensive picture of the potential imprint of bias in science, we probed for the most commonly postulated bias-related patterns and risk factors, in a large random sample of meta-analyses taken from all disciplines. The magnitude of these biases varied widely across fields and was overall relatively small. However, we consistently observed a significant risk of small, early, and highly cited studies to overestimate effects and of studies not published in peer-reviewed journals to underestimate them. We also found at least partial confirmation of previous evidence suggesting that US studies and early studies might report more extreme effects, although these effects were smaller and more heterogeneously distributed across meta-analyses and disciplines. Authors publishing at high rates and receiving many citations were, overall, not at greater risk of bias. However, effect sizes were likely to be overestimated by early-career researchers, those working in small or long-distance collaborations, and those responsible for scientific misconduct, supporting hypotheses that connect bias to situational factors, lack of mutual control, and individual integrity. Some of these patterns and risk factors might have modestly increased in intensity over time, particularly in the social sciences. Our findings suggest that, besides one being routinely cautious that published small, highly-cited, and earlier studies may yield inflated results, the feasibility and costs of interventions to attenuate biases in the literature might need to be discussed on a discipline-specific and topic-specific basis.

    View details for DOI 10.1073/pnas.1618569114

    View details for Web of Science ID 000398159000057

    View details for PubMedID 28320937

  • Empirical assessment of published effect sizes and power in the recent cognitive neuroscience and psychology literature PLOS BIOLOGY Szucs, D., Ioannidis, J. A. 2017; 15 (3): e2000797

    Abstract

    We have empirically assessed the distribution of published effect sizes and estimated power by analyzing 26,841 statistical records from 3,801 cognitive neuroscience and psychology papers published recently. The reported median effect size was D = 0.93 (interquartile range: 0.64-1.46) for nominally statistically significant results and D = 0.24 (0.11-0.42) for nonsignificant results. Median power to detect small, medium, and large effects was 0.12, 0.44, and 0.73, reflecting no improvement through the past half-century. This is so because sample sizes have remained small. Assuming similar true effect sizes in both disciplines, power was lower in cognitive neuroscience than in psychology. Journal impact factors negatively correlated with power. Assuming a realistic range of prior probabilities for null hypotheses, false report probability is likely to exceed 50% for the whole literature. In light of our findings, the recently reported low replication success in psychology is realistic, and worse performance may be expected for cognitive neuroscience.

    View details for DOI 10.1371/journal.pbio.2000797

    View details for Web of Science ID 000397909600008

    View details for PubMedID 28253258

    View details for PubMedCentralID PMC5333800

  • Evaluation of Evidence of Statistical Support and Corroboration of Subgroup Claims in Randomized Clinical Trials. JAMA internal medicine Wallach, J. D., Sullivan, P. G., Trepanowski, J. F., Sainani, K. L., Steyerberg, E. W., Ioannidis, J. P. 2017

    Abstract

    Many published randomized clinical trials (RCTs) make claims for subgroup differences.To evaluate how often subgroup claims reported in the abstracts of RCTs are actually supported by statistical evidence (P < .05 from an interaction test) and corroborated by subsequent RCTs and meta-analyses.This meta-epidemiological survey examines data sets of trials with at least 1 subgroup claim, including Subgroup Analysis of Trials Is Rarely Easy (SATIRE) articles and Discontinuation of Randomized Trials (DISCO) articles. We used Scopus (updated July 2016) to search for English-language articles citing each of the eligible index articles with at least 1 subgroup finding in the abstract.Articles with a subgroup claim in the abstract with or without evidence of statistical heterogeneity (P < .05 from an interaction test) in the text and articles attempting to corroborate the subgroup findings.Study characteristics of trials with at least 1 subgroup claim in the abstract were recorded. Two reviewers extracted the data necessary to calculate subgroup-level effect sizes, standard errors, and the P values for interaction. For individual RCTs and meta-analyses that attempted to corroborate the subgroup findings from the index articles, trial characteristics were extracted. Cochran Q test was used to reevaluate heterogeneity with the data from all available trials.The number of subgroup claims in the abstracts of RCTs, the number of subgroup claims in the abstracts of RCTs with statistical support (subgroup findings), and the number of subgroup findings corroborated by subsequent RCTs and meta-analyses.Sixty-four eligible RCTs made a total of 117 subgroup claims in their abstracts. Of these 117 claims, only 46 (39.3%) in 33 articles had evidence of statistically significant heterogeneity from a test for interaction. In addition, out of these 46 subgroup findings, only 16 (34.8%) ensured balance between randomization groups within the subgroups (eg, through stratified randomization), 13 (28.3%) entailed a prespecified subgroup analysis, and 1 (2.2%) was adjusted for multiple testing. Only 5 (10.9%) of the 46 subgroup findings had at least 1 subsequent pure corroboration attempt by a meta-analysis or an RCT. In all 5 cases, the corroboration attempts found no evidence of a statistically significant subgroup effect. In addition, all effect sizes from meta-analyses were attenuated toward the null.A minority of subgroup claims made in the abstracts of RCTs are supported by their own data (ie, a significant interaction effect). For those that have statistical support (P < .05 from an interaction test), most fail to meet other best practices for subgroup tests, including prespecification, stratified randomization, and adjustment for multiple testing. Attempts to corroborate statistically significant subgroup differences are rare; when done, the initially observed subgroup differences are not reproduced.

    View details for DOI 10.1001/jamainternmed.2016.9125

    View details for PubMedID 28192563

  • A manifesto for reproducible science NATURE HUMAN BEHAVIOUR Munafo, M. R., Nosek, B. A., Bishop, D. M., Button, K. S., Chambers, C. D., du Sert, N., Simonsohn, U., Wagenmakers, E., Ware, J. J., Ioannidis, J. A. 2017; 1 (1)

    View details for DOI 10.1038/s41562-016-0021

    View details for Web of Science ID 000418775900021

  • What does research reproducibility mean? SCIENCE TRANSLATIONAL MEDICINE Goodman, S. N., Fanelli, D., Ioannidis, J. P. 2016; 8 (341)

    Abstract

    The language and conceptual framework of "research reproducibility" are nonstandard and unsettled across the sciences. In this Perspective, we review an array of explicit and implicit definitions of reproducibility and related terminology, and discuss how to avoid potential misunderstandings when these terms are used as a surrogate for "truth."

    View details for DOI 10.1126/scitranslmed.aaf5027

    View details for Web of Science ID 000377443000001

    View details for PubMedID 27252173

  • Evidence-based medicine has been hijacked: a report to David Sackett JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P. 2016; 73: 82-86

    View details for DOI 10.1016/j.jclinepi.2016.02.012

    View details for Web of Science ID 000378464800018

    View details for PubMedID 26934549

  • Evolution of Reporting P Values in the Biomedical Literature, 1990-2015 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Chavalarias, D., Wallach, J. D., Li, A. H., Ioannidis, J. P. 2016; 315 (11): 1141-1148

    Abstract

    The use and misuse of P values has generated extensive debates.To evaluate in large scale the P values reported in the abstracts and full text of biomedical research articles over the past 25 years and determine how frequently statistical information is presented in ways other than P values.Automated text-mining analysis was performed to extract data on P values reported in 12,821,790 MEDLINE abstracts and in 843,884 abstracts and full-text articles in PubMed Central (PMC) from 1990 to 2015. Reporting of P values in 151 English-language core clinical journals and specific article types as classified by PubMed also was evaluated. A random sample of 1000 MEDLINE abstracts was manually assessed for reporting of P values and other types of statistical information; of those abstracts reporting empirical data, 100 articles were also assessed in full text.P values reported.Text mining identified 4,572,043 P values in 1,608,736 MEDLINE abstracts and 3,438,299 P values in 385,393 PMC full-text articles. Reporting of P values in abstracts increased from 7.3% in 1990 to 15.6% in 2014. In 2014, P values were reported in 33.0% of abstracts from the 151 core clinical journals (n = 29,725 abstracts), 35.7% of meta-analyses (n = 5620), 38.9% of clinical trials (n = 4624), 54.8% of randomized controlled trials (n = 13,544), and 2.4% of reviews (n = 71,529). The distribution of reported P values in abstracts and in full text showed strong clustering at P values of .05 and of .001 or smaller. Over time, the "best" (most statistically significant) reported P values were modestly smaller and the "worst" (least statistically significant) reported P values became modestly less significant. Among the MEDLINE abstracts and PMC full-text articles with P values, 96% reported at least 1 P value of .05 or lower, with the proportion remaining steady over time in PMC full-text articles. In 1000 abstracts that were manually reviewed, 796 were from articles reporting empirical data; P values were reported in 15.7% (125/796 [95% CI, 13.2%-18.4%]) of abstracts, confidence intervals in 2.3% (18/796 [95% CI, 1.3%-3.6%]), Bayes factors in 0% (0/796 [95% CI, 0%-0.5%]), effect sizes in 13.9% (111/796 [95% CI, 11.6%-16.5%]), other information that could lead to estimation of P values in 12.4% (99/796 [95% CI, 10.2%-14.9%]), and qualitative statements about significance in 18.1% (181/1000 [95% CI, 15.8%-20.6%]); only 1.8% (14/796 [95% CI, 1.0%-2.9%]) of abstracts reported at least 1 effect size and at least 1 confidence interval. Among 99 manually extracted full-text articles with data, 55 reported P values, 4 presented confidence intervals for all reported effect sizes, none used Bayesian methods, 1 used false-discovery rates, 3 used sample size/power calculations, and 5 specified the primary outcome.In this analysis of P values reported in MEDLINE abstracts and in PMC articles from 1990-2015, more MEDLINE abstracts and articles reported P values over time, almost all abstracts and articles with P values reported statistically significant results, and, in a subgroup analysis, few articles included confidence intervals, Bayes factors, or effect sizes. Rather than reporting isolated P values, articles should include effect sizes and uncertainty metrics.

    View details for DOI 10.1001/jama.2016.1952

    View details for Web of Science ID 000372159800019

  • Reproducible Research Practices and Transparency across the Biomedical Literature. PLoS biology Iqbal, S. A., Wallach, J. D., Khoury, M. J., Schully, S. D., Ioannidis, J. P. 2016; 14 (1)

    Abstract

    There is a growing movement to encourage reproducibility and transparency practices in the scientific community, including public access to raw data and protocols, the conduct of replication studies, systematic integration of evidence in systematic reviews, and the documentation of funding and potential conflicts of interest. In this survey, we assessed the current status of reproducibility and transparency addressing these indicators in a random sample of 441 biomedical journal articles published in 2000-2014. Only one study provided a full protocol and none made all raw data directly available. Replication studies were rare (n = 4), and only 16 studies had their data included in a subsequent systematic review or meta-analysis. The majority of studies did not mention anything about funding or conflicts of interest. The percentage of articles with no statement of conflict decreased substantially between 2000 and 2014 (94.4% in 2000 to 34.6% in 2014); the percentage of articles reporting statements of conflicts (0% in 2000, 15.4% in 2014) or no conflicts (5.6% in 2000, 50.0% in 2014) increased. Articles published in journals in the clinical medicine category versus other fields were almost twice as likely to not include any information on funding and to have private funding. This study provides baseline data to compare future progress in improving these indicators in the scientific literature.

    View details for DOI 10.1371/journal.pbio.1002333

    View details for PubMedID 26726926

    View details for PubMedCentralID PMC4699702

  • Meta-research: Evaluation and Improvement of Research Methods and Practices PLOS BIOLOGY Ioannidis, J. P., Fanelli, D., Dunne, D. D., Goodman, S. N. 2015; 13 (10)

    Abstract

    As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide.

    View details for DOI 10.1371/journal.pbio.1002264

    View details for Web of Science ID 000364457500001

    View details for PubMedID 26431313

    View details for PubMedCentralID PMC4592065

  • Assessment of vibration of effects due to model specification can demonstrate the instability of observational associations JOURNAL OF CLINICAL EPIDEMIOLOGY Patel, C. J., Burford, B., Ioannidis, J. P. 2015; 68 (9): 1046-1058

    Abstract

    Model specification-what adjusting variables are analytically modeled-may influence results of observational associations. We present a standardized approach to quantify the variability of results obtained with choices of adjustments called the "vibration of effects" (VoE).We estimated the VoE for 417 clinical, environmental, and physiological variables in association with all-cause mortality using National Health and Nutrition Examination Survey data. We selected 13 variables as adjustment covariates and computed 8,192 Cox models for each of 417 variables' associations with all-cause mortality.We present the VoE by assessing the variance of the effect size and in the -log10(P-value) obtained by different combinations of adjustments. We present whether there are multimodality patterns in effect sizes and P-values and the trajectory of results with increasing adjustments. For 31% of the 417 variables, we observed a Janus effect, with the effect being in opposite direction in the 99th versus the 1st percentile of analyses. For example, the vitamin E variant α-tocopherol had a VoE that indicated higher and lower risk for mortality.Estimating VoE offers empirical estimates of associations are under different model specifications. When VoE is large, claims for observational associations should be very cautious.

    View details for DOI 10.1016/j.jclinepi.2015.05.029

    View details for Web of Science ID 000360597300011

    View details for PubMedCentralID PMC4555355

  • Evaluation of Wellness Determinants and Interventions by Citizen Scientists. JAMA Naci, H., Ioannidis, J. P. 2015; 314 (2): 121-122

    View details for DOI 10.1001/jama.2015.6160

    View details for PubMedID 26068643

  • Does screening for disease save lives in asymptomatic adults? Systematic review of meta-analyses and randomized trials INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Saquib, N., Saquib, J., Ioannidis, J. P. 2015; 44 (1): 264-277

    Abstract

    Several popular screening tests, such as mammography and prostate-specific antigen, have met with wide controversy and/or have lost their endorsement recently. We systematically evaluated evidence from randomized controlled trials (RCTs) as to whether screening decreases mortality from diseases where death is a common outcome.We searched three sources: United States Preventive Services Task Force (USPSTF), Cochrane Database of Systematic Reviews, and PubMed. We extracted recommendation status, category of evidence and RCT availability on mortality for screening tests for diseases on asymptomatic adults (excluding pregnant women and children) from USPSTF. We identified meta-analyses and individual RCTs on screening and mortality from Cochrane and PubMed.We selected 19 diseases (39 tests) out of 50 diseases/disorders for which USPSTF provides screening evaluation. Screening is recommended for 6 diseases (12 tests) out of the 19. We assessed 9 non-overlapping meta-analyses and 48 individual trials for these 19 diseases. Among the results of the meta-analyses, reductions where the 95% confidence intervals (CIs) excluded the null occurred for four disease-specific mortality estimates (ultrasound for abdominal aortic aneurysm in men; mammography for breast cancer; fecal occult blood test and flexible sigmoidoscopy for colorectal cancer) and for none of the all-cause mortality estimates. Among individual RCTs, reductions in disease-specific and all-cause mortality where the 95% CIs excluded the null occurred in 30% and 11% of the estimates, respectively.Among currently available screening tests for diseases where death is a common outcome, reductions in disease-specific mortality are uncommon and reductions in all-cause mortality are very rare or non-existent.

    View details for DOI 10.1093/ije/dyu140

    View details for Web of Science ID 000350864200034

    View details for PubMedID 25596211

  • Call to improve transparency of trials of non-regulated interventions. BMJ (Clinical research ed.) Dal-Ré, R., Bracken, M. B., Ioannidis, J. P. 2015; 350: h1323-?

    View details for DOI 10.1136/bmj.h1323

    View details for PubMedID 25820265

  • An overview of methods for network meta-analysis using individual participant data: when do benefits arise? STATISTICAL METHODS IN MEDICAL RESEARCH Debray, T. A., Schuit, E., Efthimiou, O., Reitsma, J. B., Ioannidis, J. A., Salanti, G., Moons, K. M., GetReal Workpackage 2018; 27 (5): 1351–64

    Abstract

    Network meta-analysis (NMA) is a common approach to summarizing relative treatment effects from randomized trials with different treatment comparisons. Most NMAs are based on published aggregate data (AD) and have limited possibilities for investigating the extent of network consistency and between-study heterogeneity. Given that individual participant data (IPD) are considered the gold standard in evidence synthesis, we explored statistical methods for IPD-NMA and investigated their potential advantages and limitations, compared with AD-NMA. We discuss several one-stage random-effects NMA models that account for within-trial imbalances, treatment effect modifiers, missing response data and longitudinal responses. We illustrate all models in a case study of 18 antidepressant trials with a continuous endpoint (the Hamilton Depression Score). All trials suffered from drop-out; missingness of longitudinal responses ranged from 21 to 41% after 6 weeks follow-up. Our results indicate that NMA based on IPD may lead to increased precision of estimated treatment effects. Furthermore, it can help to improve network consistency and explain between-study heterogeneity by adjusting for participant-level effect modifiers and adopting more advanced models for dealing with missing response data. We conclude that implementation of IPD-NMA should be considered when trials are affected by substantial drop-out rate, and when treatment effects are potentially influenced by participant-level covariates.

    View details for DOI 10.1177/0962280216660741

    View details for Web of Science ID 000429948200004

    View details for PubMedID 27487843

  • Systematic identification of correlates of HIV infection: an X-wide association study AIDS Patel, C. J., Bhattacharya, J., Ioannidis, J. A., Bendavid, E. 2018; 32 (7): 933–43

    Abstract

    Better identification of at-risk groups could benefit HIV-1 care programmes. We systematically identified HIV-1 risk factors in two nationally representative cohorts of women in the Demographic and Health Surveys.We identified and replicated the association of 1415 social, economic, environmental, and behavioral factors with HIV-1 status. We used the 2007 and 2013-2014 surveys conducted among 5715 and 15 433 Zambian women, respectively (688 shared factors). We used false discovery rate criteria to identify factors that are strongly associated with HIV-1 in univariate and multivariate models of the entire population, as well as in subgroups stratified by wealth, residence, age, and past HIV-1 testing.In the univariate analysis, we identified 102 and 182 variables that are associated with HIV-1 in the two surveys, respectively (79 factors were associated in both). Factors that were associated with HIV-1 status in full-sample analyses and in subgroups include being formerly married (adjusted OR 2007, 2.8, P < 10; 2013-2014 2.8, P < 10), widowhood (aOR 3.7, P < 10; and 4.2, P < 10), genital ulcers within 12 months (aOR 2.4, P < 10; and 2.2, P < 10), and having a woman head of the household (aOR 1.7, P < 10; and 2.1, P < 10), while owning a bicycle (aOR 0.6, P < 10; and 0.6, P < 10) and currently breastfeeding (aOR 0.5, P < 10; and 0.4, P < 10) were associated with decreased risk. Area under the curve for HIV-1 positivity was 0.76-0.82.Our X-wide association study identifies under-recognized factors related to HIV-1 infection, including widowhood, breastfeeding, and gender of head of the household. These features could be used to improve HIV-1 identification programs.

    View details for DOI 10.1097/QAD.0000000000001767

    View details for Web of Science ID 000429434300013

    View details for PubMedID 29424772

    View details for PubMedCentralID PMC5869155

  • Improving Disclosure of Financial Conflicts of Interest for Research on Psychosocial Interventions. JAMA psychiatry Cristea, I., Ioannidis, J. P. 2018

    View details for DOI 10.1001/jamapsychiatry.2018.0382

    View details for PubMedID 29641818

  • Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis LANCET Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Levcht, S., Ruhe, H. G., Turner, E. H., Higgins, J. T., Egger, M., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J. A., Geddes, J. R. 2018; 391 (10128): 1357–66

    Abstract

    Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

    View details for DOI 10.1016/S0140-6736(17)32802-7

    View details for Web of Science ID 000429342800024

    View details for PubMedID 29477251

    View details for PubMedCentralID PMC5889788

  • Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? BMC MEDICINE Dal-Re, R., Janiaud, P., Ioannidis, J. A. 2018; 16: 49

    Abstract

    Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics).36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic).To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.

    View details for DOI 10.1186/s12916-018-1038-2

    View details for Web of Science ID 000429564500001

    View details for PubMedID 29615035

    View details for PubMedCentralID PMC5883397

  • The Obesity Paradox: A Misleading Term That Should Be Abandoned OBESITY Flegal, K. M., Ioannidis, J. A. 2018; 26 (4): 629–30

    Abstract

    The term "obesity paradox" is a figure of speech, not a scientific term. The term has no precise definition and has been used to describe numerous observations that have little in common other than the finding of an association of obesity with a favorable outcome. The terminology has led to misunderstandings among researchers and the public alike. It's time for authors and editors to abandon the use of this term. Simply labeling counterintuitive findings as the "obesity paradox" adds no value. Unexpected findings should not be viewed negatively; such findings can lead to new knowledge, better treatments, and scientific advances.

    View details for DOI 10.1002/oby.22140

    View details for Web of Science ID 000428213200001

    View details for PubMedID 29570246

  • Improving the integrity of published science: An expanded taxonomy of retractions and corrections EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Fanelli, D., Ioannidis, J. A., Goodman, S. 2018; 48 (4)

    View details for DOI 10.1111/eci.12898

    View details for Web of Science ID 000427247700005

    View details for PubMedID 29369337

  • Meta-analyses in environmental and occupational health. Occupational and environmental medicine Ioannidis, J. P. 2018

    Abstract

    OBJECTIVES: Meta-analyses are considered generally as the highest level of evidence, but concerns have been voiced about their massive, low-quality production. This paper aimed to evaluate the landscape of meta-analyses in the field of occupational and environmental health and medicine.METHODS: Using relevant search terms, all meta-analyses were searched for, but those published in 2015 were assessed for their origin, whether they included randomised trials and individual-level data and whether they had authors from the industry or consultancy firms.RESULTS: PubMed searches (last update February 2017) identified 1251 eligible meta-analyses in this field. There was a rapid increase over time (n=16 published in 1995 vs n=163 published in 2015). Of the 163 eligible meta-analyses published in 2015, 49 were from China, followed at a distance by the USA (n=19). Only 16 considered randomised (intervention) trials and 13 included individual-level data. Only 1 of the 150 meta-analyses had industry authors and none had consultancy firm authors. As an example of conflicting findings, 12 overlapping meta-analyses addressed mobile phones and brain cancer risk and they differed substantially in number of studies included, eligibility criteria and conclusions.CONCLUSIONS: There has been a major increase in the publication of meta-analyses in occupational and environmental health over time, with the majority of these studies focusing on observational data, while a commendable fraction used individual-level data. Authorship is still limited largely to academic and non-profit authors. With massive production of meta-analyses, redundancy needs to be anticipated and efforts should be made to safeguard quality and protect from bias.

    View details for DOI 10.1136/oemed-2016-104128

    View details for PubMedID 29574405

  • A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement JOURNAL OF HYPERTENSION Stergiou, G. S., Alpert, B., Mieke, S., Asmar, R., Atkins, N., Eckert, S., Frick, G., Friedman, B., Grassl, T., Ichikawa, T., Ioannidis, J. P., Lacy, P., McManus, R., Murray, A., Myers, M., Palatini, P., Parati, G., Quinn, D., Sarkis, J., Shennan, A., Usuda, T., Wang, J., Wu, C. O., O'Brien, E. 2018; 36 (3): 472–78

    Abstract

    : In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.

    View details for DOI 10.1097/HJH.0000000000001634

    View details for Web of Science ID 000429317500003

    View details for PubMedID 29384983

    View details for PubMedCentralID PMC5796427

  • A Universal Standard for the Validation of Blood Pressure Measuring Devices Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement HYPERTENSION Stergiou, G. S., Alpert, B., Mieke, S., Asmar, R., Atkins, N., Eckert, S., Frick, G., Friedman, B., Grassl, T., Ichikawa, T., Ioannidis, J. P., Lacy, P., McManus, R., Murray, A., Myers, M., Palatini, P., Parati, G., Quinn, D., Sarkis, J., Shennan, A., Usuda, T., Wang, J., Wu, C. O., O'Brien, E. 2018; 71 (3): 368–74

    Abstract

    In the past 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring, and the International Organization for Standardization (ISO), have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers, and manufacturers, would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by the AAMI, ESH, and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH, and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.

    View details for DOI 10.1161/HYPERTENSIONAHA.117.10237

    View details for Web of Science ID 000424444600003

    View details for PubMedID 29386350

  • Evidence Based Medicine and Big Genomic Data. Human molecular genetics Ioannidis, J. P., Khoury, M. J. 2018

    Abstract

    Genomic and other related big data (Big Genomic Data, BGD for short) are ushering a new era of precision medicine. This overview discusses whether principles of evidence-based medicine (EBM) hold true for BGD and how they should be operationalized in the current era. Major EBM principles include the systematic identification, description and analysis of the validity and utility of BGD, the combination of individual clinical expertise with individual patient needs and preferences, and the focus on obtaining experimental evidence, whenever possible. BGD emphasize information of single patients with an overemphasis on N-of-1 trials to personalize treatment. However, large-scale comparative population data remain indispensable for meaningful translation of BGD personalized information. The impact of BGD on population health depends on its ability to affect large segments of the population. While several frameworks have been proposed to facilitate and standardize decision-making for use of genomic tests, there are new caveats that arise from BGD that extend beyond the limitations that were applicable for more simple genetic tests. Non-evidence-based use of BGD may be harmful and result in major waste of health care resources. Randomized controlled trials (RCTs) will continue to be the strongest arbitrator for the clinical utility of genomic technologies, including BGD. Research on BGD needs to focus not only on finding robust predictive associations (clinical validity), but more importantly on evaluating the balance of health benefits and potential harms (clinical utility), as well as implementation challenges. Appropriate features of such useful research on BGD are discussed.

    View details for DOI 10.1093/hmg/ddy065

    View details for PubMedID 29474574

  • Disclosures in Nutrition Research Why It Is Different JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A., Trepanowski, J. F. 2018; 319 (6): 547–48

    View details for DOI 10.1001/jama.2017.18571

    View details for Web of Science ID 000424908400011

    View details for PubMedID 29222543

  • Data sharing and reanalysis of randomized controlled trials in leading biomedical journals with a full data sharing policy: survey of studies published in The BMJ and PLOS Medicine BMJ-BRITISH MEDICAL JOURNAL Naudet, F., Sakarovitch, C., Janiaud, P., Cristea, I., Fanelli, D., Moher, D., Ioannidis, J. A. 2018; 360: 1–11

    Abstract

    To explore the effectiveness of data sharing by randomized controlled trials (RCTs) in journals with a full data sharing policy and to describe potential difficulties encountered in the process of performing reanalyses of the primary outcomes.Survey of published RCTs.PubMed/Medline.RCTs that had been submitted and published by The BMJ and PLOS Medicine subsequent to the adoption of data sharing policies by these journals.The primary outcome was data availability, defined as the eventual receipt of complete data with clear labelling. Primary outcomes were reanalyzed to assess to what extent studies were reproduced. Difficulties encountered were described.37 RCTs (21 from The BMJ and 16 from PLOS Medicine) published between 2013 and 2016 met the eligibility criteria. 17/37 (46%, 95% confidence interval 30% to 62%) satisfied the definition of data availability and 14 of the 17 (82%, 59% to 94%) were fully reproduced on all their primary outcomes. Of the remaining RCTs, errors were identified in two but reached similar conclusions and one paper did not provide enough information in the Methods section to reproduce the analyses. Difficulties identified included problems in contacting corresponding authors and lack of resources on their behalf in preparing the datasets. In addition, there was a range of different data sharing practices across study groups.Data availability was not optimal in two journals with a strong policy for data sharing. When investigators shared data, most reanalyses largely reproduced the original results. Data sharing practices need to become more widespread and streamlined to allow meaningful reanalyses and reuse of data.Open Science Framework osf.io/c4zke.

    View details for DOI 10.1136/bmj.k400

    View details for Web of Science ID 000425582200001

    View details for PubMedID 29440066

    View details for PubMedCentralID PMC5809812

  • What causes psychosis? An umbrella review of risk and protective factors WORLD PSYCHIATRY Radua, J., Ramella-Cravaro, V., Ioannidis, J. A., Reichenberg, A., Phiphopthatsanee, N., Amir, T., Thoo, H., Oliver, D., Davies, C., Morgan, C., McGuire, P., Murray, R. M., Fusar-Poli, P. 2018; 17 (1): 49–66

    Abstract

    Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta-analyses of observational studies which examined associations between socio-demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of psychotic cases, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty-five meta-analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra-high-risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91-17.72) and Black-Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96-6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North-African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non-right handedness). When only prospective studies were considered, the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.

    View details for DOI 10.1002/wps.20490

    View details for Web of Science ID 000422959200016

    View details for PubMedID 29352556

    View details for PubMedCentralID PMC5775150

  • Beyond genomics: understanding exposotypes through metabolomics HUMAN GENOMICS Rattray, N. W., Deziel, N. C., Wallach, J. D., Khan, S. A., Vasiliou, V., Ioannidis, J. A., Johnson, C. H. 2018; 12: 4

    Abstract

    Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample. Metabolomics datasets contain a wealth of information that reflect the disease state and are consequent to both genetic variation and environment. Thus, metabolomics is being widely adopted for epidemiologic research to identify disease risk traits. In this review, we discuss the evolution and challenges of metabolomics in epidemiologic research, particularly for assessing environmental exposures and providing insights into gene-environment interactions, and mechanism of biological impact.Metabolomics can be used to measure the complex global modulating effect that an exposure event has on an individual phenotype. Combining information derived from all levels of protein synthesis and subsequent enzymatic action on metabolite production can reveal the individual exposotype. We discuss some of the methodological and statistical challenges in dealing with this type of high-dimensional data, such as the impact of study design, analytical biases, and biological variance. We show examples of disease risk inference from metabolic traits using metabolome-wide association studies. We also evaluate how these studies may drive precision medicine approaches, and pharmacogenomics, which have up to now been inefficient. Finally, we discuss how to promote transparency and open science to improve reproducibility and credibility in metabolomics.Comparison of exposotypes at the human population level may help understanding how environmental exposures affect biology at the systems level to determine cause, effect, and susceptibilities. Juxtaposition and integration of genomics and metabolomics information may offer additional insights. Clinical utility of this information for single individuals and populations has yet to be routinely demonstrated, but hopefully, recent advances to improve the robustness of large-scale metabolomics will facilitate clinical translation.

    View details for DOI 10.1186/s40246-018-0134-x

    View details for Web of Science ID 000423380700001

    View details for PubMedID 29373992

    View details for PubMedCentralID PMC5787293

  • Altmetric Scores, Citations, and Publication of Studies Posted as Preprints JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Serghiou, S., Ioannidis, J. A. 2018; 319 (4): 402–3

    View details for DOI 10.1001/jama.2017.21168

    View details for Web of Science ID 000423405300027

    View details for PubMedID 29362788

    View details for PubMedCentralID PMC5833561

  • Routinely collected data for randomized trials: promises, barriers, and implications TRIALS Mc Cord, K. A., Salman, R., Treweek, S., Gardner, H., Strech, D., Whiteley, W., Ioannidis, J. A., Hemkens, L. G. 2018; 19: 29

    Abstract

    Routinely collected health data (RCD) are increasingly used for randomized controlled trials (RCTs). This can provide three major benefits: increasing value through better feasibility (reducing costs, time, and resources), expanding the research agenda (performing trials for research questions otherwise not amenable to trials), and offering novel design and data collection options (e.g., point-of-care trials and other designs directly embedded in routine care). However, numerous hurdles and barriers must be considered pertaining to regulatory, ethical, and data aspects, as well as the costs of setting up the RCD infrastructure. Methodological considerations may be different from those in traditional RCTs: RCD are often collected by individuals not involved in the study and who are therefore blinded to the allocation of trial participants. Another consideration is that RCD trials may lead to greater misclassification biases or dilution effects, although these may be offset by randomization and larger sample sizes. Finally, valuable insights into external validity may be provided when using RCD because it allows pragmatic trials to be performed.We provide an overview of the promises, challenges, and potential barriers, methodological implications, and research needs regarding RCD for RCTs.RCD have substantial potential for improving the conduct and reducing the costs of RCTs, but a multidisciplinary approach is essential to address emerging practical barriers and methodological implications.Future research should be directed toward such issues and specifically focus on data quality validation, alternative research designs and how they affect outcome assessment, and aspects of reporting and transparency.

    View details for DOI 10.1186/s13063-017-2394-5

    View details for Web of Science ID 000422699300003

    View details for PubMedID 29325575

    View details for PubMedCentralID PMC5765645

  • Dynamics of co-authorship and productivity across different fields of scientific research PLOS ONE Parish, A. J., Boyack, K. W., Ioannidis, J. A. 2018; 13 (1): e0189742

    Abstract

    We aimed to assess which factors correlate with collaborative behavior and whether such behavior associates with scientific impact (citations and becoming a principal investigator). We used the R index which is defined for each author as log(Np)/log(I1), where I1 is the number of co-authors who appear in at least I1 papers written by that author and Np are his/her total papers. Higher R means lower collaborative behavior, i.e. not working much with others, or not collaborating repeatedly with the same co-authors. Across 249,054 researchers who had published ≥30 papers in 2000-2015 but had not published anything before 2000, R varied across scientific fields. Lower values of R (more collaboration) were seen in physics, medicine, infectious disease and brain sciences and higher values of R were seen for social science, computer science and engineering. Among the 9,314 most productive researchers already reaching Np ≥ 30 and I1 ≥ 4 by the end of 2006, R mostly remained stable for most fields from 2006 to 2015 with small increases seen in physics, chemistry, and medicine. Both US-based authorship and male gender were associated with higher values of R (lower collaboration), although the effect was small. Lower values of R (more collaboration) were associated with higher citation impact (h-index), and the effect was stronger in certain fields (physics, medicine, engineering, health sciences) than in others (brain sciences, computer science, infectious disease, chemistry). Finally, for a subset of 400 U.S. researchers in medicine, infectious disease and brain sciences, higher R (lower collaboration) was associated with a higher chance of being a principal investigator by 2016. Our analysis maps the patterns and evolution of collaborative behavior across scientific disciplines.

    View details for DOI 10.1371/journal.pone.0189742

    View details for Web of Science ID 000419689600014

    View details for PubMedID 29320509

    View details for PubMedCentralID PMC5761855

  • Diagnosis and Treatment of Hypertension in the 2017 ACC/AHA Guidelines and in the Real World JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2018; 319 (2): 115–16

    View details for DOI 10.1001/jama.2017.19672

    View details for Web of Science ID 000419775500006

    View details for PubMedID 29242891

  • Potential Reporting Bias in Neuroimaging Studies of Sex Differences. Scientific reports David, S. P., Naudet, F., Laude, J., Radua, J., Fusar-Poli, P., Chu, I., Stefanick, M. L., Ioannidis, J. P. 2018; 8 (1): 6082

    Abstract

    Numerous functional magnetic resonance imaging (fMRI) studies have reported sex differences. To empirically evaluate for evidence of excessive significance bias in this literature, we searched for published fMRI studies of human brain to evaluate sex differences, regardless of the topic investigated, in Medline and Scopus over 10 years. We analyzed the prevalence of conclusions in favor of sex differences and the correlation between study sample sizes and number of significant foci identified. In the absence of bias, larger studies (better powered) should identify a larger number of significant foci. Across 179 papers, median sample size was n = 32 (interquartile range 23-47.5). A median of 5 foci related to sex differences were reported (interquartile range, 2-9.5). Few articles (n = 2) had titles focused on no differences or on similarities (n = 3) between sexes. Overall, 158 papers (88%) reached "positive" conclusions in their abstract and presented some foci related to sex differences. There was no statistically significant relationship between sample size and the number of foci (-0.048% increase for every 10 participants, p = 0.63). The extremely high prevalence of "positive" results and the lack of the expected relationship between sample size and the number of discovered foci reflect probable reporting bias and excess significance bias in this literature.

    View details for DOI 10.1038/s41598-018-23976-1

    View details for PubMedID 29666377

  • Redefine statistical significance NATURE HUMAN BEHAVIOUR Benjamin, D. J., Berger, J. O., Johannesson, M., Nosek, B. A., Wagenmakers, E., Berk, R., Bollen, K. A., Brembs, B., Brown, L., Camerer, C., Cesarini, D., Chambers, C. D., Clyde, M., Cook, T. D., De Boeck, P., Dienes, Z., Dreber, A., Easwaran, K., Efferson, C., Fehr, E., Fidler, F., Field, A. P., Forster, M., George, E. I., Gonzalez, R., Goodman, S., Green, E., Green, D. P., Greenwald, A., Hadfield, J. D., Hedges, L. V., Held, L., Ho, T., Hoijtink, H., Hruschka, D. J., Imai, K., Imbens, G., Ioannidis, J. A., Jeon, M., Jones, J., Kirchler, M., Laibson, D., List, J., Little, R., Lupia, A., Machery, E., Maxwell, S. E., McCarthy, M., Moore, D., Morgan, S. L., Munafo, M., Nakagawa, S., Nyhan, B., Parker, T. H., Pericchi, L., Perugini, M., Rouder, J., Rousseau, J., Savalei, V., Schoenbrodt, F. D., Sellke, T., Sinclair, B., Tingley, D., Van Zandt, T., Vazire, S., Watts, D. J., Winship, C., Wolpert, R. L., Xie, Y., Young, C., Zinman, J., Johnson, V. E. 2018; 2 (1): 6–10

    View details for DOI 10.1038/s41562-017-0189-z

    View details for Web of Science ID 000428754400005

  • The 10-Item Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) for Functional and Cosmetic Rhinoplasty JAMA FACIAL PLASTIC SURGERY Moubayed, S. P., Ioannidis, J. A., Saltychev, M., Most, S. P. 2018; 20 (1): 37–42

    Abstract

    Rhinoplasty is a common operation in which shape and function are intimately related, whether the procedure is cosmetic, functional, or combined in nature. There is currently no properly developed and validated patient-reported outcome measure (PROM) to evaluate both functional and cosmetic components of rhinoplasty.To develop, validate, and field test the Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) to evaluate both functional and cosmetic outcomes of rhinoplasty.Survey development study between October 2016 and April 2017 in a tertiary referral facial plastic and reconstructive surgery clinic. Preoperative and postoperative adult patients undergoing rhinoplasty, whether cosmetic or reconstructive, were included. A fifth group of adult nonrhinoplasty patients (facial cosmetic or reconstructive) were also included for the field test.Generated and reduced items, psychometric validation measures of the SCHNOS, and differences on scales between groups.For survey development, a total of 18 patients and 5 experts were interviewed. Of these patients, 5 were male, and 13 were female. Their mean (SD) age was 38 (14.8) years (range, 20-64 years). Field testing included 191 patients (67% were women and the mean [SD] age was 41.5 [15.8] years). A total of 10 items were included after generation, cognitive interviews, and item reduction. The 10 items represent 2 domains: nasal obstruction (first 4 items) and nasal cosmesis (last 6 items). For both domains, Cronbach α was excellent: 0.94 (95% CI, 0.92-0.95) for obstruction and 0.94 (95% CI, 0.93-0.95) for cosmesis. Exploratory factor analysis using scree plots for each domain showed that the domains are unidimensional in nature with each domain evaluating what it is intended to assess (nasal obstruction and cosmesis). The factor loading estimates were high for all the items, varying from 0.74 to 0.92. Kruskal-Wallis testing showed a significance level of P < .001 when evaluating the difference between groups (preoperative cosmetic, postoperative cosmetic, preoperative functional, postoperative functional, and nonrhinoplasty) for all individual questions, composite scores, and Nasal Obstruction Symptom Evaluation (NOSE) score. Correlations between the obstruction composite score and the NOSE scores were r = 0.943 (P < .001), which is very strong. The obstruction and cosmesis composite scores were only weakly correlated (r = 0.388; P < .001).We have developed and validated a new PROM to evaluate both functional and cosmetic rhinoplasty patients. The domains of obstruction and cosmesis were found to be internally consistent and unidimensional. The SCHNOS provides a short, validated questionnaire that we recommend for use in all functional or cosmetic rhinoplasty patients.N/A.

    View details for DOI 10.1001/jamafacial.2017.1083

    View details for Web of Science ID 000423037400007

    View details for PubMedID 28880988

    View details for PubMedCentralID PMC5833673

  • Modelling science trustworthiness under publish or perish pressure ROYAL SOCIETY OPEN SCIENCE Grimes, D., Bauch, C. T., Ioannidis, J. A. 2018; 5 (1): 171511

    Abstract

    Scientific publication is immensely important to the scientific endeavour. There is, however, concern that rewarding scientists chiefly on publication creates a perverse incentive, allowing careless and fraudulent conduct to thrive, compounded by the predisposition of top-tier journals towards novel, positive findings rather than investigations confirming null hypothesis. This potentially compounds a reproducibility crisis in several fields, and risks undermining science and public trust in scientific findings. To date, there has been comparatively little modelling on factors that influence science trustworthiness, despite the importance of quantifying the problem. We present a simple phenomenological model with cohorts of diligent, careless and unethical scientists, with funding allocated by published outputs. This analysis suggests that trustworthiness of published science in a given field is influenced by false positive rate, and pressures for positive results. We find decreasing available funding has negative consequences for resulting trustworthiness, and examine strategies to combat propagation of irreproducible science.

    View details for DOI 10.1098/rsos.171511

    View details for Web of Science ID 000423777300068

    View details for PubMedID 29410855

    View details for PubMedCentralID PMC5792932

  • Greece: Crisis, smoking and tobacco conflicts in social media EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. A. 2017; 47 (12)

    View details for DOI 10.1111/eci.12841

    View details for Web of Science ID 000416334100003

    View details for PubMedID 28981138

  • Ethics and Epistemology in Big Data Research JOURNAL OF BIOETHICAL INQUIRY Lipworth, W., Mason, P. H., Kerridge, I., Ioannidis, J. A. 2017; 14 (4): 489–500

    View details for DOI 10.1007/s11673-017-9771-3

    View details for Web of Science ID 000417043400006

  • Overlapping network meta-analyses on the same topic: survey of published studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Naudet, F., Schuit, E., Ioannidis, J. A. 2017; 46 (6): 1999–2008

    Abstract

    To assess how common it is for a published network meta-analysis (NMA) to have other published overlapping NMAs, and to evaluate these overlaps.A total of 88 NMAs of randomized controlled trials evaluating the comparative effectiveness of health interventions were randomly selected. For each of these, we searched for NMAs on the same topic. A random sample of 40 pairs (an index NMA and one of its overlapping NMAs) was selected to assess the overlap in terms of nodes, treatments and references. The topic with the largest number of overlapping NMAs was described in depth.In all, 68 of the 88 index NMAs had at least one overlapping NMA: 77% [95% confidence interval (CI), 69-86%]. We identified 515 pairs of overlapping NMAs. Among the 40 randomly selected pairs, 73% (95% CI, 58-88%) of nodes, 79% (95% CI, 72-86%) of treatments and 48% (95% CI, 37-59%) of references included in the index NMAs were also found in the respective overlapping NMAs. Efficacy of biologics in rheumatoid arthritis had the largest number of overlapping NMAs, with 28 NMAs published between 2003 and 2014. Differences in selection and definition of nodes of treatments resulted in different network geometries. There were also differences in both the direction and the statistical significance of effects.Published NMAs exhibit extensive overlap and potential redundancy. Erratic retrieval of eligible trials, and lack of consensus on the range of interventions to be considered and how they might be merged or split in different nodes, may cause confusion.

    View details for DOI 10.1093/ije/dyx138

    View details for Web of Science ID 000417745100043

    View details for PubMedID 29040566

  • A Genetic Marker Associated with De Quervain's Tenosynovitis INTERNATIONAL JOURNAL OF SPORTS MEDICINE Kim, S. K., Ahmed, M. A., Avins, A. L., Ioannidis, J. A. 2017; 38 (12): 942–48

    Abstract

    De Quervain's tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain's tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain's tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain's tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.

    View details for DOI 10.1055/s-0043-116669

    View details for Web of Science ID 000418240600010

    View details for PubMedID 28985641

  • Exclusion of Elderly People from Randomized Clinical Trials of Drugs for Ischemic Heart Disease JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Bourgeois, F. T., Orenstein, L., Ballakur, S., Mandl, K. D., Ioannidis, J. A. 2017; 65 (11): 2354–61

    Abstract

    To measure exclusion of elderly adults from randomized trials studying drug interventions for ischemic heart disease (IHD) and describe the characteristics of these trials.Cross-sectional analysis.Interventional clinical trials studying a drug intervention for IHD that started in 2006 and after were identified in ClinicalTrials.gov. Data were extracted on study features, including age-based inclusion criteria. Data on participants and their age distribution were collected from trial publications, investigator inquiry, and result data in ClinicalTrials.gov.Individuals aged 65 and older.Proportion of trials excluding individuals based on age, mean age of trial participants, and proportion of enrolled participants aged 65 and older and 75 and older.Of 839 identified trials, 446 (53%) explicitly excluded elderly adults. The most-frequent upper age limits were 80 (n = 164) and 75 (n = 114), with a median upper age limit of 80 (interquartile range 75-80). Trials with upper age limit exclusions tended to be smaller (median number of participants 100 vs 201, P < .001) and were more likely to be funded primarily by nonindustry sources (78.3% vs 70.0%, P = .006). The overall mean age of trial participants was 62.7 (mean maximum age 74). The estimated proportion of participants aged 65 and older was 42.5% and the estimated proportion aged 75 and older was 12.3%.Despite the high burden of IHD in elderly adults, the majority of drug trials do not enroll participants reflective of age-related prevalence of the disease.

    View details for DOI 10.1111/jgs.14833

    View details for Web of Science ID 000417766900004

    View details for PubMedID 28306144

    View details for PubMedCentralID PMC5601009

  • How to survive the medical misinformation mess EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. A., Stuart, M. E., Brownlee, S., Strite, S. A. 2017; 47 (11): 795–802

    Abstract

    Most physicians and other healthcare professionals are unaware of the pervasiveness of poor quality clinical evidence that contributes considerably to overuse, underuse, avoidable adverse events, missed opportunities for right care and wasted healthcare resources. The Medical Misinformation Mess comprises four key problems. First, much published medical research is not reliable or is of uncertain reliability, offers no benefit to patients, or is not useful to decision makers. Second, most healthcare professionals are not aware of this problem. Third, they also lack the skills necessary to evaluate the reliability and usefulness of medical evidence. Finally, patients and families frequently lack relevant, accurate medical evidence and skilled guidance at the time of medical decision-making. Increasing the reliability of available, published evidence may not be an imminently reachable goal. Therefore, efforts should focus on making healthcare professionals, more sensitive to the limitations of the evidence, training them to do critical appraisal, and enhancing their communication skills so that they can effectively summarize and discuss medical evidence with patients to improve decision-making. Similar efforts may need to target also patients, journalists, policy makers, the lay public and other healthcare stakeholders.

    View details for DOI 10.1111/eci.12834

    View details for Web of Science ID 000417366100001

    View details for PubMedID 28881000

  • A comparison of bivariate, multivariate random-effects, and Poisson correlated gamma-frailty models to meta-analyze individual patient data of ordinal scale diagnostic tests BIOMETRICAL JOURNAL Simoneau, G., Levis, B., Cuijpers, P., Ioannidis, J. A., Patten, S. B., Shrier, I., Bombardier, C. H., Osorio, F., Fann, J. R., Gjerdingen, D., Lamers, F., Lotrakul, M., Loewe, B., Shaaban, J., Stafford, L., van Weert, H. M., Whooley, M. A., Wittkampf, K. A., Yeung, A. S., Thombs, B. D., Benedetti, A. 2017; 59 (6): 1317–38

    Abstract

    Individual patient data (IPD) meta-analyses are increasingly common in the literature. In the context of estimating the diagnostic accuracy of ordinal or semi-continuous scale tests, sensitivity and specificity are often reported for a given threshold or a small set of thresholds, and a meta-analysis is conducted via a bivariate approach to account for their correlation. When IPD are available, sensitivity and specificity can be pooled for every possible threshold. Our objective was to compare the bivariate approach, which can be applied separately at every threshold, to two multivariate methods: the ordinal multivariate random-effects model and the Poisson correlated gamma-frailty model. Our comparison was empirical, using IPD from 13 studies that evaluated the diagnostic accuracy of the 9-item Patient Health Questionnaire depression screening tool, and included simulations. The empirical comparison showed that the implementation of the two multivariate methods is more laborious in terms of computational time and sensitivity to user-supplied values compared to the bivariate approach. Simulations showed that ignoring the within-study correlation of sensitivity and specificity across thresholds did not worsen inferences with the bivariate approach compared to the Poisson model. The ordinal approach was not suitable for simulations because the model was highly sensitive to user-supplied starting values. We tentatively recommend the bivariate approach rather than more complex multivariate methods for IPD diagnostic accuracy meta-analyses of ordinal scale tests, although the limited type of diagnostic data considered in the simulation study restricts the generalization of our findings.

    View details for DOI 10.1002/bimj.201600184

    View details for Web of Science ID 000418746100014

    View details for PubMedID 28692782

  • Human Genome Sequencing at the Population Scale: A Primer on High-Throughput DNA Sequencing and Analysis AMERICAN JOURNAL OF EPIDEMIOLOGY Goldfeder, R. L., Wall, D. P., Khoury, M. J., Ioannidis, J. A., Ashley, E. A. 2017; 186 (8): 1000–1009

    Abstract

    Most human diseases have underlying genetic causes. To better understand the impact of genes on disease and its implications for medicine and public health, researchers have pursued methods for determining the sequences of individual genes, then all genes, and now complete human genomes. Massively parallel high-throughput sequencing technology, where DNA is sheared into smaller pieces, sequenced, and then computationally reordered and analyzed, enables fast and affordable sequencing of full human genomes. As the price of sequencing continues to decline, more and more individuals are having their genomes sequenced. This may facilitate better population-level disease subtyping and characterization, as well as individual-level diagnosis and personalized treatment and prevention plans. In this review, we describe several massively parallel high-throughput DNA sequencing technologies and their associated strengths, limitations, and error modes, with a focus on applications in epidemiologic research and precision medicine. We detail the methods used to computationally process and interpret sequence data to inform medical or preventative action.

    View details for DOI 10.1093/aje/kww224

    View details for Web of Science ID 000412798300013

    View details for PubMedID 29040395

  • THE POWER OF BIAS IN ECONOMICS RESEARCH ECONOMIC JOURNAL Ioannidis, J. A., Stanley, T. D., Doucouliagos, H. 2017; 127 (605): F236–F265

    View details for DOI 10.1111/ecoj.12461

    View details for Web of Science ID 000418017100011

  • Next-generation systematic reviews: prospective meta-analysis, individual-level data, networks and umbrella reviews BRITISH JOURNAL OF SPORTS MEDICINE Ioannidis, J. 2017; 51 (20): 1456–58

    View details for DOI 10.1136/bjsports-2017-097621

    View details for Web of Science ID 000412656200007

    View details for PubMedID 28223307

  • Two genetic loci associated with ankle injury PLOS ONE Kim, S. K., Kleimeyer, J. P., Ahmed, M. A., Avins, A. L., Fredericson, M., Dragoo, J. L., Ioannidis, J. A. 2017; 12 (9): e0185355

    Abstract

    Ankle injuries, including sprains, strains and other joint derangements and instability, are common, especially for athletes involved in indoor court or jumping sports. Identifying genetic loci associated with these ankle injuries could shed light on their etiologies. A genome-wide association screen was performed using publicly available data from the Research Program in Genes, Environment and Health (RPGEH) including 1,694 cases of ankle injury and 97,646 controls. An indel (chr21:47156779:D) that lies close to a collagen gene, COL18A1, showed an association with ankle injury at genome-wide significance (p = 3.8x10-8; OR = 1.99; 95% CI = 1.75-2.23). A second DNA variant (rs13286037 on chromosome 9) that lies within an intron of the transcription factor gene NFIB showed an association that was nearly genome-wide significant (p = 5.1x10-8; OR = 1.63; 95% CI = 1.46-1.80). The ACTN3 R577X mutation was previously reported to show an association with acute ankle sprains, but did not show an association in this cohort. This study is the first genome-wide screen for ankle injury that yields insights regarding the genetic etiology of ankle injuries and provides DNA markers with the potential to inform athletes about their genetic risk for ankle injury.

    View details for DOI 10.1371/journal.pone.0185355

    View details for Web of Science ID 000411985200050

    View details for PubMedID 28957384

    View details for PubMedCentralID PMC5619760

  • Systematic reviews: guidance relevant for studies of older people AGE AND AGEING Shenkin, S. D., Harrison, J. K., Wilkinson, T., Dodds, R. M., Ioannidis, J. A. 2017; 46 (5): 722–28

    Abstract

    Systematic reviews and meta-analyses are increasingly common. This article aims to provide guidance for people conducting systematic reviews relevant to the healthcare of older people. An awareness of these issues will also help people reading systematic reviews to determine whether the results will influence their clinical practice. It is essential that systematic reviews are performed by a team which includes the required technical and clinical expertise. Those performing reviews for the first time should ensure they have appropriate training and support. They must be planned and performed in a transparent and methodologically robust way: guidelines are available. The protocol should be written-and if possible published-before starting the review. Geriatricians will be interested in a table of baseline characteristics, which will help to determine if the studied samples or populations are similar to their patients. Reviews of studies of older people should consider how they will manage issues such as different age cut-offs; non-specific presentations; multiple predictors and outcomes; potential biases and confounders. Systematic reviews and meta-analyses may provide evidence to improve older people's care, or determine where new evidence is required. Newer methodologies, such as meta-analyses of individual level data, network meta-analyses and umbrella reviews, and realist synthesis, may improve the reliability and clinical utility of systematic reviews.

    View details for DOI 10.1093/ageing/afx105

    View details for Web of Science ID 000408341000007

    View details for PubMedID 28655142

    View details for PubMedCentralID PMC5860219

  • When Null Hypothesis Significance Testing Is Unsuitable for Research: A Reassessment FRONTIERS IN HUMAN NEUROSCIENCE Szucs, D., Ioannidis, J. A. 2017; 11: 390

    Abstract

    Null hypothesis significance testing (NHST) has several shortcomings that are likely contributing factors behind the widely debated replication crisis of (cognitive) neuroscience, psychology, and biomedical science in general. We review these shortcomings and suggest that, after sustained negative experience, NHST should no longer be the default, dominant statistical practice of all biomedical and psychological research. If theoretical predictions are weak we should not rely on all or nothing hypothesis tests. Different inferential methods may be most suitable for different types of research questions. Whenever researchers use NHST they should justify its use, and publish pre-study power calculations and effect sizes, including negative findings. Hypothesis-testing studies should be pre-registered and optimally raw data published. The current statistics lite educational approach for students that has sustained the widespread, spurious use of NHST should be phased out.

    View details for DOI 10.3389/fnhum.2017.00390

    View details for Web of Science ID 000407070000001

    View details for PubMedID 28824397

    View details for PubMedCentralID PMC5540883

  • Inconsistent Guideline Recommendations for Cardiovascular Prevention and the Debate About Zeroing in on and Zeroing LDL-C Levels With PCSK9 Inhibitors JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 318 (5): 419–20

    View details for DOI 10.1001/jama.2017.6765

    View details for Web of Science ID 000406659800008

    View details for PubMedID 28738115

  • A meta-analysis of individual participant data constructed to align with prior expert views: comments on Bhupathiraju et al JOURNAL OF CLINICAL EPIDEMIOLOGY Flegal, K. M., Ioannidis, J. A. 2017; 88: 33–36

    View details for DOI 10.1016/j.jclinepi.2017.04.005

    View details for Web of Science ID 000411916500007

    View details for PubMedID 28411080

  • A meta-analysis but not a systematic review: an evaluation of the Global BMI Mortality Collaboration JOURNAL OF CLINICAL EPIDEMIOLOGY Flegal, K. M., Ioannidis, J. A. 2017; 88: 21–29

    Abstract

    Meta-analyses of individual participant data (MIPDs) offer many advantages and are considered the highest level of evidence. However, MIPDs can be seriously compromised when they are not solidly founded upon a systematic review. These data-intensive collaborative projects may be led by experts who already have deep knowledge of the literature in the field and of the results of published studies and how these results vary based on different analytical approaches. If investigators tailor the searches, eligibility criteria, and analysis plan of the MIPD, they run the risk of reaching foregone conclusions. We exemplify this potential bias in a MIPD on the association of body mass index with mortality conducted by a collaboration of outstanding and extremely knowledgeable investigators. Contrary to a previous meta-analysis of group data that used a systematic review approach, the MIPD did not seem to use a formal search: it considered 239 studies, of which the senior author was previously aware of at least 238, and it violated its own listed eligibility criteria to include those studies and exclude other studies. It also preferred an analysis plan that was also known to give a specific direction of effects in already published results of most of the included evidence. MIPDs where results of constituent studies are already largely known need safeguards to their validity. These may include careful systematic searches, adherence to the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines, and exploration of the robustness of results with different analyses. They should also avoid selective emphasis on foregone conclusions based on previously known results with specific analytical choices.

    View details for DOI 10.1016/j.jclinepi.2017.04.007

    View details for Web of Science ID 000411916500005

    View details for PubMedID 28435099

  • Enhancing the usability of systematic reviews by improving the consideration and description of interventions BMJ-BRITISH MEDICAL JOURNAL Hoffmann, T. C., Oxman, A. D., Ioannidis, J. A., Moher, D., Lasserson, T. J., Tovey, D. I., Stein, K., Sutcliffe, K., Ravaud, P., Altman, D. G., Perera, R., Glasziou, P. 2017; 358: j2998

    View details for DOI 10.1136/bmj.j2998

    View details for Web of Science ID 000406318500001

    View details for PubMedID 28729459

  • Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness NATURE COMMUNICATIONS Willems, S. M., Wright, D. J., Day, F. R., Trajanoska, K., Joshi, P. K., Morris, J. A., Matteini, A. M., Garton, F. C., Grarup, N., Oskolkov, N., Thalamuthu, A., Mangino, M., Liu, J., Demirkan, A., Lek, M., Xu, L., Wang, G., Oldmeadow, C., Gaulton, K. J., Lotta, L. A., Miyamoto-Mikami, E., Rivas, M. A., White, T., Loh, P., Aadahl, M., Amin, N., Attia, J. R., Austin, K., Benyamin, B., Brage, S., Cheng, Y., Cieszczyk, P., Derave, W., Eriksson, K., Eynon, N., Linneberg, A., Lucia, A., Massidda, M., Mitchell, B. D., Miyachi, M., Murakami, H., Padmanabhan, S., Pandey, A., Papadimitriou, L., Rajpal, D. K., Sale, C., Schnurr, T. M., Sessa, F., Shrine, N., Tobin, M. D., Varley, I., Wain, L. V., Wray, N. R., Lindgren, C. M., MacArthur, D. G., Waterworth, D. M., McCarthy, M. I., Pedersen, O., Khaw, K., Kie, D. P., Pitsiladis, Y., Fuku, N., Franks, P. W., North, K. N., van Duijn, C. M., Mather, K. A., Hansen, T., Hansson, O., Spector, T., Murabito, J. M., Richards, J., Rivadeneira, F., Langenberg, C., Perry, J. B., Wareham, N. J., Scott, R. A., GEFOS Anytype Fracture Consortium 2017; 8: 16015

    Abstract

    Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

    View details for DOI 10.1038/ncomms16015

    View details for Web of Science ID 000405270700002

    View details for PubMedID 29313844

    View details for PubMedCentralID PMC5510175

  • Drivers of poor medical care LANCET Saini, V., Garcia-Armesto, S., Klemperer, D., Paris, V., Elshaug, A. G., Brownlee, S., Ioannidis, J. A., Fisher, E. S. 2017; 390 (10090): 178–90

    Abstract

    The global ubiquity of overuse and underuse of health-care resources and the gravity of resulting harms necessitate an investigation of drivers to inform potential solutions. We describe the network of influences that contribute to poor care and suggest that it is driven by factors that fall into three domains: money and finance; knowledge, bias, and uncertainty; and power and human relationships. In each domain the drivers operate at the global, national, regional, and individual level, and are modulated by the specific contexts within which they act. We discuss in detail drivers of poor care in each domain.

    View details for DOI 10.1016/S0140-6736(16)30947-3

    View details for Web of Science ID 000404976600035

    View details for PubMedID 28077235

  • Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives ADVANCES IN NUTRITION Magni, P., Bier, D. M., Pecorelli, S., Agostoni, C., Astrup, A., Brighenti, F., Cook, R., Folco, E., Fontana, L., Gibson, R. A., Guerra, R., Guyatt, G. H., Ioannidis, J. A., Jackson, A. S., Klurfeld, D. M., Makrides, M., Mathioudakis, B., Monaco, A., Patel, C. J., Racagni, G., Schunemann, H. J., Shamir, R., Zmora, N., Peracino, A. 2017; 8 (4): 532–45

    Abstract

    A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future.

    View details for DOI 10.3945/an.116.014738

    View details for Web of Science ID 000406567000002

    View details for PubMedID 28710141

    View details for PubMedCentralID PMC5502870

  • Nonreproducibility of Preclinical Research Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 317 (23): 2453

    View details for DOI 10.1001/jama.2017.5987

    View details for Web of Science ID 000403654600023

    View details for PubMedID 28632861

  • Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies BMJ-BRITISH MEDICAL JOURNAL Li, X., Meng, X., Timofeeva, M., Tzoulaki, I., Tsilidis, K. K., Ioannidis, P. A., Campbell, H., Theodoratou, E. 2017; 357: j2376

    Abstract

    Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels.Design Umbrella review.Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references.Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes.Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10-6, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies.Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

    View details for DOI 10.1136/bmj.j2376

    View details for Web of Science ID 000403221400001

    View details for PubMedID 28592419

    View details for PubMedCentralID PMC5461476

  • Timing and Characteristics of Cumulative Evidence Available on Novel Therapeutic Agents Receiving Food and Drug Administration Accelerated Approval MILBANK QUARTERLY Naci, H., Wouters, O. J., Gupta, R., Ioannidis, J. A. 2017; 95 (2): 261–90

    Abstract

    Policy Points: Randomized trials-the gold standard of evaluating effectiveness-constitute a small minority of existing evidence on agents given accelerated approval. One-third of randomized trials are in therapeutic areas outside of FDA approval and less than half evaluate the therapeutic benefits of these agents but use them instead as common backbone treatments. Agents receiving accelerated approval are often tested concurrently in several therapeutic areas. For most agents, no substantial time lag is apparent between the average start dates of randomized trials evaluating their effectiveness and those using them as part of background therapies. There appears to be a tendency for therapeutic agents receiving accelerated approval to quickly become an integral component of standard treatment, despite potential shortcomings in their evidence base.Therapeutic agents treating serious conditions are eligible for Food and Drug Administration (FDA) accelerated approval. The clinical evidence accrued on agents receiving accelerated approval has not been systematically evaluated. Our objective was to assess the timing and characteristics of available studies.We first identified clinical studies of novel therapeutic agents receiving accelerated approval. We then (1) categorized those studies as randomized or nonrandomized, (2) explored whether they evaluated the FDA-approved indications, and (3) documented the available treatment comparisons. We also meta-analyzed the difference in start times between randomized studies that (1) did or did not evaluate approved indications and (2) were or were not designed to evaluate the agent's effectiveness.In total, 37 novel therapeutic agents received accelerated approval between 2000 and 2013. Our search of ClinicalTrials.gov identified 7,757 studies, which included 1,258,315 participants. Only one-third of identified studies were randomized controlled trials. Of 1,631 randomized trials with advanced recruitment status, 906 were conducted in therapeutic areas for which agents received initial accelerated approval, 202 were in supplemental indications, and 523 were outside approved indications. Only 411 out of 906 (45.4%) trials were designed to test the effectiveness of agents that received accelerated approval ("evaluation" trials); others used these agents as common background treatment in both arms ("background" trials). There was no detectable lag between average start times of trials conducted within and outside initially approved indications. Evaluation trials started on average 1.52 years (95% CI: 0.87 to 2.17) earlier than background trials.Cumulative evidence on agents with accelerated approvals has major limitations. Most clinical studies including these agents are small and nonrandomized, and about a third are conducted in unapproved areas, typically concurrently with those conducted in approved areas. Most randomized trials including these therapeutic agents are not designed to directly evaluate their clinical benefits but to incorporate them as standard treatment.

    View details for DOI 10.1111/1468-0009.12261

    View details for Web of Science ID 000402994600011

    View details for PubMedID 28589600

    View details for PubMedCentralID PMC5461381

  • International journal of sports medicine Kim, S., Kleimeyer, J. P., Ahmed, M. A., Avins, A. L., Fredericson, M., Dragoo, J. L., Ioannidis, J. P. 2017

    Abstract

    Shoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10(-9); odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.

    View details for DOI 10.1055/s-0043-106190

    View details for PubMedID 28521375

  • Selective Cutoff Reporting in Studies of Diagnostic Test Accuracy: A Comparison of Conventional and Individual-Patient-Data Meta-Analyses of the Patient Health Questionnaire-9 Depression Screening Tool AMERICAN JOURNAL OF EPIDEMIOLOGY Levis, B., Benedetti, A., Levis, A. W., Ioannidis, J. A., Shrier, I., Cuijpers, P., Gilbody, S., Kloda, L. A., McMillan, D., Patten, S. B., Steele, R. J., Ziegelstein, R. C., Bombardier, C. H., Osorio, F., Fann, J. R., Gjerdingen, D., Lamers, F., Lotrakul, M., Loureiro, S. R., Lowe, B., Shaaban, J., Stafford, L., van Weert, H. M., Whooley, M. A., Williams, L. S., Wittkampf, K. A., Yeung, A. S., Thombs, B. D. 2017; 185 (10): 954–64

    Abstract

    In studies of diagnostic test accuracy, authors sometimes report results only for a range of cutoff points around data-driven "optimal" cutoffs. We assessed selective cutoff reporting in studies of the diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9) depression screening tool. We compared conventional meta-analysis of published results only with individual-patient-data meta-analysis of results derived from all cutoff points, using data from 13 of 16 studies published during 2004-2009 that were included in a published conventional meta-analysis. For the "standard" PHQ-9 cutoff of 10, accuracy results had been published by 11 of the studies. For all other relevant cutoffs, 3-6 studies published accuracy results. For all cutoffs examined, specificity estimates in conventional and individual-patient-data meta-analyses were within 1% of each other. Sensitivity estimates were similar for the cutoff of 10 but differed by 5%-15% for other cutoffs. In samples where the PHQ-9 was poorly sensitive at the standard cutoff, authors tended to report results for lower cutoffs that yielded optimal results. When the PHQ-9 was highly sensitive, authors more often reported results for higher cutoffs. Consequently, in the conventional meta-analysis, sensitivity increased as cutoff severity increased across part of the cutoff range-an impossibility if all data are analyzed. In sum, selective reporting by primary study authors of only results from cutoffs that perform well in their study can bias accuracy estimates in meta-analyses of published results.

    View details for DOI 10.1093/aje/kww191

    View details for Web of Science ID 000401938300013

    View details for PubMedID 28419203

    View details for PubMedCentralID PMC5430941

  • Finding the power to reduce publication bias STATISTICS IN MEDICINE STANLEY, T. D., Doucouliagos, H., Ioannidis, J. P. 2017; 36 (10): 1580-1598

    Abstract

    The central purpose of this study is to document how a sharper focus upon statistical power may reduce the impact of selective reporting bias in meta-analyses. We introduce the weighted average of the adequately powered (WAAP) as an alternative to the conventional random-effects (RE) estimator. When the results of some of the studies have been selected to be positive and statistically significant (i.e. selective reporting), our simulations show that WAAP will have smaller bias than RE at no loss to its other statistical properties. When there is no selective reporting, the difference between RE's and WAAP's statistical properties is practically negligible. Nonetheless, when selective reporting is especially severe or heterogeneity is very large, notable bias can remain in all weighted averages. The main limitation of this approach is that the majority of meta-analyses of medical research do not contain any studies with adequate power (i.e. >80%). For such areas of medical research, it remains important to document their low power, and, as we demonstrate, an alternative unrestricted weighted least squares weighted average can be used instead of WAAP. Copyright © 2017 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/sim.7228

    View details for Web of Science ID 000398518600005

    View details for PubMedID 28127782

  • Two Genetic Loci associated with Medial Collateral Ligament Injury. International journal of sports medicine Roos, A. K., Avins, A. L., Ahmed, M. A., Kleimeyer, J. P., Roos, T. R., Fredericson, M., Ioannidis, J. P., Dragoo, J. L., Kim, S. 2017

    Abstract

    Medial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10(-8)) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

    View details for DOI 10.1055/s-0043-104853

    View details for PubMedID 28482362

  • The Reproducibility Wars: Successful, Unsuccessful, Uninterpretable, Exact, Conceptual, Triangulated, Contested Replication CLINICAL CHEMISTRY Ioannidis, J. A. 2017; 63 (5): 943–45

    View details for DOI 10.1373/clinchem.2017.271965

    View details for Web of Science ID 000401951900003

    View details for PubMedID 28298413

  • Waste, Leaks, and Failures in the Biomarker Pipeline CLINICAL CHEMISTRY Ioannidis, J. A., Bossuyt, P. M. 2017; 63 (5): 963–72

    Abstract

    The large, expanding literature on biomarkers is characterized by almost ubiquitous significant results, with claims about the potential importance, but few of these discovered biomarkers are used in routine clinical care.The pipeline of biomarker development includes several specific stages: discovery, validation, clinical translation, evaluation, implementation (and, in the case of nonutility, deimplementation). Each of these stages can be plagued by problems that cause failures of the overall pipeline. Some problems are nonspecific challenges for all biomedical investigation, while others are specific to the peculiarities of biomarker research. Discovery suffers from poor methods and incomplete and selective reporting. External independent validation is limited. Selection for clinical translation is often shaped by nonrational choices. Evaluation is sparse and the clinical utility of many biomarkers remains unknown. The regulatory environment for biomarkers remains weak and guidelines can reach biased or divergent recommendations. Removing inefficient or even harmful biomarkers that have been entrenched in clinical care can meet with major resistance.The current biomarker pipeline is too prone to failures. Consideration of clinical needs should become a starting point for the development of biomarkers. Improvements can include the use of more stringent methodology, better reporting, larger collaborative studies, careful external independent validation, preregistration, rigorous systematic reviews and umbrella reviews, pivotal randomized trials, and implementation and deimplementation studies. Incentives should be aligned toward delivering useful biomarkers.

    View details for DOI 10.1373/clinchem.2016.254649

    View details for Web of Science ID 000401951900009

    View details for PubMedID 28270433

  • Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses ALZHEIMERS & DEMENTIA Bellou, V., Belbasis, L., Tzoulaki, I., Middleton, L. T., Ioannidis, J. P., Evangelou, E. 2017; 13 (4): 406-418

    Abstract

    Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors.We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance.A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease.Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

    View details for DOI 10.1016/j.jalz.2016.07.152

    View details for Web of Science ID 000398565000005

  • The credibility crisis in research: Can economics tools help? PLOS BIOLOGY Gall, T., Ioannidis, J. A., Maniadis, Z. 2017; 15 (4): e2001846

    Abstract

    The issue of nonreplicable evidence has attracted considerable attention across biomedical and other sciences. This concern is accompanied by an increasing interest in reforming research incentives and practices. How to optimally perform these reforms is a scientific problem in itself, and economics has several scientific methods that can help evaluate research reforms. Here, we review these methods and show their potential. Prominent among them are mathematical modeling and laboratory experiments that constitute affordable ways to approximate the effects of policies with wide-ranging implications.

    View details for DOI 10.1371/journal.pbio.2001846

    View details for Web of Science ID 000400423600020

    View details for PubMedID 28445470

    View details for PubMedCentralID PMC5405914

  • Hijacked evidence-based medicine: stay the course and throw the pirates overboard JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. A. 2017; 84: 11–13

    Abstract

    The article discusses a number of criticisms that have been raised against evidence-based medicine, such as focusing on benefits and ignoring adverse events; being interested in averages and ignoring the wide variability in individual risks and responsiveness; ignoring clinician-patient interaction and clinical judgement; leading to some sort of reductionism; and falling prey to corruption from conflicts of interest. I argue that none of these deficiencies are necessarily inherent to evidence-based medicine. In fact, work in evidence-based medicine has contributed a lot towards minimizing these deficiencies in medical research and medical care. However, evidence-based medicine is paying the price of its success: having become more widely recognized, it is manipulated and misused to support subverted or perverted agendas that are hijacking its reputation value. Sometimes the conflicts behind these agendas are so strong that one worries about whether the hijacking of evidence-based medicine is reversible. Nevertheless, evidence-based medicine is a valuable conceptual toolkit and it is worth to try to remove the biases of the pirates who have hijacked its ship.

    View details for DOI 10.1016/j.jclinepi.2017.02.001

    View details for Web of Science ID 000402849500004

    View details for PubMedID 28532611

  • Meta-analyses Can Be Credible and Useful A New Standard JAMA PSYCHIATRY Ioannidis, J. A. 2017; 74 (4): 311–12

    View details for DOI 10.1001/jamapsychiatry.2017.0035

    View details for Web of Science ID 000398434600001

    View details for PubMedID 28241194

  • Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy PLOS ONE Kim, S. K., Roos, T. R., Roos, A. K., Kleimeyer, J. P., Ahmed, M. A., Goodlin, G. T., Fredericson, M., Ioannidis, J. P., Avins, A. L., Dragoo, J. L. 2017; 12 (3)

    Abstract

    Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

    View details for DOI 10.1371/journal.pone.0170422

    View details for Web of Science ID 000399174800001

    View details for PubMedID 28358823

  • Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy PLOS ONE Kim, S. K., Roos, T. R., Roos, A. K., Kleimeyer, J. P., Ahmed, M. A., Goodlin, G. T., Fredericson, M., Ioannidis, J. P., Avins, A. L., Dragoo, J. L. 2017; 12 (3)

    Abstract

    Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

    View details for DOI 10.1371/journal.pone.0170422

    View details for Web of Science ID 000399174800001

    View details for PubMedID 28358823

  • Acknowledging and Overcoming Nonreproducibility in Basic and Preclinical Research JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 317 (10): 1019–20

    View details for DOI 10.1001/jama.2017.0549

    View details for Web of Science ID 000396713400011

    View details for PubMedID 28192565

  • A simulation study of the strength of evidence in the recommendation of medications based on two trials with statistically significant results PLOS ONE van Ravenzwaaij, D., Ioannidis, J. A. 2017; 12 (3): e0173184

    Abstract

    A typical rule that has been used for the endorsement of new medications by the Food and Drug Administration is to have two trials, each convincing on its own, demonstrating effectiveness. "Convincing" may be subjectively interpreted, but the use of p-values and the focus on statistical significance (in particular with p < .05 being coined significant) is pervasive in clinical research. Therefore, in this paper, we calculate with simulations what it means to have exactly two trials, each with p < .05, in terms of the actual strength of evidence quantified by Bayes factors. Our results show that different cases where two trials have a p-value below .05 have wildly differing Bayes factors. Bayes factors of at least 20 in favor of the alternative hypothesis are not necessarily achieved and they fail to be reached in a large proportion of cases, in particular when the true effect size is small (0.2 standard deviations) or zero. In a non-trivial number of cases, evidence actually points to the null hypothesis, in particular when the true effect size is zero, when the number of trials is large, and when the number of participants in both groups is low. We recommend use of Bayes factors as a routine tool to assess endorsement of new medications, because Bayes factors consistently quantify strength of evidence. Use of p-values may lead to paradoxical and spurious decision-making regarding the use of new medications.

    View details for DOI 10.1371/journal.pone.0173184

    View details for Web of Science ID 000396073700043

    View details for PubMedID 28273140

    View details for PubMedCentralID PMC5342224

  • Increasing efficiency of preclinical research by group sequential designs PLOS BIOLOGY Neumann, K., Grittner, U., Piper, S. K., Rex, A., Florez-Vargas, O., Karystianis, G., Schneider, A., Wellwood, I., Siegerink, B., Ioannidis, J. P., Kimmelman, J., Dirnagl, U. 2017; 15 (3)

    Abstract

    Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain.

    View details for DOI 10.1371/journal.pbio.2001307

    View details for Web of Science ID 000397909600012

    View details for PubMedID 28282371

  • Does evidence-based hearsay determine the use of medical treatments? SOCIAL SCIENCE & MEDICINE Ioannidis, J. A. 2017; 177: 256–58

    View details for DOI 10.1016/j.socscimed.2017.02.004

    View details for Web of Science ID 000397552900029

    View details for PubMedID 28190627

  • Outcome reporting bias in clinical trials: why monitoring matters. BMJ (Clinical research ed.) Ioannidis, J. P., Caplan, A. L., Dal-Ré, R. 2017; 356: j408-?

    View details for DOI 10.1136/bmj.j408

    View details for PubMedID 28196819

  • DIETFITS study (diet intervention examining the factors interacting with treatment success) - Study design and methods. Contemporary clinical trials Stanton, M. V., Robinson, J. L., Kirkpatrick, S. M., Farzinkhou, S., Avery, E. C., Rigdon, J., Offringa, L. C., Trepanowski, J. F., Hauser, M. E., Hartle, J. C., Cherin, R. J., King, A. C., Ioannidis, J. P., Desai, M., Gardner, C. D. 2017; 53: 151-161

    Abstract

    Numerous studies have attempted to identify successful dietary strategies for weight loss, and many have focused on Low-Fat vs. Low-Carbohydrate comparisons. Despite relatively small between-group differences in weight loss found in most previous studies, researchers have consistently observed relatively large between-subject differences in weight loss within any given diet group (e.g., ~25kg weight loss to ~5kg weight gain). The primary objective of this study was to identify predisposing individual factors at baseline that help explain differential weight loss achieved by individuals assigned to the same diet, particularly a pre-determined multi-locus genotype pattern and insulin resistance status. Secondary objectives included discovery strategies for further identifying potential genetic risk scores. Exploratory objectives included investigation of an extensive set of physiological, psychosocial, dietary, and behavioral variables as moderating and/or mediating variables and/or secondary outcomes. The target population was generally healthy, free-living adults with BMI 28-40kg/m(2) (n=600). The intervention consisted of a 12-month protocol of 22 one-hour evening instructional sessions led by registered dietitians, with ~15-20 participants/class. Key objectives of dietary instruction included focusing on maximizing the dietary quality of both Low-Fat and Low-Carbohydrate diets (i.e., Healthy Low-Fat vs. Healthy Low-Carbohydrate), and maximally differentiating the two diets from one another. Rather than seeking to determine if one dietary approach was better than the other for the general population, this study sought to examine whether greater overall weight loss success could be achieved by matching different people to different diets. Here we present the design and methods of the study.

    View details for DOI 10.1016/j.cct.2016.12.021

    View details for PubMedID 28027950

  • Biomedical Journals and Preprint Services: Friends or Foes? CLINICAL CHEMISTRY Annesley, T., Scott, M., Bastian, H., Fonseca, V., Ioannidis, J. A., Keller, M. A., Polka, J. 2017; 63 (2): 453–58

    View details for DOI 10.1373/clinchem.2016.268227

    View details for Web of Science ID 000393360000004

    View details for PubMedID 27998906

  • Underperforming Big Ideas in Biomedical Research In Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Joyner, M. J., Paneth, N., Ioannidis, J. A. 2017; 317 (3): 322

    View details for DOI 10.1001/jama.2016.20003

    View details for Web of Science ID 000392089200030

    View details for PubMedID 28114549

  • Methods to increase reproducibility in differential gene expression via meta-analysis. Nucleic acids research Sweeney, T. E., Haynes, W. A., Vallania, F., Ioannidis, J. P., Khatri, P. 2017; 45 (1)

    Abstract

    Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would allow for systematic identification of best practices to improve reproducibility. We therefore constructed three very large gene expression meta-analyses from clinical samples, and then examined meta-analyses of subsets of the datasets (all combinations of datasets with up to N/2 samples and K/2 datasets) compared to a 'silver standard' of differentially expressed genes found in the entire cohort. We tested three random-effects meta-analysis models using this procedure. We showed relatively greater reproducibility with more-stringent effect size thresholds with relaxed significance thresholds; relatively lower reproducibility when imposing extraneous constraints on residual heterogeneity; and an underestimation of actual false positive rate by Benjamini-Hochberg correction. In addition, multivariate regression showed that the accuracy of a meta-analysis increased significantly with more included datasets even when controlling for sample size.

    View details for DOI 10.1093/nar/gkw797

    View details for PubMedID 27634930

    View details for PubMedCentralID PMC5224496

  • Opportunities and challenges in developing risk prediction models with electronic health records data: a systematic review JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION Goldstein, B. A., Navar, A. M., Pencina, M. J., Ioannidis, J. P. 2017; 24 (1): 198-208

    Abstract

    Electronic health records (EHRs) are an increasingly common data source for clinical risk prediction, presenting both unique analytic opportunities and challenges. We sought to evaluate the current state of EHR based risk prediction modeling through a systematic review of clinical prediction studies using EHR data.We searched PubMed for articles that reported on the use of an EHR to develop a risk prediction model from 2009 to 2014. Articles were extracted by two reviewers, and we abstracted information on study design, use of EHR data, model building, and performance from each publication and supplementary documentation.We identified 107 articles from 15 different countries. Studies were generally very large (median sample size = 26 100) and utilized a diverse array of predictors. Most used validation techniques (n = 94 of 107) and reported model coefficients for reproducibility (n = 83). However, studies did not fully leverage the breadth of EHR data, as they uncommonly used longitudinal information (n = 37) and employed relatively few predictor variables (median = 27 variables). Less than half of the studies were multicenter (n = 50) and only 26 performed validation across sites. Many studies did not fully address biases of EHR data such as missing data or loss to follow-up. Average c-statistics for different outcomes were: mortality (0.84), clinical prediction (0.83), hospitalization (0.71), and service utilization (0.71).EHR data present both opportunities and challenges for clinical risk prediction. There is room for improvement in designing such studies.

    View details for DOI 10.1093/jamia/ocw042

    View details for Web of Science ID 000397028000028

    View details for PubMedID 27189013

  • METHODS TO ENSURE THE REPRODUCIBILITY OF BIOMEDICAL RESEARCH Karczewski, K. J., Tatonetti, N. P., Manrai, A. K., Patel, C. J., Brown, C., Ioannidis, J. A., Altman, R. B., Dunker, A. K., Hunter, L., Ritchie, M. D., Murray, T., Klein, T. E. WORLD SCIENTIFIC PUBL CO PTE LTD. 2017: 117–19

    Abstract

    Science is not done in a vacuum - across fields of biomedicine, scientists have built on previous research and used data published in previous papers. A mainstay of scientific inquiry is the publication of one's research and recognition for this work is given in the form of citations and notoriety - ideally given in proportion to the quality of the work. Academic incentives, however, may encourage individual researchers to prioritize career ambitions over scientific truth. Recently, the New England Journal of Medicine published a commentary calling scientists who repurpose data "research parasites" who misuse data generated by others to demonstrate alternative hypotheses. In our opinion, the concept of data hoarding not only runs contrary to the spirit of, but also hinders scientific progress. Scientific research is meant to seek objective truth, rather than promote a personal agenda, and the only way to do so is through maximum transparency and reproducibility, no matter who is using the data….

    View details for Web of Science ID 000391254200012

    View details for PubMedID 27896967

  • Nature, Nurture, and Cancer Risks: Genetic and Nutritional Contributions to Cancer ANNUAL REVIEW OF NUTRITION, VOL 37 Theodoratou, E., Timofeeva, M., Li, X., Meng, X., Ioannidis, J. A., Stover, P. J., Balling, R. 2017; 37: 293–320

    Abstract

    It is speculated that genetic variants are associated with differential responses to nutrients (known as gene-diet interactions) and that these variations may be linked to different cancer risks. In this review, we critically evaluate the evidence across 314 meta-analyses of observational studies and randomized controlled trials of dietary risk factors and the five most common cancers (breast, lung, prostate, colorectal, and stomach). We also critically evaluate the evidence across 13 meta-analyses of observational studies of gene-diet interactions for the same cancers. Convincing evidence for association was found only for the intake of alcohol and whole grains in relation to colorectal cancer risk. Three nutrient associations had highly suggestive evidence and another 15 associations had suggestive evidence. Among the examined gene-diet interactions, only one had moderately strong evidence.

    View details for DOI 10.1146/annurev-nutr-071715-051004

    View details for Web of Science ID 000410544800013

    View details for PubMedID 28826375

  • Neurosurgical Randomized Controlled Trials-Distance Travelled. Neurosurgery Azad, T. D., Veeravagu, A., Mittal, V., Esparza, R., Johnson, E., Ioannidis, J. P., Grant, G. A. 2017

    Abstract

    The evidence base for many neurosurgical procedures has been limited. We performed a comprehensive and systematic analysis of study design, quality of reporting, and trial results of neurosurgical randomized controlled trials (RCTs).To systematically assess the design and quality characteristics of neurosurgical RCTs.From January 1961 to June 2016, RCTs with >5 patients assessing any 1 neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, Scopus, and Cochrane Library.The median sample size in the 401 eligible RCTs was 73 patients with a mean patient age of 49.6. Only 111 trials (27.1%) described allocation concealment, 140 (34.6%) provided power calculations, and 117 (28.9%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 226 reports (56.4%), no difference between the procedures was found in 166 trials (41.4%), and significant harm was reported in 9 trials (2.2%). Trials with a larger sample size were more likely to report randomization mode, specify allocation concealment, and power calculations (all P < .001). Government funding was associated with better specification of power calculations ( P = .008) and of allocation concealment ( P = .026), while industry funding was associated with reporting significant efficacy ( P = .02). Reporting of funding, specification of randomization mode and primary outcomes, and mention of power calculations improved significantly (all, P < .05) over time.Several aspects of the design and reporting of RCTs on neurosurgical procedures have improved over time. Better powered and accurately reported trials are needed in neurosurgery to deliver evidence-based care and achieve optimal outcomes.

    View details for DOI 10.1093/neuros/nyx319

    View details for PubMedID 28645203

  • Interpretation of epidemiologic studies very often lacked adequate consideration of confounding. Journal of clinical epidemiology Hemkens, L. G., Ewald, H., Naudet, F., Ladanie, A., Shaw, J. G., Sajeev, G., Ioannidis, J. P. 2017

    Abstract

    Confounding bias is a most pervasive threat to validity of observational epidemiologic research. We assessed whether authors of observational epidemiologic studies consider confounding bias when interpreting the findings.We randomly selected 120 cohort or case-control studies published in 2011 and 2012 by the general medical, epidemiologic, and specialty journals with the highest impact factors. We used Web of Science to assess citation metrics through January 2017.Sixty-eight studies (56.7%, 95% confidence interval: 47.8-65.5%) mentioned "confounding" in the Abstract or Discussion sections, another 20 (16.7%; 10.0-23.3%) alluded to it, and there was no mention or allusion at all in 32 studies (26.7%; 18.8-34.6%). Authors often acknowledged that for specific confounders, there was no adjustment (34 studies; 28.3%) or deem it possible or likely that confounding affected their main findings (29 studies; 24.2%). However, only two studies (1.7%; 0-4.0%) specifically used the words "caution" or "cautious" for the interpretation because of confounding-related reasons and eventually only four studies (3.3%; 0.1-6.5%) had limitations related to confounding or any other bias in their Conclusions. Studies mentioning that the findings were possibly or likely affected by confounding were more frequently cited than studies with a statement that findings were unlikely affected (median 6.3 vs. 4.0 citations per year, P = 0.04).Many observational studies lack satisfactory discussion of confounding bias. Even when confounding bias is mentioned, authors are typically confident that it is rather irrelevant to their findings and they rarely call for cautious interpretation. More careful acknowledgment of possible impact of confounding is not associated with lower citation impact.

    View details for DOI 10.1016/j.jclinepi.2017.09.013

    View details for PubMedID 28943377

  • Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study. Frontiers in cardiovascular medicine Knowles, J. W., Zarafshar, S., Pavlovic, A., Goldstein, B. A., Tsai, S., Li, J., McConnell, M. V., Absher, D., Ashley, E. A., Kiernan, M., Ioannidis, J. P., Assimes, T. L. 2017; 4: 53

    Abstract

    We tested whether providing a genetic risk score (GRS) for coronary artery disease (CAD) would serve as a motivator to improve adherence to risk-reducing strategies.We randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49) or without (N = 45) their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C) between the 3- and 6-month follow-up visits (ΔLDL-C). Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS.Sixty-five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (ΔLDL-C: -13 vs. -9 mg/dl). Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry.Adding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials.

    View details for DOI 10.3389/fcvm.2017.00053

    View details for PubMedID 28856136

    View details for PubMedCentralID PMC5558259

  • Insomnia From Drug Treatments: Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information. Mayo Clinic proceedings Doufas, A. G., Panagiotou, O. A., Panousis, P., Wong, S. S., Ioannidis, J. P. 2017; 92 (1): 72-87

    Abstract

    To determine whether drugs used to treat diverse conditions cause insomnia symptoms and whether their prescription information is concordant with this evidence.We conducted a survey of meta-analyses (Cochrane Database of Systematic Reviews) and comparisons with package inserts compiled in the Physicians' Desk Reference (PDR). We identified randomized controlled trials (RCTs) in which any drug had been evaluated vs placebo and sleep had been assessed. We collectively referred to insomnia-related outcomes as sleep disturbance. We also searched the PDR to identify any insomnia symptoms listed for drugs with RCT evidence available.Seventy-four Cochrane systematic reviews corresponding to 274 RCTs assessed 88 drugs in 27 different conditions, providing evidence on 109 drug-condition pairs. Of these 88 drugs, 5 decreased sleep problems and 19 increased sleep problems; 64 drugs had no nominally statistically significant effect on sleep. Acetylcholinesterase inhibitors, dopamine agonists, and selective serotonin reuptake inhibitors were the drug classes most importantly associated with sleep disturbance. Of 35 drugs that included disturbed sleep as an adverse effect in the PDR, only 14 had RCT evidence supporting such effect, and 2 had evidence of increasing and decreasing sleep problems in RCTs, although this was not shown in the PDR. We identified weak concordance between the PDR and RCTs (weighted κ=0.31; P<.001).The RCTs offer substantial evidence about the common effects of drugs on the risk of sleep disturbance; currently, prescription information only partially agrees with the available randomized evidence.

    View details for DOI 10.1016/j.mayocp.2016.09.005

    View details for PubMedID 27842706

  • Impact of vaccine herd-protection effects in cost-effectiveness analyses of childhood vaccinations. A quantitative comparative analysis. PloS one Holubar, M., Stavroulakis, M. C., Maldonado, Y., Ioannidis, J. P., Contopoulos-Ioannidis, D. 2017; 12 (3)

    Abstract

    Inclusion of vaccine herd-protection effects in cost-effectiveness analyses (CEAs) can impact the CEAs-conclusions. However, empirical epidemiologic data on the size of herd-protection effects from original studies are limited.We performed a quantitative comparative analysis of the impact of herd-protection effects in CEAs for four childhood vaccinations (pneumococcal, meningococcal, rotavirus and influenza). We considered CEAs reporting incremental-cost-effectiveness-ratios (ICERs) (per quality-adjusted-life-years [QALY] gained; per life-years [LY] gained or per disability-adjusted-life-years [DALY] avoided), both with and without herd protection, while keeping all other model parameters stable. We calculated the size of the ICER-differences without vs with-herd-protection and estimated how often inclusion of herd-protection led to crossing of the cost-effectiveness threshold (of an assumed societal-willingness-to-pay) of $50,000 for more-developed countries or X3GDP/capita (WHO-threshold) for less-developed countries.We identified 35 CEA studies (20 pneumococcal, 4 meningococcal, 8 rotavirus and 3 influenza vaccines) with 99 ICER-analyses (55 per-QALY, 27 per-LY and 17 per-DALY). The median ICER-absolute differences per QALY, LY and DALY (without minus with herd-protection) were $15,620 (IQR: $877 to $48,376); $54,871 (IQR: $787 to $115,026) and $49 (IQR: $15 to $1,636) respectively. When the target-vaccination strategy was not cost-saving without herd-protection, inclusion of herd-protection always resulted in more favorable results. In CEAs that had ICERs above the cost-effectiveness threshold without herd-protection, inclusion of herd-protection led to crossing of that threshold in 45% of the cases. This impacted only CEAs for more developed countries, as all but one CEAs for less developed countries had ICERs below the WHO-cost-effectiveness threshold even without herd-protection. In several analyses, recommendation for the adoption of the target vaccination strategy depended on the inclusion of the herd protection effect.Inclusion of herd-protection effects in CEAs had a substantial impact in the estimated ICERs and made target-vaccination strategies more attractive options in almost half of the cases where ICERs were above the societal-willingness to pay threshold without herd-protection. More empirical epidemiologic data are needed to determine the size of herd-protection effects across diverse settings and also the size of negative vaccine effects, e.g. from serotype substitution.

    View details for DOI 10.1371/journal.pone.0172414

    View details for PubMedID 28249046

    View details for PubMedCentralID PMC5332092

  • Bias in medical literature on health outcomes: bias in commentary? Reply BMJ-BRITISH MEDICAL JOURNAL Stavropoulou, C., Parmar, D., Ioannidis, J. A. 2016; 355: i6639

    View details for DOI 10.1136/bmj.i6639

    View details for Web of Science ID 000390151900003

    View details for PubMedID 27986758

  • Enhancing reproducibility for computational methods SCIENCE Stodden, V., McNutt, M., Bailey, D. H., Deelman, E., Gil, Y., Hanson, B., Heroux, M. A., Ioannidis, J. A., Taufer, M. 2016; 354 (6317): 1240–41

    View details for DOI 10.1126/science.aah6168

    View details for Web of Science ID 000389598800044

    View details for PubMedID 27940837

  • Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses BMJ-BRITISH MEDICAL JOURNAL Wallach, J. D., Sullivan, P. G., Trepanowski, J. F., Steyerberg, E. W., Ioannidis, J. P. 2016; 355

    Abstract

     To evaluate the frequency, validity, and relevance of statistically significant (P<0.05) sex-treatment interactions in randomized controlled trials in Cochrane meta-analyses. Meta-epidemiological study. Cochrane Database of Systematic Reviews (CDSR) and PubMed. Reviews published in the CDSR with sex-treatment subgroup analyses in the forest plots, using data from randomized controlled trials. Information on the study design and sex subgroup data were extracted from reviews and forest plots that met inclusion criteria. For each statistically significant sex-treatment interaction, the potential for biological plausibility and clinical significance was considered. Among the 41 reviews with relevant data, there were 109 separate treatment-outcome analyses ("topics"). Among the 109 topics, eight (7%) had a statistically significant sex-treatment interaction. The 109 topics included 311 randomized controlled trials (162 with both sexes, 46 with males only, 103 with females only). Of the 162 individual randomized controlled trials that included both sexes, 15 (9%) had a statistically significant sex-treatment interaction. Of four topics where the first published randomized controlled trial had a statistically significant sex-treatment interaction, no meta-analyses that included other randomized controlled trials retained the statistical significance and no meta-analyses showed statistical significance when data from the first published randomized controlled trial were excluded. Of the eight statistically significant sex-treatment interactions from the overall analyses, only three were discussed by the CDSR reviewers for a potential impact on different clinical management for males compared with females. None of these topics had a sex-treatment interaction that influenced treatment recommendations in recent guidelines. UpToDate, an online physician-authored clinical decision support resource, suggested differential management of men and women for one of these sex-treatment interactions. Statistically significant sex-treatment interactions are only slightly more frequent than what would be expected by chance and there is little evidence of subsequent corroboration or clinical relevance of sex-treatment interactions.

    View details for DOI 10.1136/bmj.i5826

    View details for Web of Science ID 000388917400001

    View details for PubMedID 27884869

    View details for PubMedCentralID PMC5122320

  • Meta-Analysis Comparing Established Risk Prediction Models (EuroSCORE II, STS Score, and ACEF Score) for Perioperative Mortality During Cardiac Surgery. American journal of cardiology Sullivan, P. G., Wallach, J. D., Ioannidis, J. P. 2016; 118 (10): 1574-1582

    Abstract

    A wide variety of multivariable risk models have been developed to predict mortality in the setting of cardiac surgery; however, the relative utility of these models is unknown. This study investigated the literature related to comparisons made between established risk prediction models for perioperative mortality used in the setting of cardiac surgery. A systematic review was conducted to capture studies in cardiac surgery comparing the relative performance of at least 2 prediction models cited in recent guidelines (European System for Cardiac Operative Risk Evaluation [EuroSCORE II], Society for Thoracic Surgeons 2008 Cardiac Surgery Risk Models [STS] score, and Age, Creatinine, Ejection Fraction [ACEF] score) for the outcomes of 1-month or inhospital mortality. For articles that met inclusion criteria, we extracted information on study design, predictive performance of risk models, and potential for bias. Meta-analyses were conducted to calculate a summary estimate of the difference in AUCs between models. We identified 22 eligible studies that contained 33 comparisons among the above models. Meta-analysis of differences in AUCs revealed that the EuroSCORE II and STS score performed similarly (with a summary difference in AUC = 0.00), while outperforming the ACEF score (with summary differences in AUC of 0.10 and 0.08, respectively, p <0.05). Other metrics of discrimination and calibration were presented less consistently, and no study presented any metric of reclassification. Small sample size and absent descriptions of missing data were common in these studies. In conclusion, the EuroSCORE II and STS score outperform the ACEF score on discrimination.

    View details for DOI 10.1016/j.amjcard.2016.08.024

    View details for PubMedID 27687052

  • Diet, body size, physical activity and risk of prostate cancer: An umbrella review of the evidence. European journal of cancer Markozannes, G., Tzoulaki, I., Karli, D., Evangelou, E., Ntzani, E., Gunter, M. J., Norat, T., Ioannidis, J. P., Tsilidis, K. K. 2016; 69: 61-69

    Abstract

    The existing literature on the relationship between diet, body size, physical activity and prostate cancer risk was summarised by the World Cancer Research Fund Continuous Update Project (CUP). An evaluation of the robustness of this evidence is required to help inform public health policy. The robustness of this evidence was evaluated using several criteria addressing evidence strength and validity, including the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, number of prostate cancer cases, between-study heterogeneity, 95% prediction intervals, small-study effects bias, excess significance bias and sensitivity analyses with credibility ceilings. A total of 248 meta-analyses were extracted from the CUP, which studied associations of 23 foods, 31 nutrients, eight indices of body size and three indices of physical activity with risk of total prostate cancer development, mortality or cancer development by stage and grade. Of the 176 meta-analyses using a continuous scale to measure the exposures, no association presented strong evidence by satisfying all the aforementioned criteria. Only the association of height with total prostate cancer incidence and mortality presented highly suggestive evidence with a 4% higher risk per 5 cm greater height (95% confidence interval, 1.03, 1.05). Associations for body mass index, weight, height, dietary calcium and spirits intake were supported by suggestive evidence. Overall, the association of diet, body size, physical activity and prostate cancer has been extensively studied, but no association was graded with strong evidence.

    View details for DOI 10.1016/j.ejca.2016.09.026

    View details for PubMedID 27816833

  • Randomized trials are frequently fragmented in multiple secondary publications JOURNAL OF CLINICAL EPIDEMIOLOGY Ebrahim, S., Montoya, L., el Din, M. K., Sohani, Z. N., Agarwal, A., Bance, S., Saquib, J., Saquib, N., Ioannidis, J. P. 2016; 79: 130-139

    Abstract

    To assess the frequency and features of secondary publications of randomized controlled trials (RCTs).For 191 RCTs published in high-impact journals in 2009, we searched for secondary publications coauthored by at least one same author of the primary trial publication. We evaluated the probability of having secondary publications, characteristics of the primary trial publication that predict having secondary publications, types of secondary analyses conducted, and statistical significance of those analyses.Of 191 primary trials, 88 (46%) had a total of 475 secondary publications by 2/2014. Eight trials had >10 (up to 51) secondary publications each. In multivariable modeling, the risk of having subsequent secondary publications increased 1.32-fold (95% CI 1.05-1.68) per 10-fold increase in sample size, and 1.71-fold (95% CI 1.19-2.45) in the presence of a design article. In a sample of 197 secondary publications examined in depth, 193 tested different hypotheses than the primary publication. Of the 193, 43 tested differences between subgroups, 85 assessed predictive factors associated with an outcome of interest, 118 evaluated different outcomes than the original article, 71 had differences in eligibility criteria, and 21 assessed different durations of follow-up; 176 (91%) presented at least one analysis with statistically significant results.Approximately half of randomized trials in high-impact journals have secondary publications published with a few trials followed by numerous secondary publications. Almost all of these publications report some statistically significant results.

    View details for DOI 10.1016/j.jclinepi.2016.05.016

    View details for Web of Science ID 000389967700020

    View details for PubMedID 27387965

  • Very large treatment effects in randomised trials as an empirical marker to indicate whether subsequent trials are necessary: meta-epidemiological assessment. BMJ (Clinical research ed.) Nagendran, M., Pereira, T. V., Kiew, G., Altman, D. G., Maruthappu, M., Ioannidis, J. P., McCulloch, P. 2016; 355: i5432-?

    Abstract

     To examine whether a very large effect (VLE; defined as a relative risk of ≤0.2 or ≥5) in a randomised trial could be an empirical marker that subsequent trials are unnecessary. Meta-epidemiological assessment of existing published data on randomised trials. Cochrane Database of Systematic Reviews (2010, issue 7) with data on subsequent large trials updated to 2015, issue 12. All binary outcome forest plots were selected, which contained an index randomised trial with a VLE that was nominally statistically significant (P<0.05), included a subsequent large randomised trial (≥200 events and ≥200 non-events) for validation of the effect, assessed a primary outcome of the review, and was not a subgroup or sensitivity analysis. Of 3082 reviews yielding 85 002 forest plots, only 44 (0.05%) satisfied the inclusion criteria. Index trials were generally small, with a median sample of 99 (median 14 events). Few index trials were rated at low risk of bias (9 of 44; 20%). The relative risk was closer to the null in the subsequent large trials in 43 of 44 cases. Subsequent large trial data failed to find a statistically significant (P<0.05) effect in the same direction in 19 cases (43%, 95% confidence interval 29% to 58%). Even when the subsequent large trials did find a significant effect in the same direction, the additional primary outcomes in most of these trials would have to be considered before deciding in favour of using the intervention. Subsequent large trial data found a statistically significant effect in the same direction in 19 of 21 cases when the index trial also had a value of P<0.001. The frequency of VLEs followed by a large trial is vanishingly small, and where they occur they do not appear to be a reliable marker for a benefit that is reproducible and directly actionable. An empirical rule using a VLE in a randomised controlled trial as a marker that further trials are unnecessary would be neither practical nor useful. Caution should be taken when interpreting small studies with very large treatment effects.

    View details for DOI 10.1136/bmj.i5432

    View details for PubMedID 27789483

    View details for PubMedCentralID PMC5081692

  • What Happens When Underperforming Big Ideas in Research Become Entrenched? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Joyner, M. J., Paneth, N., Ioannidis, J. A. 2016; 316 (13): 1355–56

    View details for DOI 10.1001/jama.2016.11076

    View details for Web of Science ID 000384591300011

    View details for PubMedID 27467098

  • Comparative rates of harms in randomized trials from more developed versus less developed countries may be different JOURNAL OF CLINICAL EPIDEMIOLOGY Contopoulos-Ioannidis, D., Tseretopoulou, X., Ancker, M., Walterspiel, J. N., Panagiotou, O. A., Maldonado, Y., Ioannidis, J. P. 2016; 78: 10-21

    Abstract

    We set up to evaluate the relative risk of harms in trials performed in less developed vs. more developed countries.Meta-epidemiologic evaluation using the Cochrane Database of Systematic Reviews. We considered meta-analyses with at least one randomized clinical trial (RCT) in a less developed country and one RCT in a more developed country. We targeted severe adverse events (AEs), discontinuations due to AEs, any AE, organ system-specific AEs, individual AEs, and all discontinuations due to any reason. We estimated the relative odds ratio (ROR) of harms between more and less developed countries for each topic and the summary ROR (sROR) across topics under each category of harms.We identified 42 systematic reviews (128 meta-analyses, 521 independent RCTs). Summary sRORs did not differ significantly from 1.00 for any harm category. Nominally significant RORs were found in only 6/128 meta-analyses. However, in 27% (35/128) of meta-analyses the ROR point estimates indicated relative differences between country settings >2-fold. Considering also ROR 95% confidence intervals, in 92% (118/128) of meta-analyses one could not exclude a 2-fold difference in both directions.We identified limited comparative evidence on harms in trials from these two country settings. Substantial differences in the risk point estimates were common; the potential for modest differences could rarely be excluded with confidence.

    View details for DOI 10.1016/j.jclinepi.2016.02.032

    View details for Web of Science ID 000389615400004

    View details for PubMedID 27063207

  • High quality of the evidence for medical and other health-related interventions was uncommon in Cochrane systematic reviews JOURNAL OF CLINICAL EPIDEMIOLOGY Fleming, P. S., Koletsi, D., Ioannidis, J. A., Pandis, N. 2016; 78: 34–42

    Abstract

    To appraise the quality of evidence in systematic reviews (SRs) within the Cochrane Database of Systematic Reviews (CDSRs) across diverse topics and to explore the relationship between the strength of evidence using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) and the probability that authors would interpret that an intervention may be of value.We evaluated the SRs published on the CDSR from January 1, 2013, to June 30, 2014. Two authors identified relevant SRs by independent searching of the Cochrane register. We further focused on SRs that incorporated tables with GRADE [summary of findings (SoF)]. Data were extracted independently by two authors. The quality of the evidence for the first listed primary outcome in SoF tables in each review and reasons for upgrade or downgrade were recorded.Overall, 1,394 SRs were identified. Of these, 608 (43.6%) incorporated GRADE. Within these reviews, only 13.5% (n = 82) reported a high quality and 30.8% (n = 187) a moderate quality of evidence for the first listed primary outcome, whereas 31.7% (n = 193) had low level and 24% (n = 146) had very low level of evidence. High quality of evidence was more common in updated compared to new reviews and in pharmacologic than other types of interventions. Even when all outcomes listed in the SoFs were considered, only 116/608 (19.1%) of SRs had at least one outcome with high quality of evidence. Overall, only 4.1% (25/608) of SRs incorporating GRADE in SoF tables had high quality of evidence, allied both to significant results and a favorable interpretation of the intervention by the reviewers.Evidence of high quality is uncommon for medical and health-related interventions assessed with GRADE within the CDSR, and favorable evidence of high quality is even more uncommon.

    View details for DOI 10.1016/j.jclinepi.2016.03.012

    View details for Web of Science ID 000389615400006

    View details for PubMedID 27032875

  • Effect of diastolic dysfunction on postoperative outcomes after cardiovascular surgery: A systematic review and meta-analysis JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kaw, R., Hernandez, A. V., Pasupuleti, V., Deshpande, A., Nagarajan, V., Bueno, H., Coleman, C. I., Ioannidis, J. P., Bhatt, D. L., Blackstone, E. H. 2016; 152 (4): 1142-1153

    Abstract

    The objective of this study was to investigate the effect of preoperative diastolic dysfunction on postoperative mortality and morbidity after cardiovascular surgery.We systematically searched for articles that assessed the prognostic role of diastolic dysfunction on cardiovascular surgery in PubMed, Cochrane Library, Web of Science, Embase, and Scopus until February 2016. Twelve studies (n = 8224) met our inclusion criteria. Because of the scarcity of outcome events, fixed-effects meta-analysis was performed via the Mantel-Haenszel method.Preoperative diagnosis of diastolic dysfunction was associated with greater postoperative mortality (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.54-3.71; P < .0001), major adverse cardiac events (OR, 2.07; 95% CI, 1.55-2.78; P ≤ .0001), and prolonged mechanical ventilation (OR, 2.08; 95% CI, 1.04-4.16; P = .04) compared with patients without diastolic dysfunction among patients who underwent cardiovascular surgery. The odds of postoperative myocardial infarction (OR, 1.29; 95% CI, 0.82-2.05; P = .28) and atrial fibrillation (OR, 2.67; 95% CI, 0.49-14.43; P = .25) did not significantly differ between the 2 groups. Severity of preoperative diastolic dysfunction was associated with increased postoperative mortality (OR, 21.22; 95% CI, 3.74-120.33; P = .0006) for Grade 3 diastolic dysfunction compared with patients with normal diastolic function. Inclusion of left ventricular ejection fraction (LVEF) <40% accompanying diastolic dysfunction did not further impact postoperative mortality (P = .27; I(2) = 18%) compared with patients with normal LVEF and diastolic dysfunction.Presence of preoperative diastolic dysfunction was associated with greater postoperative mortality and major adverse cardiac events, regardless of LVEF. Mortality was significantly greater in grade III diastolic dysfunction.

    View details for DOI 10.1016/j.jtcvs.2016.05.057

    View details for Web of Science ID 000386748700055

    View details for PubMedID 27364601

  • The Cancer Epidemiology Descriptive Cohort Database: A Tool to Support Population-Based Interdisciplinary Research CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kennedy, A. E., Khoury, M. J., Ioannidis, J. P., Brotzman, M., Miller, A., Lane, C., Lai, G. Y., Rogers, S. D., Harvey, C., Elena, J. W., Seminara, D. 2016; 25 (10): 1392-1401

    Abstract

    We report on the establishment of a web-based Cancer Epidemiology Descriptive Cohort Database (CEDCD). The CEDCD's goals are to enhance awareness of resources, facilitate interdisciplinary research collaborations, and support existing cohorts for the study of cancer-related outcomes.Comprehensive descriptive data were collected from large cohorts established to study cancer as primary outcome using a newly developed questionnaire. These included an inventory of baseline and follow-up data, biospecimens, genomics, policies, and protocols. Additional descriptive data extracted from publicly available sources were also collected. This information was entered in a searchable and publicly accessible database. We summarized the descriptive data across cohorts and reported the characteristics of this resource.As of December 2015, the CEDCD includes data from 46 cohorts representing more than 6.5 million individuals (29% ethnic/racial minorities). Overall, 78% of the cohorts have collected blood at least once, 57% at multiple time points, and 46% collected tissue samples. Genotyping has been performed by 67% of the cohorts, while 46% have performed whole-genome or exome sequencing in subsets of enrolled individuals. Information on medical conditions other than cancer has been collected in more than 50% of the cohorts. More than 600,000 incident cancer cases and more than 40,000 prevalent cases are reported, with 24 cancer sites represented.The CEDCD assembles detailed descriptive information on a large number of cancer cohorts in a searchable database.Information from the CEDCD may assist the interdisciplinary research community by facilitating identification of well-established population resources and large-scale collaborative and integrative research. Cancer Epidemiol Biomarkers Prev; 25(10); 1392-401. ©2016 AACR.

    View details for DOI 10.1158/1055-9965.EPI-16-0412

    View details for Web of Science ID 000385642800004

    View details for PubMedID 27439404

  • Short-term economic impact of the Zika virus outbreak NEW MICROBIOLOGICA Macciocchi, D., Lanini, S., Vairo, F., Zumla, A., Moraes Figueiredo, L., Lauria, F., Strada, G., Brouqui, P., Puro, V., Krishna, S., Kremsner, P., Scognamiglio, P., Kohler, C., Nicastri, E., Di Caro, A., Cieri, R., Ioannidis, J. A., Kobinger, G., Burattini, M., Ippolito, G. 2016; 39 (4): 287–89

    Abstract

    Zika virus (ZIKV) is mainly transmitted by mosquitoes bites. However, transmission by sexual contacts has been reported in 11 non endemic countries. The rapid spread of ZIKV in Latin American and Caribbean Countries (LCR), person-to-person transmission and perceived risk on people's well being can affect the emerging economies of LCR which historically dependent on truism. Here we present an analysis on economic outputs for assessing the current impact of ZIKV on markets. Our analysis show an unexpected resilience of LCR markets to international alerts. This positive response represents an opportunity to scale-up interventions for preventing the further spreading of the ZIKV epidemic.

    View details for Web of Science ID 000392469400007

    View details for PubMedID 28004846

  • Health outcomes during the 2008 financial crisis in Europe: systematic literature review BMJ-BRITISH MEDICAL JOURNAL Parmar, D., Stavropoulou, C., Ioannidis, J. A. 2016; 354: i4588

    Abstract

     To systematically identify, critically appraise, and synthesise empirical studies about the impact of the 2008 financial crisis in Europe on health outcomes. Systematic literature review. Structural searches of key databases, healthcare journals, and organisation based websites. Empirical studies reporting on the impact of the financial crisis on health outcomes in Europe, published from January 2008 to December 2015, were included. All selected studies were assessed for risk of bias. Owing to the heterogeneity of studies in terms of study design and analysis and the use of overlapping datasets across studies, studies were analysed thematically per outcome, and the evidence was synthesised on different health outcomes without formal meta-analysis. 41 studies met the inclusion criteria, and focused on suicide, mental health, self rated health, mortality, and other health outcomes. Of those studies, 30 (73%) were deemed to be at high risk of bias, nine (22%) at moderate risk of bias, and only two (5%) at low risk of bias, limiting the conclusions that can be drawn. Although there were differences across countries and groups, there was some indication that suicides increased and mental health deteriorated during the crisis. The crisis did not seem to reverse the trend of decreasing overall mortality. Evidence on self rated health and other indicators was mixed. Most published studies on the impact of financial crisis on health in Europe had a substantial risk of bias; therefore, results need to be cautiously interpreted. Overall, the financial crisis in Europe seemed to have had heterogeneous effects on health outcomes, with the evidence being most consistent for suicides and mental health. There is a need for better empirical studies, especially those focused on identifying mechanisms that can mitigate the adverse effects of the crisis.

    View details for DOI 10.1136/bmj.i4588

    View details for Web of Science ID 000383100600003

    View details for PubMedID 27601477

    View details for PubMedCentralID PMC5013230

  • Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses. Alzheimer's & dementia : the journal of the Alzheimer's Association Bellou, V., Belbasis, L., Tzoulaki, I., Middleton, L. T., Ioannidis, J. P., Evangelou, E. 2016

    Abstract

    Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors.We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance.A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease.Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

    View details for DOI 10.1016/j.jalz.2016.07.152

    View details for PubMedID 27599208

  • Citation Metrics: A Primer on How (Not) to Normalize. PLoS biology Ioannidis, J. P., Boyack, K., Wouters, P. F. 2016; 14 (9)

    Abstract

    Citation metrics are increasingly used to appraise published research. One challenge is whether and how to normalize these metrics to account for differences across scientific fields, age (year of publication), type of document, database coverage, and other factors. We discuss the pros and cons for normalizations using different approaches. Additional challenges emerge when citation metrics need to be combined across multiple papers to appraise the corpus of scientists, institutions, journals, or countries, as well as when trying to attribute credit in multiauthored papers. Different citation metrics may offer complementary insights, but one should carefully consider the assumptions that underlie their calculation.

    View details for DOI 10.1371/journal.pbio.1002542

    View details for PubMedID 27599158

    View details for PubMedCentralID PMC5012555

  • The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses MILBANK QUARTERLY Ioannidis, J. P. 2016; 94 (5): 485-514

    Abstract

    Currently, there is massive production of unnecessary, misleading, and conflicted systematic reviews and meta-analyses. Instead of promoting evidence-based medicine and health care, these instruments often serve mostly as easily produced publishable units or marketing tools. Suboptimal systematic reviews and meta-analyses can be harmful given the major prestige and influence these types of studies have acquired. The publication of systematic reviews and meta-analyses should be realigned to remove biases and vested interests and to integrate them better with the primary production of evidence.Currently, most systematic reviews and meta-analyses are done retrospectively with fragmented published information. This article aims to explore the growth of published systematic reviews and meta-analyses and to estimate how often they are redundant, misleading, or serving conflicted interests.Data included information from PubMed surveys and from empirical evaluations of meta-analyses.Publication of systematic reviews and meta-analyses has increased rapidly. In the period January 1, 1986, to December 4, 2015, PubMed tags 266,782 items as "systematic reviews" and 58,611 as "meta-analyses." Annual publications between 1991 and 2014 increased 2,728% for systematic reviews and 2,635% for meta-analyses versus only 153% for all PubMed-indexed items. Currently, probably more systematic reviews of trials than new randomized trials are published annually. Most topics addressed by meta-analyses of randomized trials have overlapping, redundant meta-analyses; same-topic meta-analyses may exceed 20 sometimes. Some fields produce massive numbers of meta-analyses; for example, 185 meta-analyses of antidepressants for depression were published between 2007 and 2014. These meta-analyses are often produced either by industry employees or by authors with industry ties and results are aligned with sponsor interests. China has rapidly become the most prolific producer of English-language, PubMed-indexed meta-analyses. The most massive presence of Chinese meta-analyses is on genetic associations (63% of global production in 2014), where almost all results are misleading since they combine fragmented information from mostly abandoned era of candidate genes. Furthermore, many contracting companies working on evidence synthesis receive industry contracts to produce meta-analyses, many of which probably remain unpublished. Many other meta-analyses have serious flaws. Of the remaining, most have weak or insufficient evidence to inform decision making. Few systematic reviews and meta-analyses are both non-misleading and useful.The production of systematic reviews and meta-analyses has reached epidemic proportions. Possibly, the large majority of produced systematic reviews and meta-analyses are unnecessary, misleading, and/or conflicted.

    View details for DOI 10.1111/1468-0009.12210

    View details for Web of Science ID 000384419900010

    View details for PubMedCentralID PMC5020151

  • Registered Randomized Trials Comparing Generic and Brand-Name Drugs: A Survey. Mayo Clinic proceedings Flacco, M. E., Manzoli, L., Boccia, S., Puggina, A., Rosso, A., Marzuillo, C., Scaioli, G., Gualano, M. R., Ricciardi, W., Villari, P., Ioannidis, J. P. 2016; 91 (8): 1021-1034

    Abstract

    To evaluate the research agenda of registered randomized trials comparing generic and brand-name drugs in terms of who sponsors them, whether they are published promptly, and whether they find favorable results.We included randomized trials comparing the safety or efficacy of brand-name vs generic medications that were registered in ClinicalTrials.gov or other registries from January 1, 2000, through July 31, 2015. To identify published articles or results generated from such trials, we searched PubMed, Scopus, Google, and registry databases. Data were compared across sponsorship categories ("inbred" if the compared drugs were owned by the same company or its partners/subsidiaries, "competitive" if the compared drugs were owned by competing companies, and "apparently nonprofit"), and time to publication was evaluated with Cox analysis.We found 207 registered protocols reporting on 186 completed trials. Among those trials, 37 had published their results and another 56 had posted results in registries, for a total of 93 trials with available results. Four years after trial completion, results were available for 64 of 138 trials (46.4%), with substantial differences by sponsor: 70.8% (34 of 48), 28.1% (18 of 64), and 46.2% (12 of 26) of the inbred, competitive, and nonprofit trials, respectively. In multivariate modeling, inbred trials had a 1.73-fold risk of having results available compared with competitive trials (P=.04). Almost all trials reported favorable results, with the exception of 4 (4.3% of the 93 trials with results).Despite the importance of generic drugs, relatively few registered randomized trials have compared the health effects of generic vs brand-name medicines, and there is an associated unsatisfactory publication rate and almost ubiquitous favorable results. The overall literature on the topic is at high risk of bias, possibly in favor of generic drugs. Higher nonprofit funding and stronger pressure to register trials and publish results are needed.

    View details for DOI 10.1016/j.mayocp.2016.04.032

    View details for PubMedID 27402583

  • Stealth Research and Theranos Reflections and Update 1 Year Later JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2016; 316 (4): 389–90

    View details for DOI 10.1001/jama.2016.6986

    View details for Web of Science ID 000380221700012

    View details for PubMedID 27191700

  • Multiple Citation Indicators and Their Composite across Scientific Disciplines. PLoS biology Ioannidis, J. P., Klavans, R., Boyack, K. W. 2016; 14 (7)

    Abstract

    Many fields face an increasing prevalence of multi-authorship, and this poses challenges in assessing citation metrics. Here, we explore multiple citation indicators that address total impact (number of citations, Hirsch H index [H]), co-authorship adjustment (Schreiber Hm index [Hm]), and author order (total citations to papers as single; single or first; or single, first, or last author). We demonstrate the correlation patterns between these indicators across 84,116 scientists (those among the top 30,000 for impact in a single year [2013] in at least one of these indicators) and separately across 12 scientific fields. Correlation patterns vary across these 12 fields. In physics, total citations are highly negatively correlated with indicators of co-authorship adjustment and of author order, while in other sciences the negative correlation is seen only for total citation impact and citations to papers as single author. We propose a composite score that sums standardized values of these six log-transformed indicators. Of the 1,000 top-ranked scientists with the composite score, only 322 are in the top 1,000 based on total citations. Many Nobel laureates and other extremely influential scientists rank among the top-1,000 with the composite indicator, but would rank much lower based on total citations. Conversely, many of the top 1,000 authors on total citations have had no single/first/last-authored cited paper. More Nobel laureates of 2011-2015 are among the top authors when authors are ranked by the composite score than by total citations, H index, or Hm index; 40/47 of these laureates are among the top 30,000 by at least one of the six indicators. We also explore the sensitivity of indicators to self-citation and alphabetic ordering of authors in papers across different scientific fields. Multiple indicators and their composite may give a more comprehensive picture of impact, although no citation indicator, single or composite, can be expected to select all the best scientists.

    View details for DOI 10.1371/journal.pbio.1002501

    View details for PubMedID 27367269

    View details for PubMedCentralID PMC4930269

  • Inadequacies of 'Inadequacies of Physical Examination' Reply AMERICAN JOURNAL OF MEDICINE Verghese, A., Charlton, B., Kassirer, J. P., Ramsey, M., Ioannidis, J. A. 2016; 129 (7): E85

    View details for DOI 10.1016/j.amjmed.2016.02.034

    View details for Web of Science ID 000378065800016

    View details for PubMedID 27320713

  • Long noncoding RNAs as novel predictors of survival in human cancer: a systematic review and meta-analysis MOLECULAR CANCER Serghiou, S., Kyriakopoulou, A., Ioannidis, J. P. 2016; 15

    Abstract

    Expression of various long noncoding RNAs (lncRNAs) may affect cancer prognosis. Here, we aim to gather and examine all evidence on the potential role of lncRNAs as novel predictors of survival in human cancer.We systematically searched through PubMed, to identify all published studies reporting on the association between any individual lncRNA or group of lncRNAs with prognosis in human cancer (death or other clinical outcomes). Where appropriate, we then performed quantitative synthesis of those results using meta-analytic methods to identify the true effect size of lncRNAs on cancer prognosis. The reliability of those results was then examined using measures of heterogeneity and testing for selective reporting biases.Three hundred ninety-two studies were screened to eventually identify 111 eligible studies on 127 datasets. In total, these represented 16,754 independent participants pertaining to 53 individual and 6 grouped lncRNAs within a total of 19 cancer sites. Overall, 83 % of the studies we identified addressed overall survival and 32 % of the studies addressed recurrence-free survival. For overall survival, 96 % (88/92) of studies identified a statistically significant association of lncRNA expression to prognosis. Meta-analysis of 6 out of 7 lncRNAs for which three or more studies were available, identified statistically significant associations with overall survival. The lncRNA HOTAIR was by far the most broadly studied lncRNA (n = 29; of 111 studies) and featured a summary hazard ratio (HR) of 2.22 (95 % confidence interval (CI), 1.86-2.65) with modest heterogeneity (I(2) = 49 %; 95 % CI, 14-79 %). Prominent excess significance was demonstrated across all meta-analyses (p-value = 0.0003), raising the possibility of substantial selective reporting biases.Multiple lncRNAs have been shown to be strongly associated with prognosis in diverse cancers, but substantial bias cannot be excluded in this field and larger studies are needed to understand whether these prognostic information may eventually be useful.

    View details for DOI 10.1186/s12943-016-0535-1

    View details for Web of Science ID 000379401400001

    View details for PubMedID 27352941

    View details for PubMedCentralID PMC4924330

  • Response to Therapy in Antiretroviral Therapy-Naive Patients With Isolated Nonnucleoside Reverse Transcriptase Inhibitor-Associated Transmitted Drug Resistance JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Clutter, D. S., Fessel, W. J., Rhee, S., Hurley, L. B., Klein, D. B., Ioannidis, J. P., Silverberg, M. J., Shafer, R. W. 2016; 72 (2): 171-176

    Abstract

    Nonnucleoside reverse-transcriptase inhibitor (NNRTI)-associated transmitted drug resistance (TDR) is the most common type of TDR. Few data guide the selection of antiretroviral therapy (ART) for patients with such resistance.We reviewed treatment outcomes in a cohort of HIV-1-infected patients with isolated NNRTI TDR who initiated ART between April 2002 and May 2014. In an as-treated analysis, virological failure (VF) was defined as not reaching undetectable virus levels within 24 weeks, virological rebound, or switching regimens during viremia. In an intention-to-treat (ITT) analysis, failure was defined more broadly as VF, loss to follow-up (LTFU), and switching during virological suppression.Of 3,245 patients, 131 (4.0%) had isolated NNRTI TDR. 122 received a standard regimen comprising two NRTIs plus a boosted protease inhibitor (bPI; n=54), an integrase strand transfer inhibitor (INSTI; n=52), or an NNRTI (n=16). The median follow-up was 100 weeks. In the as-treated analysis, VF occurred in 15% (n=8), 2% (n=1) and 25% (n=4) of patients in the bPI, INSTI and NNRTI groups, respectively. In multivariate regression, there was a trend toward a lower risk of VF with INSTIs than with bPIs (HR 0.14; 95% CI, 0.02,1.1; p = 0.07). In ITT multivariate regression, INSTIs had a lower risk of failure than bPIs (HR 0.38; 95% CI, 0.18,0.82; p = 0.01).Patients with isolated NNRTI TDR experienced low VF rates with INSTIs and bPIs. INSTIs were non-inferior to bPIs in an analysis of VF but superior to bPIs when frequency of switching and LTFU were also considered.

    View details for Web of Science ID 000378059300017

    View details for PubMedID 26855248

  • We need more randomized trials in nutrition-preferably large, long-term, and with negative results AMERICAN JOURNAL OF CLINICAL NUTRITION Ioannidis, J. A. 2016; 103 (6): 1385–86

    View details for DOI 10.3945/ajcn.116.136085

    View details for Web of Science ID 000377054000003

    View details for PubMedID 27146649

  • Why Most Clinical Research Is Not Useful PLOS MEDICINE Ioannidis, J. P. 2016; 13 (6)

    Abstract

    John Ioannidis argues that problem base, context placement, information gain, pragmatism, patient centeredness, value for money, feasibility, and transparency define useful clinical research. He suggests most clinical research is not useful and reform is overdue.

    View details for DOI 10.1371/journal.pmed.1002049

    View details for Web of Science ID 000379128200003

    View details for PubMedID 27328301

  • Exposure-wide epidemiology: revisiting Bradford Hill STATISTICS IN MEDICINE Ioannidis, J. P. 2016; 35 (11): 1749-1762

    Abstract

    Fifty years after Bradford Hill published his extremely influential criteria to offer some guides for separating causation from association, we have accumulated millions of papers and extensive data on observational research that depends on epidemiologic methods and principles. This allows us to re-examine the accumulated empirical evidence for the nine criteria, and to re-approach epidemiology through the lens of exposure-wide approaches. The lecture discusses the evolution of these exposure-wide approaches and tries to use the evidence from meta-epidemiologic assessments to reassess each of the nine criteria and whether they work well as guides for causation. I argue that of the nine criteria, experiment remains important and consistency (replication) is also very essential. Temporality also makes sense, but it is often difficult to document. Of the other six criteria, strength mostly does not work and may even have to be inversed: small and even tiny effects are more plausible than large effects; when large effects are seen, they are mostly transient and almost always represent biases and errors. There is little evidence for specificity in causation in nature. Biological gradient is often unclear how it should it modeled and thus difficult to prove. Coherence remains usually unclear how to operationalize. Finally, plausibility as well as analogy do not work well in most fields of investigation, and their invocation has been mostly detrimental, although exceptions may exist. Copyright © 2015 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/sim.6825

    View details for Web of Science ID 000373935700001

    View details for PubMedID 26646432

  • Prevalence and Characteristics of Interventional Trials Conducted Exclusively in Elderly Persons: A Cross-Sectional Analysis of Registered Clinical Trials PLOS ONE Bourgeois, F. T., Olson, K. L., Tse, T., Ioannidis, J. P., Mandl, K. D. 2016; 11 (5)

    Abstract

    Elderly patients represent the greatest consumers of healthcare per capita but have historically been underrepresented in clinical trials. It is unknown how many trials are designed to focus exclusively on elderly patients.To define the prevalence of interventional trials that study exclusively elderly persons and describe the characteristics of these trials, including their distribution across conditions most prevalent in the elderly.All interventional clinical trials enrolling exclusively elderly patients (≥65 years), conducted primarily in high-income countries, and initiated between 2006 and 2014, identified through ClincialTrials.gov.Trials were identified and characterized according to design features and disease categories studied. Across disease categories we examined the burden of disease in the elderly in high-income countries (measured in disability-adjusted life years [DALYs]) and compared to the number of trials conducted exclusively in the elderly.Among 80,965 interventional trials, 1,112 (1.4%) focused on elderly patients. Diverse types of interventions were studied in these trials (medications 33%, behavioral interventions 18%, and dietary supplements 10%) and the majority was funded by non-profit organizations (81%). Studies tended to be small (median sample size 122 participants [IQR 58, 305]), single-center studies (67%). Only 43% of 126 disease categories affecting elderly persons were studied in trials focused on the elderly. Among these disease categories, there was a 5162-fold range in the ratio of DALYs per trial. Across 5 conditions where over 80% of DALYs are in the elderly, there were a total of only 117 trials done exclusively in the elderly.Very few and mostly small studies are conducted exclusively in elderly persons, even for conditions that affect almost exclusively the elderly.

    View details for DOI 10.1371/journal.pone.0155948

    View details for Web of Science ID 000376291100140

    View details for PubMedID 27196289

    View details for PubMedCentralID PMC4873036

  • Routinely collected data and comparative effectiveness evidence: promises and limitations CANADIAN MEDICAL ASSOCIATION JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 188 (8): E158-E164

    View details for DOI 10.1503/cmaj.150653

    View details for Web of Science ID 000379981400009

    View details for PubMedID 26883316

  • The departure/flight of Greek scientists. A meta-analysis ARCHIVES OF HELLENIC MEDICINE Ioannidis, J. A. 2016; 33 (3): 297–306

    View details for Web of Science ID 000376889100002

  • Obtaining evidence by a single well-powered trial or several modestly powered trials STATISTICAL METHODS IN MEDICAL RESEARCH IntHout, J., Ioannidis, J. P., Borm, G. F. 2016; 25 (2): 538-552

    Abstract

    There is debate whether clinical trials with suboptimal power are justified and whether results from large studies are more reliable than the (combined) results of smaller trials. We quantified the error rates for evaluations based on single conventionally powered trials (80% or 90% power) versus evaluations based on the random-effects meta-analysis of a series of smaller trials. When a treatment was assumed to have no effect but heterogeneity was present, the error rates for a single trial were increased more than 10-fold above the nominal rate, even for low heterogeneity. Conversely, for meta-analyses on a series of trials, the error rates were correct. When selective publication was present, the error rates were always increased, but they still tended to be lower for a series of trials than single trials. We conclude that evidence of efficacy based on a series of (smaller) trials, may lower the error rates compared with using a single well-powered trial. Only when both heterogeneity and selective publication can be excluded, a single trial is able to provide conclusive evidence.

    View details for DOI 10.1177/0962280212461098

    View details for Web of Science ID 000374792800003

    View details for PubMedID 23070590

  • Biases in obesity research: Identify, correct, endorse, or abandon effort? OBESITY Ioannidis, J. A. 2016; 24 (4): 767

    View details for DOI 10.1002/oby.21457

    View details for Web of Science ID 000373613200001

    View details for PubMedID 27028277

  • Non-randomised Ebola trials-lessons for optimal outbreak research LANCET INFECTIOUS DISEASES Ippolito, G., Lanini, S., Brouqui, P., Di Caro, A., Vairo, F., Fusco, F., Krishna, S., Capobianchi, M., Kyobe-Bosa, H., Puro, V., Woelfel, R., Avsic-Zupanc, T., Ioannidis, J. A., Portella, G., Kremsner, P., Dar, O., Bates, M., Zumla, A. 2016; 16 (4): 407–8

    View details for DOI 10.1016/S1473-3099(16)00132-8

    View details for Web of Science ID 000372449600019

    View details for PubMedID 27036341

  • Current use of routinely collected health data to complement randomized controlled trials: a meta-epidemiological survey. CMAJ open Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 4 (2): E132-40

    Abstract

    Studies that use routinely collected health data (RCD studies) are advocated to complement evidence from randomized controlled trials (RCTs) for comparative effectiveness research and to inform health care decisions when RCTs would be unfeasible. We aimed to evaluate the current use of routinely collected health data to complement RCT evidence.We searched PubMed for RCD studies published to 2010 that evaluated the comparative effectiveness of medical treatments on mortality using propensity scores. We identified RCTs of the same treatment comparisons and evaluated how frequently the RCD studies analyzed treatments that had not been compared previously in randomized trials. When RCTs did exist, we noted the claimed motivations for each RCD study. We also analyzed the citation impact of the RCD studies.Of 337 eligible RCD studies identified, 231 (68.5%) analyzed treatments that had already been compared in RCTs. The study investigators rarely claimed that it would be unethical (6/337) or difficult (18/337) to perform RCTs on the same question. Evidence from RCTs was mentioned or cited by authors of 213 RCD studies. The most common motivations for conducting the RCD studies were alleged limited generalizability of trial results to the "real world" (37.6%), evaluation of specific outcomes (31.9%) or specific populations (23.5%), and inconclusive or inconsistent evidence from randomized trials (25.8%). Studies evaluating "real world" effects had the lowest citation impact.Most of the RCD studies we identified explored comparative treatment effects that had already been investigated in RCTs. The objective of such studies needs to shift more toward answering pivotal questions that are not supported by trial evidence or for which RCTs would be unfeasible.

    View details for DOI 10.9778/cmajo.20150036

    View details for PubMedID 27398355

    View details for PubMedCentralID PMC4933635

  • Generic versus brand-name drugs used in cardiovascular diseases EUROPEAN JOURNAL OF EPIDEMIOLOGY Manzoli, L., Flacco, M. E., Boccia, S., D'Andrea, E., Panic, N., Marzuillo, C., Siliquini, R., Ricciardi, W., Villari, P., Ioannidis, J. P. 2016; 31 (4): 351-368

    Abstract

    This meta-analysis aimed to compare the efficacy and adverse events, either serious or mild/moderate, of all generic versus brand-name cardiovascular medicines. We searched randomized trials in MEDLINE, Scopus, EMBASE, Cochrane Controlled Clinical Trial Register, and ClinicalTrials.gov (last update December 1, 2014). Attempts were made to contact the investigators of all potentially eligible trials. Two investigators independently extracted and analyzed soft (including systolic blood pressure, LDL cholesterol, and others) and hard efficacy outcomes (including major cardiovascular adverse events and death), minor/moderate and serious adverse events. We included 74 randomized trials; 53 reported ≥1 efficacy outcome (overall sample 3051), 32 measured mild/moderate adverse events (n = 2407), and 51 evaluated serious adverse events (n = 2892). We included trials assessing ACE inhibitors (n = 12), anticoagulants (n = 5), antiplatelet agents (n = 17), beta-blockers (n = 11), calcium channel blockers (n = 7); diuretics (n = 13); statins (n = 6); and others (n = 3). For both soft and hard efficacy outcomes, 100 % of the trials showed non-significant differences between generic and brand-name drugs. The aggregate effect size was 0.01 (95 % CI -0.05; 0.08) for soft outcomes; -0.06 (-0.71; 0.59) for hard outcomes. All but two trials showed non-significant differences in mild/moderate adverse events, and aggregate effect size was 0.07 (-0.06; 0.20). Comparable results were observed for each drug class and in each stratified meta-analysis. Overall, 8 serious possibly drug-related adverse events were reported: 5/2074 subjects on generics; 3/2076 subjects on brand-name drugs (OR 1.69; 95 % CI 0.40-7.20). This meta-analysis strengthens the evidence for clinical equivalence between brand-name and generic cardiovascular drugs. Physicians could be reassured about prescribing generic cardiovascular drugs, and health care organization about endorsing their wider use.

    View details for DOI 10.1007/s10654-015-0104-8

    View details for Web of Science ID 000376675000003

    View details for PubMedID 26620809

  • Clinical Genomics: From Pathogenicity Claims to Quantitative Risk Estimates. JAMA Manrai, A. K., Ioannidis, J. P., Kohane, I. S. 2016; 315 (12): 1233-1234

    View details for DOI 10.1001/jama.2016.1519

    View details for PubMedID 26925924

  • Prediction of Melanoma Risk in a Southern European Population Based on a Weighted Genetic Risk Score JOURNAL OF INVESTIGATIVE DERMATOLOGY Kypreou, K. P., Stefanaki, I., Antonopoulou, K., Karagianni, F., Ntritsos, G., Zaras, A., Nikolaou, V., Kalfa, I., Chasapi, V., Polydorou, D., Gogas, H., Spyrou, G. M., Bertram, L., Lill, C. M., Ioannidis, J. P., Antoniou, C., Evangelou, E., Stratigos, A. I. 2016; 136 (3): 690-695

    Abstract

    Many single nucleotide polymorphisms (SNPs) have been described as putative risk factors for melanoma. The aim of our study was to validate the most prominent genetic risk loci in an independent Greek melanoma case-control dataset and to assess their cumulative effect solely or combined with established phenotypic risk factors on individualized risk prediction. We genotyped 59 SNPs in 800 patients and 800 controls and tested their association with melanoma using logistic regression analyses. We constructed a weighted genetic risk score (GRSGWS) based on SNPs that showed genome-wide significant (GWS) association with melanoma in previous studies and assessed their impact on risk prediction. Fifteen independent SNPs from 12 loci were significantly associated with melanoma (P < 0.05). Risk score analysis yielded an odds ratio of 1.36 per standard deviation increase of the GRSGWS (P = 1.1 × 10(-7)). Individuals in the highest 20% of the GRSGWS had a 1.88-fold increase in melanoma risk compared with those in the middle quintile. By adding the GRSGWS to a phenotypic risk model, the C-statistic increased from 0.764 to 0.775 (P = 0.007). In summary, the GRSGWS is associated with melanoma risk and achieves a modest improvement in risk prediction when added to a phenotypic risk model.

    View details for DOI 10.1016/j.jid.2015.12.007

    View details for Web of Science ID 000370623100024

  • Field-wide meta-analyses of observational associations can map selective availability of risk factors and the impact of model specifications JOURNAL OF CLINICAL EPIDEMIOLOGY Serghiou, S., Patel, C. J., Tan, Y. Y., Koay, P., Ioannidis, J. P. 2016; 71: 58-67

    Abstract

    Instead of evaluating one risk factor at a time, we illustrate the utility of "field-wide meta-analyses" in considering all available data on all putative risk factors of a disease simultaneously.We identified studies on putative risk factors of pterygium (surfer's eye) in PubMed, EMBASE, and Web of Science. We mapped which factors were considered, reported, and adjusted for in each study. For each putative risk factor, four meta-analyses were done using univariate only, multivariate only, preferentially univariate, or preferentially multivariate estimates.A total of 2052 records were screened to identify 60 eligible studies reporting on 65 putative risk factors. Only 4 of 60 studies reported both multivariate and univariate regression analyses. None of the 32 studies using multivariate analysis adjusted for the same set of risk factors. Effect sizes from different types of regression analyses led to significantly different summary effect sizes (P-value < 0.001). Observed heterogeneity was very high for both multivariate (median I(2), 76.1%) and univariate (median I(2), 85.8%) estimates. No single study investigated all 11 risk factors that were statistically significant in at least one of our meta-analyses.Field-wide meta-analyses can map availability of risk factors and trends in modeling, adjustments and reporting, as well as the impact of differences in model specification.

    View details for DOI 10.1016/j.jclinepi.2015.09.004

    View details for Web of Science ID 000370908900009

    View details for PubMedID 26415577

    View details for PubMedCentralID PMC5108175

  • p-Curve and p-Hacking in Observational Research PLOS ONE Bruns, S. B., Ioannidis, J. P. 2016; 11 (2)

    Abstract

    The p-curve, the distribution of statistically significant p-values of published studies, has been used to make inferences on the proportion of true effects and on the presence of p-hacking in the published literature. We analyze the p-curve for observational research in the presence of p-hacking. We show by means of simulations that even with minimal omitted-variable bias (e.g., unaccounted confounding) p-curves based on true effects and p-curves based on null-effects with p-hacking cannot be reliably distinguished. We also demonstrate this problem using as practical example the evaluation of the effect of malaria prevalence on economic growth between 1960 and 1996. These findings call recent studies into question that use the p-curve to infer that most published research findings are based on true effects in the medical literature and in a wide range of disciplines. p-values in observational research may need to be empirically calibrated to be interpretable with respect to the commonly used significance threshold of 0.05. Violations of randomization in experimental studies may also result in situations where the use of p-curves is similarly unreliable.

    View details for DOI 10.1371/journal.pone.0149144

    View details for Web of Science ID 000371218400062

    View details for PubMedID 26886098

    View details for PubMedCentralID PMC4757561

  • Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey BMJ-BRITISH MEDICAL JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 352

    Abstract

     To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question. Meta-epidemiological survey. PubMed searched up to November 2014. Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results. The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17 275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I(2)=0%)). Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.

    View details for DOI 10.1136/bmj.i493

    View details for Web of Science ID 000370380000002

    View details for PubMedID 26858277

    View details for PubMedCentralID PMC4772787

  • Registration practices for observational studies on ClinicalTrials.gov indicated low adherence. Journal of clinical epidemiology Boccia, S., Rothman, K. J., Panic, N., Flacco, M. E., Rosso, A., Pastorino, R., Manzoli, L., La Vecchia, C., Villari, P., Boffetta, P., Ricciardi, W., Ioannidis, J. P. 2016; 70: 176-182

    Abstract

    The study aims to assess the status of registration of observational studies.We identified studies on cancer research with prospective recruitment of participants that were registered from February 2000 to December 2011 in ClinicalTrials.gov. We recorded the dates of registration and start of recruitment, outcomes, and description of statistical method. We searched for publications corresponding to the registered studies through May 31, 2014.One thousand one hundred nine registered studies were eligible. Primary and secondary outcomes were reported in 809 (73.0%) and 464 (41.8%) of them. The date of registration preceded the month of the study start in 145 (13.8%) and coincided in 205 (19.5%). A total of 151 publications from 120 (10.8%) registered studies were identified. In 2 (33.3%) of the 6 publications where ClinicalTrials.gov reported that the study started recruitment after registration, and in 9 (50.0%) of 18 publications where ClinicalTrials.gov reported the same date for registration and start of recruitment, the articles showed that the study had actually started recruiting before registration.During the period reviewed, few observational studies have been registered. Registration usually occurred after the study started, and prespecification of outcomes and statistical analysis rarely occurred.

    View details for DOI 10.1016/j.jclinepi.2015.09.009

    View details for PubMedID 26386325

  • Meta-analyses with industry involvement are massively published and report no caveats for antidepressants. Journal of clinical epidemiology Ebrahim, S., Bance, S., Athale, A., Malachowski, C., Ioannidis, J. P. 2016; 70: 155-163

    Abstract

    To identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant trials in depression.Using MEDLINE, we identified all meta-analyses evaluating antidepressants for depression published in January 2007-March 2014. We extracted data pertaining to author affiliations, conflicts of interest, and whether the conclusion of the abstract included negative statements on whether the antidepressant(s) were effective or safe.We identified 185 eligible meta-analyses. Fifty-four meta-analyses (29%) had authors who were employees of the assessed drug manufacturer, and 147 (79%) had some industry link (sponsorship or authors who were industry employees and/or had conflicts of interest). Only 58 meta-analyses (31%) had negative statements in the concluding statement of the abstract. Meta-analyses including an author who were employees of the manufacturer of the assessed drug were 22-fold less likely to have negative statements about the drug than other meta-analyses [1/54 (2%) vs. 57/131 (44%); P < 0.001].There is a massive production of meta-analyses of antidepressants for depression authored by or linked to the industry, and they almost never report any caveats about antidepressants in their abstracts. Our findings add a note of caution for meta-analyses with ties to the manufacturers of the assessed products.

    View details for DOI 10.1016/j.jclinepi.2015.08.021

    View details for PubMedID 26399904

  • Environmental risk factors and Parkinson's disease: An umbrella review of meta-analyses. Parkinsonism & related disorders Bellou, V., Belbasis, L., Tzoulaki, I., Evangelou, E., Ioannidis, J. P. 2016; 23: 1-9

    Abstract

    Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support.We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2), evidence of small-study effects and evidence of excess significance bias.Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10(-6) by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity.Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.

    View details for DOI 10.1016/j.parkreldis.2015.12.008

    View details for PubMedID 26739246

  • PRISMA harms checklist: improving harms reporting in systematic reviews BMJ-BRITISH MEDICAL JOURNAL Zorzela, L., Loke, Y. K., Ioannidis, J. P., Golder, S., Santaguida, P., Altman, D. G., Moher, D., Vohra, S. 2016; 352

    Abstract

     For any health intervention, accurate knowledge of both benefits and harms is needed. Systematic reviews often compound poor reporting of harms in primary studies by failing to report harms or doing so inadequately. While the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) helps systematic review authors ensure complete and transparent reporting, it is focused mainly on efficacy. Thus, a PRISMA harms checklist has been developed to improve harms reporting in systematic reviews, promoting a more balanced assessment of benefits and harms. A development strategy, endorsed by the EQUATOR Network and existing reporting guidelines (including the PRISMA statement, PRISMA for abstracts, and PRISMA for protocols), was used. After the development of a draft checklist of items, a modified Delphi process was initiated. The Delphi consisted of three rounds of electronic feedback followed by an in-person meeting. The PRISMA harms checklist contains four essential reporting elements to be added to the original PRISMA statement to improve harms reporting in reviews. These are reported in the title ("Specifically mention 'harms' or other related terms, or the harm of interest in the review"), synthesis of results ("Specify how zero events were handled, if relevant"), study characteristics ("Define each harm addressed, how it was ascertained (eg, patient report, active search), and over what time period"), and synthesis of results ("Describe any assessment of possible causality"). Additional guidance regarding existing PRISMA items was developed to demonstrate relevance when synthesising information about harms. The PRISMA harms checklist identifies a minimal set of items to be reported when reviewing adverse events. This guideline extension is intended to improve harms reporting in systematic reviews, whether harms are a primary or secondary outcome.

    View details for DOI 10.1136/bmj.i157

    View details for Web of Science ID 000369766400002

    View details for PubMedID 26830668

  • Anticipating consequences of sharing raw data and code and of awarding badges for sharing. Journal of clinical epidemiology Ioannidis, J. P. 2016; 70: 258-260

    View details for DOI 10.1016/j.jclinepi.2015.04.015

    View details for PubMedID 26163123

  • Reply to letter by Ferrante di Ruffano et al.: Patient outcomes in randomized comparisons of diagnostic tests are still the ultimate judge JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, K. C., Siontis, G. C., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 69: 267-268

    View details for DOI 10.1016/j.jclinepi.2015.06.012

    View details for Web of Science ID 000367127600050

    View details for PubMedID 26130596

  • Response to letter by Forike et al.: more rigorous, not less, external validation is needed JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, G. M., Ioannidis, J. A. 2016; 69: 250–51

    View details for DOI 10.1016/j.jclinepi.2015.01.021

    View details for Web of Science ID 000367127600035

    View details for PubMedID 25724895

  • METHODS TO ENHANCE THE REPRODUCIBILITY OF PRECISION MEDICINE. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Manrai, A. K., Patel, C. J., Gehlenborg, N., Tatonetti, N. P., Ioannidis, J. P., Kohane, I. S. 2016; 21: 180-182

    View details for PubMedID 28004011

    View details for PubMedCentralID PMC5167531

  • Transparent Communication of Radiology Research: Reporting Guidelines and Beyond. Academic radiology Lu, Y., Ioannidis, J. P. 2016; 23 (5): 529–30

    View details for DOI 10.1016/j.acra.2016.02.009

    View details for PubMedID 27017133

  • Plea for routinely presenting prediction intervals in meta-analysis BMJ OPEN IntHout, J., Ioannidis, J. P., Rovers, M. M., Goeman, J. J. 2016; 6 (7)

    Abstract

    Evaluating the variation in the strength of the effect across studies is a key feature of meta-analyses. This variability is reflected by measures like τ(2) or I(2), but their clinical interpretation is not straightforward. A prediction interval is less complicated: it presents the expected range of true effects in similar studies. We aimed to show the advantages of having the prediction interval routinely reported in meta-analyses.We show how the prediction interval can help understand the uncertainty about whether an intervention works or not. To evaluate the implications of using this interval to interpret the results, we selected the first meta-analysis per intervention review of the Cochrane Database of Systematic Reviews Issues 2009-2013 with a dichotomous (n=2009) or continuous (n=1254) outcome, and generated 95% prediction intervals for them.In 72.4% of 479 statistically significant (random-effects p<0.05) meta-analyses in the Cochrane Database 2009-2013 with heterogeneity (I(2)>0), the 95% prediction interval suggested that the intervention effect could be null or even be in the opposite direction. In 20.3% of those 479 meta-analyses, the prediction interval showed that the effect could be completely opposite to the point estimate of the meta-analysis. We demonstrate also how the prediction interval can be used to calculate the probability that a new trial will show a negative effect and to improve the calculations of the power of a new trial.The prediction interval reflects the variation in treatment effects over different settings, including what effect is to be expected in future patients, such as the patients that a clinician is interested to treat. Prediction intervals should be routinely reported to allow more informative inferences in meta-analyses.

    View details for DOI 10.1136/bmjopen-2015-010247

    View details for Web of Science ID 000382252100059

    View details for PubMedID 27406637

    View details for PubMedCentralID PMC4947751

  • Diagnostic accuracy of the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) for detecting major depression: protocol for a systematic review and individual patient data meta-analyses BMJ OPEN Thombs, B. D., Benedetti, A., Kloda, L. A., Levis, B., Azar, M., Riehm, K. E., Saadat, N., Cuijpers, P., Gilbody, S., Ioannidis, J. P., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C., Loiselle, C. G., Henry, M., Ismail, Z., Mitchell, N., Tonelli, M. 2016; 6 (4)

    Abstract

    The Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) has been recommended for depression screening in medically ill patients. Many existing HADS-D studies have used exploratory methods to select optimal cut-offs. Often, these studies report results from a small range of cut-off thresholds; cut-offs with more favourable accuracy results are more likely to be reported than others with worse accuracy estimates. When published data are combined in meta-analyses, selective reporting may generate biased summary estimates. Individual patient data (IPD) meta-analyses can address this problem by estimating accuracy with data from all studies for all relevant cut-off scores. In addition, a predictive algorithm can be generated to estimate the probability that a patient has depression based on a HADS-D score and clinical characteristics rather than dichotomous screening classification alone. The primary objectives of our IPD meta-analyses are to determine the diagnostic accuracy of the HADS-D to detect major depression among adults across all potentially relevant cut-off scores and to generate a predictive algorithm for individual patients. We are already aware of over 100 eligible studies, and more may be identified with our comprehensive search.Data sources will include MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO and Web of Science. Eligible studies will have datasets where patients are assessed for major depression based on a validated structured or semistructured clinical interview and complete the HADS-D within 2 weeks (before or after). Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values, and a predictive algorithm for individual patients will be generated.The findings of this study will be of interest to stakeholders involved in research, clinical practice and policy.

    View details for DOI 10.1136/bmjopen-2016-011913

    View details for Web of Science ID 000376391400152

    View details for PubMedID 27075844

    View details for PubMedCentralID PMC4838677

  • Systematic assessment of pharmaceutical prescriptions in association with cancer risk: a method to conduct a population-wide medication-wide longitudinal study. Scientific reports Patel, C. J., Ji, J., Sundquist, J., Ioannidis, J. P., Sundquist, K. 2016; 6: 31308-?

    Abstract

    It is a public health priority to identify the adverse and non-adverse associations between pharmaceutical medications and cancer. We search for and evaluate associations between all prescribed medications and longitudinal cancer risk in participants of the Swedish Cancer Register (N = 9,014,975). We associated 552 different medications with incident cancer risk (any, breast, colon, and prostate) during 5.5 years of follow-up (7/1/2005-12/31/2010) in two types of statistical models, time-to-event and case-crossover. After multiple hypotheses correction and replication, 141 (26%) drugs were associated with any cancer in a time-to-event analysis constraining drug exposure to 1 year before first cancer diagnosis and adjusting for history of medication use. In a case-crossover analysis, 36 drugs (7%) were associated with decreased cancer risk. 12 drugs were found in common in both analyses with concordant direction of association. We found 14, 10, 7% of all drugs associated with colon, prostate, and breast cancers in time-to-event models. We only found 1, 2%, and 0% for these cancers, respectively, in case-crossover analyses. Pharmacoepidemiologic analyses of cancer risk are sensitive to modeling choices and false-positive findings are a threat. Medication-wide analyses using different analytical models may help suggest consistent signals of increased cancer risk.

    View details for DOI 10.1038/srep31308

    View details for PubMedID 27507038

    View details for PubMedCentralID PMC4979093

  • METHODS TO ENHANCE THE REPRODUCIBILITY OF PRECISION MEDICINE. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Manrai, A. K., Patel, C. J., Gehlenborg, N., Tatonetti, N. P., Ioannidis, J. P., Kohane, I. S. 2016; 21: 180-182

    Abstract

    During January 2015, President Obama announced the Precision Medicine Initiative [1], strengthening communal efforts to integrate patient-centric molecular, environmental, and clinical "big" data. Such efforts have already improved aspects of clinical management for diseases such as non-small cell lung carcinoma [2], breast cancer [3], and hypertrophic cardiomyopathy [4]. To maintain this track record, it is necessary to cultivate practices that ensure reproducibility as large-scale heterogeneous datasets and databases proliferate. For example, the NIH has outlined initiatives to enhance reproducibility in preclinical research [5], both Science [6] and Nature [7] have featured recent editorials on reproducibility, and several authors have noted the issues of utilizing big data for public health [8], but few methods exist to ensure that big data resources motivated by precision medicine are being used reproducibly. Relevant challenges include: (1) integrative analyses of heterogeneous measurement platforms (e.g. genomic, clinical, quantified self, and exposure data), (2) the tradeoff in making personalized decisions using more targeted (e.g. individual-level) but potentially much noisier subsets of data, and (3) the unprecedented scale of asynchronous observational and population level inquiry (i.e. many investigators separately mining shared/publicly-available data)….

    View details for PubMedID 26776184

  • Commentary: Salt and the assault of opinion on evidence. International journal of epidemiology Ioannidis, J. P. 2016

    View details for DOI 10.1093/ije/dyw015

    View details for PubMedID 26888871

  • Academic criteria for appointment, promotion and rewards in medical research: where's the evidence? European journal of clinical investigation Moher, D., Goodman, S. N., Ioannidis, J. P. 2016

    Abstract

    It has been argued that incentive systems should be multi-dimensional, including productivity, quality, reproducibility, sharing, and translation potential ("PQRST"),(1) but many current systems weight productivity particularly heavily. These systems directly affect the volume, and indirectly the quality of the scientific publication record. This was recognized at least as far back as the 1980s, with a proposal that promotion committees consider only a handful of a scientist's publications, in the hopes of improving the quality of our "large and largely trivial" literature. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/eci.12612

    View details for PubMedID 26924551

  • Korean National Health Insurance Database Reply JAMA INTERNAL MEDICINE Hsing, A., Ioannidis, J. P. 2016; 176 (1): 138-139

    View details for Web of Science ID 000367549100042

    View details for PubMedID 26747668

  • Noninferiority is almost certain with lenient noninferiority margins. Journal of clinical epidemiology Flacco, M. E., Manzoli, L., Ioannidis, J. P. 2016; 71: 118

    View details for DOI 10.1016/j.jclinepi.2015.11.010

    View details for PubMedID 26607237

  • Network meta-analyses performed by contracting companies and commissioned by industry. Systematic reviews Schuit, E., Ioannidis, J. P. 2016; 5 (1): 198

    Abstract

    BACKGROUND: Industry commissions contracting companies to perform network meta-analysis for health technology assessment (HTA) and reimbursement submissions. Our objective was to estimate the number of network meta-analyses performed by consulting companies contracted by industry, to assess whether they were published, and to explore reasons for non-publication.METHODS: We searched MEDLINE for network meta-analyses of randomized trials. Papers were included if they had authors affiliated with any contracting company. All identified contracting companies as well as additional ones from the list of the exhibitors at the International Society for Pharmacoeconomics and Outcomes Research, an annual meeting that representatives from many contracting companies attend and exhibit at, were surveyed regarding conduct and publication of network meta-analyses.RESULTS: In 162 of 822 (20%) network meta-analysis papers, authors were affiliated to 66 contracting companies. Another 36 contracting companies were identified by the exhibitors list. Three companies had no contact information and six merged with others, therefore 93 companies were contacted. Thirty seven out of ninety three (40%) companies responded, and 19 indicated that they had performed a total of 476 network meta-analyses, but only 102 (21%) papers were published. Thirteen companies that disclosed to have conducted 174 network meta-analyses (45 published) provided reasons for non-publication. Of the 129 still unpublished meta-analyses, for 40 there were plans for future publication, for 37 the sponsor did not allow publication, for 16 the contracting companies did not plan to publish the meta-analysis, for another 23 plans were unclear, and the remaining 13 were used as HTA submission. The protocol of the network meta-analysis was publically available from 11/162 (6.8%) network meta-analyses published by authors affiliated with contracting companies.CONCLUSIONS: There is a prolific sector of professional contracting companies that perform network meta-analyses. Industry commissions many network meta-analyses, but most are not registered before or published after analyses in the scientific literature. Mechanisms to improve publication rates of network meta-analysis commissioned by industry are warranted.

    View details for PubMedID 27884175

  • Most psychotherapies do not really work, but those that might work should be assessed in biased studies. Epidemiology and psychiatric sciences Ioannidis, J. P. 2016: 1–3

    View details for DOI 10.1017/S2045796015000888

    View details for PubMedID 26952766

  • Inadequacies of Physical Examination as a Cause of Medical Errors and Adverse Events: A Collection of Vignettes. American journal of medicine Verghese, A., Charlton, B., Kassirer, J. P., Ramsey, M., Ioannidis, J. P. 2015; 128 (12): 1322-1324 e3

    Abstract

    Oversights in the physical examination are a type of medical error not easily studied by chart review. They may be a major contributor to missed or delayed diagnosis, unnecessary exposure to contrast and radiation, incorrect treatment, and other adverse consequences. Our purpose was to collect vignettes of physical examination oversights and to capture the diversity of their characteristics and consequences.A cross-sectional study using an 11-question qualitative survey for physicians was distributed electronically, with data collected from February to June of 2011. The participants were all physicians responding to e-mail or social media invitations to complete the survey. There were no limitations on geography, specialty, or practice setting.Of the 208 reported vignettes that met inclusion criteria, the oversight was caused by a failure to perform the physical examination in 63%; 14% reported that the correct physical examination sign was elicited but misinterpreted, whereas 11% reported that the relevant sign was missed or not sought. Consequence of the physical examination inadequacy included missed or delayed diagnosis in 76% of cases, incorrect diagnosis in 27%, unnecessary treatment in 18%, no or delayed treatment in 42%, unnecessary diagnostic cost in 25%, unnecessary exposure to radiation or contrast in 17%, and complications caused by treatments in 4%. The mode of the number of physicians missing the finding was 2, but many oversights were missed by many physicians. Most oversights took up to 5 days to identify, but 66 took longer. Special attention and skill in examining the skin and its appendages, as well as the abdomen, groin, and genitourinary area could reduce the reported oversights by half.Physical examination inadequacies are a preventable source of medical error, and adverse events are caused mostly by failure to perform the relevant examination.

    View details for DOI 10.1016/j.amjmed.2015.06.004

    View details for PubMedID 26144103

  • Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study BRITISH JOURNAL OF SPORTS MEDICINE Naci, H., Ioannidis, J. P. 2015; 49 (21): 1414-1422

    Abstract

    To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes.Metaepidemiological study.Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care).Medline and Cochrane Database of Systematic Reviews, May 2013.Mortality.We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise vanticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11,1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant.Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

    View details for DOI 10.1136/bjsports-2015-f5577rep

    View details for Web of Science ID 000363144200013

    View details for PubMedID 26476429

    View details for PubMedCentralID PMC4680125

  • Unhealthy stealth NEW SCIENTIST Ioannidis, J. 2015; 228 (3045): 26-+

    View details for DOI 10.1016/S0262-4079(15)31510-4

    View details for Web of Science ID 000364114000015

  • Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study. The Lancet. Neurology Nalls, M. A., McLean, C. Y., Rick, J., Eberly, S., Hutten, S. J., Gwinn, K., Sutherland, M., Martinez, M., Heutink, P., Williams, N. M., Hardy, J., Gasser, T., Brice, A., Price, T. R., Nicolas, A., Keller, M. F., Molony, C., Gibbs, J. R., Chen-Plotkin, A., Suh, E., Letson, C., Fiandaca, M. S., Mapstone, M., Federoff, H. J., Noyce, A. J., Morris, H., Van Deerlin, V. M., Weintraub, D., Zabetian, C., Hernandez, D. G., Lesage, S., Mullins, M., Conley, E. D., Northover, C. A., Frasier, M., Marek, K., Day-Williams, A. G., Stone, D. J., Ioannidis, J. P., Singleton, A. B. 2015; 14 (10): 1002-1009

    Abstract

    Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

    View details for DOI 10.1016/S1474-4422(15)00178-7

    View details for PubMedID 26271532

    View details for PubMedCentralID PMC4575273

  • John Ioannidis: Uncompromising gentle maniac BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. 2015; 351: h4992

    View details for DOI 10.1136/bmj.h4992

    View details for Web of Science ID 000361959200003

    View details for PubMedID 26404555

  • Is It Possible to Recognize a Major Scientific Discovery? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2015; 314 (11): 1135-1137

    View details for Web of Science ID 000361284500022

    View details for PubMedID 26372580

  • Nationwide Population Science: Lessons From the Taiwan National Health Insurance Research Database. JAMA internal medicine Hsing, A. W., Ioannidis, J. P. 2015; 175 (9): 1527-1529

    View details for DOI 10.1001/jamainternmed.2015.3540

    View details for PubMedID 26192815

  • Small studies are more heterogeneous than large ones: a meta-meta-analysis JOURNAL OF CLINICAL EPIDEMIOLOGY IntHout, J., Ioannidis, J. P., Borm, G. F., Goeman, J. J. 2015; 68 (8): 860-869

    Abstract

    Between-study heterogeneity plays an important role in random-effects models for meta-analysis. Most clinical trials are small, and small trials are often associated with larger effect sizes. We empirically evaluated whether there is also a relationship between trial size and heterogeneity (τ).We selected the first meta-analysis per intervention review of the Cochrane Database of Systematic Reviews Issues 2009-2013 with a dichotomous (n = 2,009) or continuous (n = 1,254) outcome. The association between estimated τ and trial size was evaluated across meta-analyses using regression and within meta-analyses using a Bayesian approach. Small trials were predefined as those having standard errors (SEs) over 0.2 standardized effects.Most meta-analyses were based on few (median 4) trials. Within the same meta-analysis, the small study τS(2) was larger than the large-study τL(2) [average ratio 2.11; 95% credible interval (1.05, 3.87) for dichotomous and 3.11 (2.00, 4.78) for continuous meta-analyses]. The imprecision of τS was larger than of τL: median SE 0.39 vs. 0.20 for dichotomous and 0.22 vs. 0.13 for continuous small-study and large-study meta-analyses.Heterogeneity between small studies is larger than between larger studies. The large imprecision with which τ is estimated in a typical small-studies' meta-analysis is another reason for concern, and sensitivity analyses are recommended.

    View details for DOI 10.1016/j.jclinepi.2015.03.017

    View details for Web of Science ID 000357623700004

    View details for PubMedID 25959635

  • Research and Theories on the Etiology of Mental Diseases: Doomed to Failure? PSYCHOLOGICAL INQUIRY Ioannidis, J. A. 2015; 26 (3): 239–43

    View details for DOI 10.1080/1047840X.2015.1021188

    View details for Web of Science ID 000360223800003

  • Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor JOURNAL OF CLINICAL EPIDEMIOLOGY Flacco, M. E., Manzoli, L., Boccia, S., Capasso, L., Aleksovska, K., Rosso, A., Scaioli, G., De Vito, C., Siliquini, R., Villari, P., Ioannidis, J. P. 2015; 68 (7): 811-820

    Abstract

    To map the current status of head-to-head comparative randomized evidence and to assess whether funding may impact on trial design and results.From a 50% random sample of the randomized controlled trials (RCTs) published in journals indexed in PubMed during 2011, we selected the trials with ≥ 100 participants, evaluating the efficacy and safety of drugs, biologics, and medical devices through a head-to-head comparison.We analyzed 319 trials. Overall, 238,386 of the 289,718 randomized subjects (82.3%) were included in the 182 trials funded by companies. Of the 182 industry-sponsored trials, only 23 had two industry sponsors and only three involved truly antagonistic comparisons. Industry-sponsored trials were larger, more commonly registered, used more frequently noninferiority/equivalence designs, had higher citation impact, and were more likely to have "favorable" results (superiority or noninferiority/equivalence for the experimental treatment) than nonindustry-sponsored trials. Industry funding [odds ratio (OR) 2.8; 95% confidence interval (CI): 1.6, 4.7] and noninferiority/equivalence designs (OR 3.2; 95% CI: 1.5, 6.6), but not sample size, were strongly associated with "favorable" findings. Fifty-five of the 57 (96.5%) industry-funded noninferiority/equivalence trials got desirable "favorable" results.The literature of head-to-head RCTs is dominated by the industry. Industry-sponsored comparative assessments systematically yield favorable results for the sponsors, even more so when noninferiority designs are involved.

    View details for DOI 10.1016/j.jclinepi.2014.12.016

    View details for Web of Science ID 000356634100013

  • The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and Explanations ANNALS OF INTERNAL MEDICINE Hutton, B., Salanti, G., Caldwell, D. M., Chaimani, A., Schmid, C. H., Cameron, C., Ioannidis, J. P., Straus, S., Thorlund, K., Jansen, J. P., Mulrow, C., Catala-Lopez, F., Gotzsche, P. C., Dickersin, K., Boutron, I., Altman, D. G., Moher, D. 2015; 162 (11): 777-784

    Abstract

    The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers.

    View details for DOI 10.7326/M14-2385

    View details for Web of Science ID 000355572300005

    View details for PubMedID 26030634

  • Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa? LANCET INFECTIOUS DISEASES Lanini, S., Zumla, A., Ioannidis, J. A., Di Caro, A., Krishna, S., Gostin, L., Girardi, E., Pletschette, M., Strada, G., Baritussio, A., Portella, G., Apolone, G., Cavuto, S., Satolli, R., Kremsner, P., Vairo, F., Ippolito, G. 2015; 15 (6): 738–45

    Abstract

    The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group.

    View details for DOI 10.1016/S1473-3099(15)70106-4

    View details for Web of Science ID 000354638000039

    View details for PubMedID 25881871

  • An overview of recommendations and translational milestones for genomic tests in cancer GENETICS IN MEDICINE Chang, C. Q., Tingle, S. R., Filipski, K. K., Khoury, M. J., Lam, T. K., Schully, S. D., Ioannidis, J. P. 2015; 17 (6): 431-440

    Abstract

    To understand the translational trajectory of genomic tests in cancer screening, diagnosis, prognosis, and treatment, we reviewed tests that have been assessed by recommendation and guideline developers.For each test, we marked translational milestones by determining when the genomic association with cancer was first discovered and studied in patients, and when a health application for a specified clinical use was successfully demonstrated and approved or cleared by the US Food and Drug Administration. To identify recommendations and guidelines, we reviewed the websites of cancer, genomic, and general guideline developers and professional organizations. We searched the in vitro diagnostics database of the US Food and Drug Administration for information, and we searched PubMed for translational milestones. Milestones were examined against type of recommendation, Food and Drug Administration approval or clearance, disease rarity, and test purpose.Of the 45 tests we identified, 9 received strong recommendations for their usage in clinical settings, 14 received positive but moderate recommendations, and 22 were not currently recommended. For 18 tests, two or more different sources had issued recommendations, with 67% concordance. Only five tests had Food and Drug Administration approval, and an additional five had clearance. The median time from discovery to recommendation statement was 14.7 years.In general, there were no associations found between translational trajectory and recommendation category.Genet Med 17 6, 431-440.

    View details for DOI 10.1038/gim.2014.133

    View details for Web of Science ID 000355564200001

    View details for PubMedID 25341115

  • Clinical trials: A transparent future for clinical trial reporting. Nature reviews. Rheumatology Karassa, F. B., Ioannidis, J. P. 2015; 11 (6): 324-326

    View details for DOI 10.1038/nrrheum.2015.65

    View details for PubMedID 25939418

  • Epidemiologic Design and Analysis for Proteomic Studies: A Primer on -Omic Technologies AMERICAN JOURNAL OF EPIDEMIOLOGY Mischak, H., Critselis, E., Hanash, S., Gallagher, W. M., Vlahou, A., Ioannidis, J. P. 2015; 181 (9): 635-647

    Abstract

    Proteome analysis is increasingly being used in investigations elucidating the molecular basis of disease, identifying diagnostic and prognostic markers, and ultimately improving patient care. We appraised the current status of proteomic investigations using human samples, including the state of the art in proteomic technologies, from sample preparation to data evaluation approaches, as well as key epidemiologic, statistical, and translational issues. We systematically reviewed the most highly cited clinical proteomic studies published between January 2009 and March 2014 that included a minimum of 100 samples, as well as strategies that have been successfully implemented to enhance the translational relevance of proteomic investigations. Limited comparability between studies and lack of specification of biomarker context of use are frequently observed. Nevertheless, there are initial examples of successful biomarker discovery in cross-sectional studies followed by validation in high-risk longitudinal cohorts. Translational potential is currently hindered, as limitations in proteomic investigations are not accounted for. Interdisciplinary communication between proteomics experts, basic researchers, epidemiologists, and clinicians, an orchestrated assimilation of required resources, and a more systematic translational outlook for accumulation of evidence may augment the public health impact of proteomic investigations.

    View details for DOI 10.1093/aje/kwu462

    View details for Web of Science ID 000353817100001

    View details for PubMedID 25792606

  • Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database JOURNAL OF INVESTIGATIVE DERMATOLOGY Antonopoulou, K., Stefanaki, I., Lill, C. M., Chatzinasiou, F., Kypreou, K. P., Karagianni, F., Athanasiadis, E., Spyrou, G. M., Ioannidis, J. P., Bertram, L., Evangelou, E., Stratigos, A. J. 2015; 135 (4): 1074-1079

    Abstract

    We updated a field synopsis of genetic associations of cutaneous melanoma (CM) by systematically retrieving and combining data from all studies in the field published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 data sets confirmed 20 single-nucleotide polymorphisms across 10 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10(-8)) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, and PLA2G6) were also significantly associated with 5 × 10(-8)

    View details for DOI 10.1038/jid.2014.491

    View details for Web of Science ID 000351188600023

    View details for PubMedID 25407435

  • Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis. PLoS medicine Rhee, S., Blanco, J. L., Jordan, M. R., Taylor, J., Lemey, P., Varghese, V., Hamers, R. L., Bertagnolio, S., de Wit, T. F., Aghokeng, A. F., Albert, J., Avi, R., Avila-Rios, S., Bessong, P. O., Brooks, J. I., Boucher, C. A., Brumme, Z. L., Busch, M. P., Bussmann, H., Chaix, M., Chin, B. S., D'Aquin, T. T., De Gascun, C. F., Derache, A., Descamps, D., Deshpande, A. K., Djoko, C. F., Eshleman, S. H., Fleury, H., Frange, P., Fujisaki, S., Harrigan, P. R., Hattori, J., Holguin, A., Hunt, G. M., Ichimura, H., Kaleebu, P., Katzenstein, D., Kiertiburanakul, S., Kim, J. H., Kim, S. S., Li, Y., Lutsar, I., Morris, L., Ndembi, N., Ng, K. P., Paranjape, R. S., Peeters, M., Poljak, M., Price, M. A., Ragonnet-Cronin, M. L., Reyes-Terán, G., Rolland, M., Sirivichayakul, S., Smith, D. M., Soares, M. A., Soriano, V. V., Ssemwanga, D., Stanojevic, M., Stefani, M. A., Sugiura, W., Sungkanuparph, S., Tanuri, A., Tee, K. K., Truong, H. M., Van De Vijver, D. A., Vidal, N., Yang, C., Yang, R., Yebra, G., Ioannidis, J. P., Vandamme, A., Shafer, R. W. 2015; 12 (4)

    View details for DOI 10.1371/journal.pmed.1001810

    View details for PubMedID 25849352

  • Modern health care as a game theory problem: reply. European journal of clinical investigation Djulbegovic, B., Hozo, I., Ioannidis, J. 2015; 45 (4): 443-?

    View details for DOI 10.1111/eci.12414

    View details for PubMedID 25630659

  • Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses LANCET NEUROLOGY Belbasis, L., Bellou, V., Evangelou, E., Ioannidis, J. P., Tzoulaki, I. 2015; 14 (3): 263-273

    Abstract

    The cause of multiple sclerosis is believed to involve environmental exposure and genetic susceptibility. We aimed to summarise the environmental risk factors that have been studied in relation to onset of multiple sclerosis, assess whether there is evidence for diverse biases in this literature, and identify risk factors without evidence of biases.We searched PubMed from inception to Nov 22, 2014, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and multiple sclerosis. For each meta-analysis we estimated the summary effect size by use of random-effects and fixed-effects models, the 95% CI, and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2) (defined as large for I(2)≥50%), evidence of small-study effects (ie, large studies had significantly more conservative results than smaller studies), and evidence of excess significance bias (ie, more studies than expected with significant results).Overall, 44 unique meta-analyses including 416 primary studies of different risk factors and multiple sclerosis were examined, covering a wide range of risk factors: vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers. 23 of 44 meta-analyses had results that were significant at p values less than 0·05 and 11 at p values less than 0·001 under the random-effects model. Only three of the 11 significant meta-analyses (p<0·001) included more than 1000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I(2)<50%), small-study effects (p for Egger's test >0·10), or excess significance (p>0·05). These were IgG seropositivity to Epstein-Barr virus nuclear antigen (EBNA) (random effects odds ratio [OR] 4·46, 95% CI 3·26-6·09; p for effect size=1·5 × 10(-19); I(2)=43%), infectious mononucleosis (2·17, 1·97-2·39; p=3·1 × 10(-50); I(2)=0%), and smoking (1·52, 1·39-1·66; p=1·7 × 10(-18;)I(2)=0%).Many studies on environmental factors associated with multiple sclerosis have caveats casting doubts on their validity. Data from more and better-designed studies are needed to establish robust evidence. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking showed the strongest consistent evidence of an association.None.

    View details for DOI 10.1016/S1474-4422(14)70267-4

    View details for Web of Science ID 000349594000009

    View details for PubMedID 25662901

  • Preventing tooth loss with biannual dental visits and genetic testing Does it work? JOURNAL OF THE AMERICAN DENTAL ASSOCIATION Ioannidis, J. A. 2015; 146 (3): 141–43

    View details for DOI 10.1016/j.adaj.2015.01.015

    View details for Web of Science ID 000352152600001

    View details for PubMedID 25726336

  • Recent Randomized Controlled Trials in Otolaryngology OTOLARYNGOLOGY-HEAD AND NECK SURGERY Banglawala, S. M., Lawrence, L. A., Franko-Tobin, E., Soler, Z. M., Schlosser, R. J., Ioannidis, J. 2015; 152 (3): 418–23

    Abstract

    To assess recent trends in the prevalence and quality of reporting of randomized controlled trials (RCTs) in 4 otolaryngology journals.Methodology and reporting analysis.Randomized controlled trials in 4 otolaryngology journals.All RCTs published from 2011 to 2013 in 4 major otolaryngology journals were examined for characteristics of study design, quality of design and reporting, and funding.Of 5279 articles published in 4 leading otolaryngology journals from 2011 to 2013, 189 (3.3%) were RCTs. The majority of RCTs were clinical studies (86%), with the largest proportion consisting of sinonasal topics (31%). Most interventions were medical (46%), followed by surgical (38%) and mixed (16%). In terms of quality, randomization method was reported in 54% of RCTs, blinding in 33%, and adverse events in 65%. Intention-to-treat analysis was used in 32%; P values were reported in 87% and confidence intervals in 10%. Research funding was most often absent or not reported (55%), followed by not-for-profit (25%).Based on review of 4 otolaryngology journals, RCTs are still a small proportion of all published studies in the field of otolaryngology. There seem to be trends toward improvement in quality of design and reporting of RCTs, although many quality features remain suboptimal. Practitioners both designing and interpreting RCTs should critically evaluate RCTs for quality.

    View details for DOI 10.1177/0194599814563518

    View details for Web of Science ID 000350477100006

    View details for PubMedID 25550226

  • SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease GASTROINTESTINAL ENDOSCOPY Laine, L., Kaltenbach, T., Barkun, A., Mcquaid, K. R., Subramanian, V., Soetikno, R. 2015; 81 (3): 489-U417

    View details for DOI 10.1016/j.gie.2014.12.009

    View details for Web of Science ID 000351666800001

    View details for PubMedID 25708752

  • SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease GASTROENTEROLOGY Laine, L., Kaltenbach, T., Barkun, A., Mcquaid, K. R., Subramanian, V., Soetikno, R. 2015; 148 (3): 639-?

    View details for DOI 10.1053/j.gastro.2015.01.031

    View details for Web of Science ID 000349968200034

    View details for PubMedID 25702852

  • Stealth Research Is Biomedical Innovation Happening Outside the Peer-Reviewed Literature? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2015; 313 (7): 663–64

    View details for DOI 10.1001/jama.2014.17662

    View details for Web of Science ID 000349476100006

    View details for PubMedID 25688775

  • Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature Do, R., Stitziel, N. O., Won, H., Jørgensen, A. B., Duga, S., Angelica Merlini, P., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., Lange, L. A., Peloso, G. M., Auer, P. L., Girelli, D., Martinelli, N., Farlow, D. N., DePristo, M. A., Roberts, R., Stewart, A. F., Saleheen, D., Danesh, J., Epstein, S. E., Sivapalaratnam, S., Hovingh, G. K., Kastelein, J. J., Samani, N. J., Schunkert, H., Erdmann, J., Shah, S. H., Kraus, W. E., Davies, R., Nikpay, M., Johansen, C. T., Wang, J., Hegele, R. A., Hechter, E., Marz, W., Kleber, M. E., Huang, J., Johnson, A. D., Li, M., Burke, G. L., Gross, M., Liu, Y., Assimes, T. L., Heiss, G., Lange, E. M., Folsom, A. R., Taylor, H. A., Olivieri, O., Hamsten, A., Clarke, R., Reilly, D. F., Yin, W., Rivas, M. A., Donnelly, P., Rossouw, J. E., Psaty, B. M., Herrington, D. M., Wilson, J. G., Rich, S. S., Bamshad, M. J., Tracy, R. P., Cupples, L. A., Rader, D. J., Reilly, M. P., Spertus, J. A., Cresci, S., Hartiala, J., Tang, W. H., Hazen, S. L., Allayee, H., Reiner, A. P., Carlson, C. S., Kooperberg, C., Jackson, R. D., Boerwinkle, E., Lander, E. S., Schwartz, S. M., Siscovick, D. S., McPherson, R., Tybjaerg-Hansen, A., Abecasis, G. R., Watkins, H., Nickerson, D. A., Ardissino, D., Sunyaev, S. R., O'Donnell, C. J., Altshuler, D., Gabriel, S., Kathiresan, S. 2015; 518 (7537): 102-106

    Abstract

    Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

    View details for DOI 10.1038/nature13917

    View details for PubMedID 25487149

  • Application of credibility ceilings probes the robustness of meta-analyses of biomarkers and cancer risk JOURNAL OF CLINICAL EPIDEMIOLOGY Papatheodorou, S. I., Tsilidis, K. K., Evangelou, E., Ioannidis, J. P. 2015; 68 (2): 163-174

    Abstract

    Meta-analyses of biomarkers often present spurious significant results and large effects. We applied sensitivity analyses with the use of credibility ceilings to assess whether and how the results of meta-analyses of biomarkers and cancer risk would change.We evaluated 98 meta-analyses, 43 (44%) of which had nominally statistically significant results. We assumed that any single study cannot give more than a maximum certainty 100 - c% (c, credibility ceiling) that the effect estimate [odds ratio (OR)] exceeds 1 (null) or 1.2.Nominal statistical significance was maintained for 21 (21%) meta-analyses, for c = 10% and OR >1, and these proportions changed to 7%, 3%, and 6% with ceilings of 20%, 30%, and 40%, respectively. For ceilings for OR >1.2, the respective proportions were 37%, 21%, 7%, and 3%. Seven meta-analyses on infectious agents retained statistical significance even with a high ceiling of c = 20% for OR >1.00. Meta-analyses without other hints of bias (large between-study heterogeneity, small-study effects, excess significance) were more likely to retain statistical significance than those that had such hints of bias.Credibility ceilings may be helpful in meta-analyses of biomarkers to understand the robustness of the results to different levels of uncertainty.

    View details for DOI 10.1016/j.jclinepi.2014.09.004

    View details for Web of Science ID 000348974400007

    View details for PubMedID 25433443

  • Systematic assessment of the correlations of household income with infectious, biochemical, physiological, and environmental factors in the United States, 1999-2006. American journal of epidemiology Patel, C. J., Ioannidis, J. P., Cullen, M. R., Rehkopf, D. H. 2015; 181 (3): 171-179

    Abstract

    A fuller understanding of the social epidemiology of disease requires an extended description of the relationships between social factors and health indicators in a systematic manner. In the present study, we investigated the correlations between income and 330 indicators of physiological, biochemical, and environmental health in participants in the US National Health and Nutrition Examination Survey (NHANES) (1999-2006). We combined data from 3 survey waves (n = 249-23,649 for various indicators) to search for linear and nonlinear (quadratic) correlates of income, and we validated significant (P < 0.00015) correlations in an independent testing data set (n = 255-7,855). We validated 66 out of 330 factors, including infectious (e.g., hepatitis A), biochemical (e.g., carotenoids, high-density lipoprotein cholesterol), physiological (e.g., upper leg length), and environmental (e.g., lead, cotinine) measures. We found only a modest amount of association modification by age, race/ethnicity, and gender, and there was no association modification for blacks. The present study is descriptive, not causal. We have shown in our systematic investigation the crucial place income has in relation to health risk factors. Future research can use these correlations to better inform theory and studies of pathways to disease, as well as utilize these findings to understand when confounding by income is most likely to introduce bias.

    View details for DOI 10.1093/aje/kwu277

    View details for PubMedID 25589242

    View details for PubMedCentralID PMC4312426

  • Completeness of main outcomes across randomized trials in entire discipline: survey of chronic lung disease outcomes in preterm infants BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. P., Horbar, J. D., Ovelman, C. M., Brosseau, Y., Thorlund, K., Buus-Frank, M. E., Mills, E. J., Soll, R. F. 2015; 350

    Abstract

    To map the availability of information on a major clinical outcome--chronic lung disease--across the randomized controlled trials in systematic reviews of an entire specialty, specifically interventions in preterm infants.Survey of systematic reviews.Cochrane Database of Systematic Reviews.All Cochrane systematic reviews (as of November 2013) that had evaluated interventions in preterm infants. We identified how many of those systematic reviews had looked for information on chronic lung disease, how many reported on chronic lung disease, and how many of the randomized controlled trials included in the systematic reviews reported on chronic lung disease. We also randomly selected 10 systematic reviews that did not report on chronic lung disease and 10 that reported on any such outcomes and identified whether any information on chronic lung disease appeared in the primary reports of the randomized controlled trials but not in the systematic reviews.Whether availability of chronic lung disease outcomes differed by type of population and intervention and whether additional non-extracted data might have been available in trial reports.174 systematic reviews with 1041 trials exclusively concerned preterm infants. Of those, 105 reviews looked for chronic lung disease outcomes, and 79 reported on these outcomes. Of the 1041 included trials, 202 reported on chronic lung disease at 28 days and 200 at 36 weeks postmenstrual; 320 reported on chronic lung disease with any definition. The proportion of systematic reviews that looked for or reported on chronic lung disease and the proportion of trials that reported on chronic lung disease was larger in preterm infants with respiratory distress or support than others (P<0.001) and differed across interventions (P<0.001). Even for trials on children with ventilation interventions, only 56% (48/86) reported on chronic lung disease. In the random sample, 45 of 84 trials (54%) had no outcomes on chronic lung disease in the systematic reviews, and only 9/45 (20%) had such information in the primary trial reports.Most trials included in systematic reviews of interventions on preterm infants are missing information on one of the most common serious outcomes in this population. Use of standardized clinical outcomes that would have to be collected and reported by default in all trials in a given specialty should be considered.

    View details for DOI 10.1136/bmj.h72

    View details for Web of Science ID 000348775100017

    View details for PubMedID 25623087

  • Reanalyses of trial results--reply. JAMA Ebrahim, S., Ioannidis, J. P. 2015; 313 (1): 93-?

    View details for DOI 10.1001/jama.2014.15644

    View details for PubMedID 25562278

  • Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): Explanation and Elaboration ANNALS OF INTERNAL MEDICINE Moons, K. G., Altman, D. G., Reitsma, J. B., Ioannidis, J. P., Macaskill, P., Steyerberg, E. W., Vickers, A. J., Ransohoff, D. F., Collins, G. S. 2015; 162 (1): W1-W73

    Abstract

    The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) Statement includes a 22-item checklist, which aims to improve the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD Statement is explained in detail and accompanied by published examples of good reporting. The document also provides a valuable reference of issues to consider when designing, conducting, and analyzing prediction model studies. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, it is recommended that authors include a completed checklist in their submission. The TRIPOD checklist can also be downloaded from www.tripod-statement.org.

    View details for DOI 10.7326/M14-0698

    View details for Web of Science ID 000360564000001

  • Reproducibility in Science Improving the Standard for Basic and Preclinical Research CIRCULATION RESEARCH Begley, C. G., Ioannidis, J. P. 2015; 116 (1): 116-126

    Abstract

    Medical and scientific advances are predicated on new knowledge that is robust and reliable and that serves as a solid foundation on which further advances can be built. In biomedical research, we are in the midst of a revolution with the generation of new data and scientific publications at a previously unprecedented rate. However, unfortunately, there is compelling evidence that the majority of these discoveries will not stand the test of time. To a large extent, this reproducibility crisis in basic and preclinical research may be as a result of failure to adhere to good scientific practice and the desperation to publish or perish. This is a multifaceted, multistakeholder problem. No single party is solely responsible, and no single solution will suffice. Here we review the reproducibility problems in basic and preclinical biomedical research, highlight some of the complexities, and discuss potential solutions that may help improve research quality and reproducibility.

    View details for DOI 10.1161/CIRCRESAHA.114.303819

    View details for Web of Science ID 000347052800019

    View details for PubMedID 25552691

  • Modern health care as a game theory problem EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Djulbegovic, B., Hozo, I., Ioannidis, J. P. 2015; 45 (1): 1-12

    View details for DOI 10.1111/eci.12380

    View details for Web of Science ID 000347056700001

  • A generalized view of self-citation: Direct, co-author, collaborative, and coercive induced self-citation JOURNAL OF PSYCHOSOMATIC RESEARCH Ioannidis, J. A. 2015; 78 (1): 7–11

    Abstract

    The phenomenon of self-citation can present in many different forms, including direct, co-author, collaborative, and coercive induced self-citation. It can also pertain to the citation of single scientists, groups of scientists, journals, and institutions. This article presents some case studies of extreme self-citation practices. It also discusses the implications of different types of self-citation. Self-citation is not necessarily inappropriate by default. In fact, usually it is fully appropriate but often it is even necessary. Conversely, inappropriate self-citation practices may be highly misleading and may distort the scientific literature. Coercive induced self-citation is the most difficult to discover. Coercive Induced self-citation may happen directly from reviewers of articles, but also indirectly from reviewers of grants, scientific advisors who steer a research agenda, and leaders of funding agencies who may espouse spending disproportionately large funds in research domains that perpetuate their own self-legacy. Inappropriate self-citation can be only a surrogate marker of what might be much greater distortions of the scientific corpus towards conformity to specific opinions and biases. Inappropriate self-citations eventually affect also impact metrics. Different impact metrics vary in the extent to which they can be gamed through self-citation practices. Citation indices that are more gaming-proof are available and should be more widely used. We need more empirical studies to dissect the impact of different types of inappropriate self-citation and to examine the effectiveness of interventions to limit them.

    View details for DOI 10.1016/j.jpsychores.2014.11.008

    View details for Web of Science ID 000348247400002

    View details for PubMedID 25466321

  • Inferior vena cava filters and postoperative outcomes in patients undergoing bariatric surgery: a meta-analysis (vol 10, pg 725, 2014) SURGERY FOR OBESITY AND RELATED DISEASES Kaw, R., Pasupuleti, V., Overby, D., Deshpande, A., Coleman, C. I., Ioannidis, J. A., Hernandez, A. V., Cardiovasc Meta-analyses Res Grp 2015; 11 (1): 268–69

    View details for DOI 10.1016/j.soard.2014.10.002

    View details for Web of Science ID 000350534300045

  • HANDLING THE FRAGILE VASE OF SCIENTIFIC PRACTICES ADDICTION Ioannidis, J. A. 2015; 110 (1): 9–10

    View details for DOI 10.1111/add.12720

    View details for Web of Science ID 000346699700003

    View details for PubMedID 25515825

  • Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2015; 6: 231-?

    Abstract

    [This corrects the article on p. 254 in vol. 5, PMID: 25136350.].

    View details for DOI 10.3389/fgene.2015.00231

    View details for PubMedID 26217377

    View details for PubMedCentralID PMC4493401

  • Diagnostic accuracy of the Edinburgh Postnatal Depression Scale (EPDS) for detecting major depression in pregnant and postnatal women: protocol for a systematic review and individual patient data meta-analyses BMJ OPEN Thombs, B. D., Benedetti, A., Kloda, L. A., Levis, B., Riehm, K. E., Azar, M., Cuijpers, P., Gilbody, S., Ioannidis, J. P., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C., Tonelli, M., Mitchell, N., Comeau, L., Schinazi, J., Vigod, S. 2015; 5 (10)

    Abstract

    Studies of the diagnostic accuracy of depression screening tools often used data-driven methods to select optimal cut-offs. Typically, these studies report results from a small range of cut-off points around whatever cut-off score is identified as most accurate. When published data are combined in meta-analyses, estimates of accuracy for different cut-off points may be based on data from different studies, rather than data from all studies for each cut-off point. Thus, traditional meta-analyses may exaggerate accuracy estimates. Individual patient data (IPD) meta-analyses synthesise data from all studies for each cut-off score to obtain accuracy estimates. The 10-item Edinburgh Postnatal Depression Scale (EPDS) is commonly recommended for depression screening in the perinatal period. The primary objective of this IPD meta-analysis is to determine the diagnostic accuracy of the EPDS to detect major depression among women during pregnancy and in the postpartum period across all potentially relevant cut-off scores, accounting for patient factors that may influence accuracy (age, pregnancy vs postpartum).Data sources will include Medline, Medline In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. Studies that include a diagnosis of major depression based on a validated structured or semistructured clinical interview administered within 2 weeks of (before or after) the administration of the EPDS will be included. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values. Analyses will evaluate data from pregnancy and the postpartum period separately, as well as combining data from all women in a single model.This study does not require ethics approval. Dissemination will include journal articles and presentations to policymakers, healthcare providers and researchers.PROSPERO 2015:CRD42015024785.

    View details for DOI 10.1136/bmjopen-2015-009742

    View details for Web of Science ID 000365467600117

    View details for PubMedID 26486977

    View details for PubMedCentralID PMC4620163

  • Is widespread screening for hepatitis C justified? BMJ (Clinical research ed.) Koretz, R. L., Lin, K. W., Ioannidis, J. P., Lenzer, J. 2015; 350: g7809-?

    View details for DOI 10.1136/bmj.g7809

    View details for PubMedID 25587052

  • Making Optimal Use of and Extending beyond Polygenic Additive Liability Models HUMAN HEREDITY Ioannidis, J. A. 2015; 80 (4): 158–61

    View details for DOI 10.1159/000448200

    View details for Web of Science ID 000382711600002

    View details for PubMedID 27576754

  • Modern health care as a game theory problem. European journal of clinical investigation Djulbegovic, B., Hozo, I., Ioannidis, J. P. 2015; 45 (1): 1-12

    View details for DOI 10.1111/eci.12380

    View details for PubMedID 25413314

  • Authors' reply to editorial linked to their umbrella review of meta-analyses of observational studies on type 2 diabetes and cancer. BMJ (Clinical research ed.) Tsilidis, K. K., Ioannidis, J. P. 2015; 350: h711-?

    View details for DOI 10.1136/bmj.h711

    View details for PubMedID 25673332

  • Authors' reply to Foster and colleagues. BMJ (Clinical research ed.) Koretz, R. L., Lin, K. W., Ioannidis, J. P., Lenzer, J. 2015; 350: h1000-?

    View details for DOI 10.1136/bmj.h1000

    View details for PubMedID 25711887

  • How Good Is "Evidence" from Clinical Studies of Drug Effects and Why Might Such Evidence Fail in the Prediction of the Clinical Utility of Drugs? ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 Naci, H., Ioannidis, J. P. 2015; 55: 169-189

    Abstract

    Promising evidence from clinical studies of drug effects does not always translate to improvements in patient outcomes. In this review, we discuss why early evidence is often ill suited to the task of predicting the clinical utility of drugs. The current gap between initially described drug effects and their subsequent clinical utility results from deficits in the design, conduct, analysis, reporting, and synthesis of clinical studies-often creating conditions that generate favorable, but ultimately incorrect, conclusions regarding drug effects. There are potential solutions that could improve the relevance of clinical evidence in predicting the real-world effectiveness of drugs. What is needed is a new emphasis on clinical utility, with nonconflicted entities playing a greater role in the generation, synthesis, and interpretation of clinical evidence. Clinical studies should adopt strong design features, reflect clinical practice, and evaluate outcomes and comparisons that are meaningful to patients. Transformative changes to the research agenda may generate more meaningful and accurate evidence on drug effects to guide clinical decision making.

    View details for DOI 10.1146/annurev-pharmtox-010814-124614

    View details for Web of Science ID 000348560500011

    View details for PubMedID 25149917

  • External validation of new risk prediction models is infrequent and reveals worse prognostic discrimination JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, G. C., Tzoulaki, J., Castaldi, P. J., Ioannidis, J. P. 2015; 68 (1): 25-34

    Abstract

    To evaluate how often newly developed risk prediction models undergo external validation and how well they perform in such validations.We reviewed derivation studies of newly proposed risk models and their subsequent external validations. Study characteristics, outcome(s), and models' discriminatory performance [area under the curve, (AUC)] in derivation and validation studies were extracted. We estimated the probability of having a validation, change in discriminatory performance with more stringent external validation by overlapping or different authors compared to the derivation estimates.We evaluated 127 new prediction models. Of those, for 32 models (25%), at least an external validation study was identified; in 22 models (17%), the validation had been done by entirely different authors. The probability of having an external validation by different authors within 5 years was 16%. AUC estimates significantly decreased during external validation vs. the derivation study [median AUC change: -0.05 (P < 0.001) overall; -0.04 (P = 0.009) for validation by overlapping authors; -0.05 (P < 0.001) for validation by different authors]. On external validation, AUC decreased by at least 0.03 in 19 models and never increased by at least 0.03 (P < 0.001).External independent validation of predictive models in different studies is uncommon. Predictive performance may worsen substantially on external validation.

    View details for DOI 10.1016/j.jclinepi.2014.09.007

    View details for Web of Science ID 000346690800004

    View details for PubMedID 25441703

  • Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ (Clinical research ed.) Tsilidis, K. K., Kasimis, J. C., Lopez, D. S., Ntzani, E. E., Ioannidis, J. P. 2015; 350: g7607-?

    Abstract

    To summarise the evidence and evaluate the validity of the associations between type 2 diabetes and the risk of developing or dying from cancer.An umbrella review of the evidence across meta-analyses of observational studies of type 2 diabetes with risk of developing or dying from any cancer.PubMed, Embase, Cochrane database of systematic reviews, and manual screening of references.Meta-analyses or systematic reviews of observational studies in humans that examined the association between type 2 diabetes and risk of developing or dying from cancer.Eligible meta-analyses assessed associations between type 2 diabetes and risk of developing cancer in 20 sites and mortality for seven cancer sites. The summary random effects estimates were significant at P=0.05 in 20 meta-analyses (74%); and all reported increased risks of developing cancer for participants with versus without diabetes. Of the 27 meta-analyses, eventually only seven (26%) compiled evidence on more than 1000 cases, had significant summary associations at P ≤ 0.001 for both random and fixed effects calculations, and had neither evidence of small study effects nor evidence for excess significance. Of those, only six (22%) did not have substantial heterogeneity (I(2)>75%), pertaining to associations between type 2 diabetes and risk of developing breast, cholangiocarcinoma (both intrahepatic and extrahepatic), colorectal, endometrial, and gallbladder cancer. The 95% prediction intervals excluded the null value for four of these associations (breast, intrahepatic cholangiocarcinoma, colorectal, and endometrial cancer).Though type 2 diabetes has been extensively studied in relation to risk of developing cancer and cancer mortality and strong claims of significance exist for most of the studied associations, only a minority of these associations have robust supporting evidence without hints of bias.

    View details for DOI 10.1136/bmj.g7607

    View details for PubMedID 25555821

  • Authors' reply to Selvapatt and colleagues, Matthews and colleagues, Badrinath, and Ward and Lee. BMJ (Clinical research ed.) Koretz, R. L., Lin, K. W., Ioannidis, J. P., Lenzer, J. 2015; 350: h674-?

    View details for DOI 10.1136/bmj.h674

    View details for PubMedID 25711896

  • Clinical trials: what a waste BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. A. 2014; 349: g7089

    View details for DOI 10.1136/bmj.g7089

    View details for Web of Science ID 000346165000002

    View details for PubMedID 25499097

  • A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip ANNALS OF THE RHEUMATIC DISEASES Evangelou, E., Kerkhof, H. J., Styrkarsdottir, U., Ntzani, E. E., Bos, S. D., Esko, T., Evans, D. S., Metrustry, S., Panoutsopoulou, K., Ramos, Y. F., Thorleifsson, G., Tsilidis, K. K., Arden, N., Aslam, N., Bellamy, N., Birrell, F., Blanco, F. J., Carr, A., Chapman, K., Day-Williams, A. G., Deloukas, P., Doherty, M., Engstrom, G., Helgadottir, H. T., Hofman, A., Ingvarsson, T., Jonsson, H., Keis, A., Keurentjes, J. C., Kloppenburg, M., Lind, P. A., McCaskie, A., Martin, N. G., Milani, L., Montgomery, G. W., Nelissen, R. G., Nevitt, M. C., Nilsson, P. M., Ollier, W. E., Parimi, N., Rai, A., Ralston, S. H., Reed, M. R., Riancho, J. A., Rivadeneira, F., Rodriguez-Fontenla, C., Southam, L., Thorsteinsdottir, U., Tsezou, A., AWallis, G., Wilkinson, J. M., Gonzalez, A., Lane, N. E., Lohmander, L. S., Loughlin, J., Metspalu, A., Uitterlinden, A. G., Jonsdottir, I., Stefansson, K., Slagboom, P. E., Zeggini, E., Meulenbelt, I., Ioannidis, J. P., Spector, T. D., van Meurs, J. B., Valdes, A. M. 2014; 73 (12): 2130-2136

    Abstract

    Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

    View details for DOI 10.1136/annrheumdis-2012-203114

    View details for Web of Science ID 000344783900016

    View details for PubMedID 23989986

  • Big data meets public health SCIENCE Khoury, M. J., Ioannidis, J. A. 2014; 346 (6213): 1054–55

    View details for DOI 10.1126/science.aaa2709

    View details for Web of Science ID 000345763400019

    View details for PubMedID 25430753

    View details for PubMedCentralID PMC4684636

  • A Web-based database of genetic association studies in cutaneous melanoma enhanced with network-driven data exploration tools DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION Athanasiadis, E. I., Antonopoulou, K., Chatzinasiou, F., Lill, C. M., Bourdakou, M. M., Sakellariou, A., Kypreou, K., Stefanaki, I., Evangelou, E., Ioannidis, J. P., Bertram, L., Stratigos, A. J., Spyrou, G. M. 2014

    Abstract

    The publicly available online database MelGene provides a comprehensive, regularly updated, collection of data from genetic association studies in cutaneous melanoma (CM), including random-effects meta-analysis results of all eligible polymorphisms. The updated database version includes data from 192 publications with information on 1114 significantly associated polymorphisms across 280 genes, along with new front-end and back-end capabilities. Various types of relationships between data are calculated and visualized as networks. We constructed 13 different networks containing the polymorphisms and the genes included in MelGene. We explored the derived network representations under the following questions: (i) are there nodes that deserve consideration regarding their network connectivity characteristics? (ii) What is the relation of either the genome-wide or nominally significant CM polymorphisms/genes with the ones highlighted by the network representation? We show that our network approach using the MelGene data reveals connections between statistically significant genes/ polymorphisms and other genes/polymorphisms acting as 'hubs' in the reconstructed networks. To the best of our knowledge, this is the first database containing data from a comprehensive field synopsis and systematic meta-analyses of genetic polymorphisms in CM that provides user-friendly tools for in-depth molecular network visualization and exploration. The proposed network connections highlight potentially new loci requiring further investigation of their relation to melanoma risk. Database URL: http://www.melgene.org.

    View details for DOI 10.1093/database/bau101

    View details for Web of Science ID 000344943700001

    View details for PubMedID 25380778

    View details for PubMedCentralID PMC4224266

  • HELOW: A program for testing extreme homogeneity in meta-analysis COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE Zintzaras, E., Ioannidis, J. P. 2014; 117 (2): 383-386

    Abstract

    Meta-analysis aims to synthesize results from different studies. Although, in a meta-analysis the presence of large between-study heterogeneity is routinely evaluated, in some instances is also important to probe whether there is extreme between-study homogeneity (i.e. extreme low between-study heterogeneity). HELOW (HEterogeneity LOW) is a program for testing extreme homogeneity in a meta-analysis of risk ratios when binary outcome and Mantel-Haenszel fixed effects summary risk ratio estimate are employed. The significance of extreme homogeneity is assessed using a Monte Carlo test. Extreme homogeneity may yield insights for the statistical and clinical interpretation of the data.

    View details for DOI 10.1016/j.cmpb.2014.06.009

    View details for Web of Science ID 000343091400031

    View details for PubMedID 25023534

  • Placing epidemiological results in the context of multiplicity and typical correlations of exposures JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Patel, C. J., Ioannidis, J. P. 2014; 68 (11): 1096-1100

    Abstract

    Epidemiological studies evaluate multiple exposures, but the extent of multiplicity often remains non-transparent when results are reported. There is extensive debate in the literature on whether multiplicity should be adjusted for in the design, analysis, and reporting of most epidemiological studies, and, if so, how this should be done. The challenges become more acute in an era where the number of exposures that can be studied (the exposome) can be very large. Here, we argue that it can be very insightful to visualize and describe the extent of multiplicity by reporting the number of effective exposures for each category of exposures being assessed, and to describe the distribution of correlation between exposures and/or between exposures and outcomes in epidemiological datasets. The results of new proposed associations can be placed in the context of this background information. An association can be assigned to a percentile of magnitude of effect based on the distribution of effects seen in the field. We offer an example of how such information can be routinely presented in an epidemiological study/dataset using data on 530 exposure and demographic variables classified in 32 categories in the National Health and Nutrition Examination Survey (NHANES). Effects that survive multiplicity considerations and that are large may be prioritized for further scrutiny.

    View details for DOI 10.1136/jech-2014-204195

    View details for Web of Science ID 000343225800014

    View details for PubMedID 24923805

  • Bibliometrics: Is your most cited work your best? Nature Ioannidis, J. P., Boyack, K. W., Small, H., Sorensen, A. A., Klavans, R. 2014; 514 (7524): 561-562

    View details for DOI 10.1038/514561a

    View details for PubMedID 25355346

  • How to Make More Published Research True PLOS MEDICINE Ioannidis, J. A. 2014; 11 (10): e1001747

    Abstract

    In a 2005 paper that has been accessed more than a million times, John Ioannidis explained why most published research findings were false. Here he revisits the topic, this time to address how to improve matters. Please see later in the article for the Editors' Summary.

    View details for DOI 10.1371/journal.pmed.1001747

    View details for Web of Science ID 000344460900009

    View details for PubMedID 25334033

    View details for PubMedCentralID PMC4204808

  • Metformin and cancer risk: A cohort study in the UK Clinical Practice Research Datalink analyzed like a randomized trial Tsilidis, K. K., Capothanassi, D., Allen, N., Rizos, E., Lopez, D., van Veldhoven, K., Sacerdote, C., Ashby, D., Vineis, P., Tzoulaki, I., Ioannidis, J. AMER ASSOC CANCER RESEARCH. 2014

    View details for DOI 10.1158/1538-7445.AM2014-2161

    View details for Web of Science ID 000349906902373

  • A test for reporting bias in trial networks: simulation and case studies BMC MEDICAL RESEARCH METHODOLOGY Trinquart, L., Ioannidis, J. A., Chatellier, G., Ravaud, P. 2014; 14: 112

    Abstract

    Networks of trials assessing several treatment options available for the same condition are increasingly considered. Randomized trial evidence may be missing because of reporting bias. We propose a test for reporting bias in trial networks.We test whether there is an excess of trials with statistically significant results across a network of trials. The observed number of trials with nominally statistically significant p-values across the network is compared with the expected number. The performance of the test (type I error rate and power) was assessed using simulation studies under different scenarios of selective reporting bias. Examples are provided for networks of antidepressant and antipsychotic trials, where reporting biases have been previously demonstrated by comparing published to Food and Drug Administration (FDA) data.In simulations, the test maintained the type I error rate and was moderately powerful after adjustment for type I error rate, except when the between-trial variance was substantial. In all, a positive test result increased moderately or markedly the probability of reporting bias being present, while a negative test result was not very informative. In the two examples, the test gave a signal for an excess of statistically significant results in the network of published data but not in the network of FDA data.The test could be useful to document an excess of significant findings in trial networks, providing a signal for potential publication bias or other selective analysis and outcome reporting biases.

    View details for DOI 10.1186/1471-2288-14-112

    View details for Web of Science ID 000346746600001

    View details for PubMedID 25262204

    View details for PubMedCentralID PMC4193287

  • Editorial: Updated Guidance on Human Genome Epidemiology (HuGE) Reviews and Meta-Analyses of Genetic Associations AMERICAN JOURNAL OF EPIDEMIOLOGY Gwinn, M., Ioannidis, J. P., Little, J., Khoury, M. J. 2014; 180 (6): 559–61

    View details for DOI 10.1093/aje/kwu196

    View details for Web of Science ID 000343033400001

    View details for PubMedID 25164421

  • Reanalyses of randomized clinical trial data. JAMA Ebrahim, S., Sohani, Z. N., Montoya, L., Agarwal, A., Thorlund, K., Mills, E. J., Ioannidis, J. P. 2014; 312 (10): 1024-1032

    Abstract

    Reanalyses of randomized clinical trial (RCT) data may help the scientific community assess the validity of reported trial results.To identify published reanalyses of RCT data, to characterize methodological and other differences between the original trial and reanalysis, to evaluate the independence of authors performing the reanalyses, and to assess whether the reanalysis changed interpretations from the original article about the types or numbers of patients who should be treated.We completed an electronic search of MEDLINE from inception to March 9, 2014, to identify all published studies that completed a reanalysis of individual patient data from previously published RCTs addressing the same hypothesis as the original RCT. Four data extractors independently screened articles and extracted data.Changes in direction and magnitude of treatment effect, statistical significance, and interpretation about the types or numbers of patients who should be treated.We identified 37 eligible reanalyses in 36 published articles, 5 of which were performed by entirely independent authors (2 based on publicly available data and 2 on data that were provided on request; data availability was unclear for 1). Reanalyses differed most commonly in statistical or analytical approaches (n = 18) and in definitions or measurements of the outcome of interest (n = 12). Four reanalyses changed the direction and 2 changed the magnitude of treatment effect, whereas 4 led to changes in statistical significance of findings. Thirteen reanalyses (35%) led to interpretations different from that of the original article, 3 (8%) showing that different patients should be treated; 1 (3%), that fewer patients should be treated; and 9 (24%), that more patients should be treated.A small number of reanalyses of RCTs have been published to date. Only a few were conducted by entirely independent authors. Thirty-five percent of published reanalyses led to changes in findings that implied conclusions different from those of the original article about the types and number of patients who should be treated.

    View details for DOI 10.1001/jama.2014.9646

    View details for PubMedID 25203082

  • Metformin Does Not Affect Cancer Risk: A Cohort Study in the UK Clinical Practice Research Datalink Analyzed Like an Intention-to-Treat Trial DIABETES CARE Tsilidis, K. K., Capothanassi, D., Allen, N. E., Rizos, E. C., Lopez, D. S., van Veldhoven, K., Sacerdote, C., Ashby, D., Vineis, P., Tzoulaki, I., Ioannidis, J. P. 2014; 37 (9): 2522-2532

    Abstract

    Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis.RESEARCH DESIGN AND METHODS: A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first-incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI.RESULTS: A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first-incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89-1.04) and colorectal (HR 0.92; 95% CI 0.76-1.13), prostate (HR 1.02; 95% CI 0.83-1.25), lung (HR 0.85; 95% CI 0.68-1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82-1.31) cancer, or any other cancer.CONCLUSIONS: In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas.

    View details for DOI 10.2337/dc14-0584

    View details for Web of Science ID 000340846300026

    View details for PubMedID 24898303

  • Citation Classic: Modeling and Research on Research CLINICAL CHEMISTRY Ioannidis, J. A. 2014; 60 (9): 1238–39

    View details for DOI 10.1373/clinchem.2013.218453

    View details for Web of Science ID 000344779400019

    View details for PubMedID 25037936

  • Unscientific Beliefs about Scientific Topics in Nutrition ADVANCES IN NUTRITION Brown, A. W., Ioannidis, J. P., Cope, M. B., Bier, D. M., Allison, D. B. 2014; 5 (5): 563-565

    Abstract

    Humans interact with food daily. Such repeated exposure creates a widespread, superficial familiarity with nutrition. Personal familiarity with nutrition from individual and cultural perspectives may give rise to beliefs about food not grounded in scientific evidence. In this summary of the session entitled “Unscientific Beliefs about Scientific Topics in Nutrition,” we discuss accumulated work illustrating and quantifying potentially misleading practices in the conduct and, more so, reporting of nutrition science along with proposed approaches to amelioration. We begin by defining “unscientific beliefs” and from where such beliefs may come, followed by discussing how large bodies of nutritional epidemiologic observations not only create highly improbable patterns of association but implausible magnitudes of implied effect. Poor reporting practices, biases, and methodologic issues that have distorted scientific understandings of nutrition are presented, followed by potential influences of conflicts of interest that extend beyond financial considerations. We conclude with recommendations for improving the conduct, reporting, and communication of nutrition-related research to ground discussions in evidence rather than solely on beliefs.

    View details for DOI 10.3945/an.114006577

    View details for Web of Science ID 000342972200016

    View details for PubMedID 25469397

    View details for PubMedCentralID PMC4188234

  • Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease NATURE GENETICS Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B., Hernandez, D. G., Saad, M., DeStefano, A. L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M. F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J. H., Cheng, R., Ikram, M. A., Ioannidis, J. P., Hadjigeorgiou, G. M., Bis, J. C., Martinez, M., Perlmutter, J. S., Goate, A., Marder, K., Fiske, B., Sutherland, M., Xiromerisiou, G., Myers, R. H., Clark, L. N., Stefansson, K., Hardy, J. A., Heutink, P., Chen, H., Wood, N. W., Houlden, H., Payami, H., Brice, A., Scott, W. K., Gasser, T., Bertram, L., Eriksson, N., Foroud, T., Singleton, A. B. 2014; 46 (9): 989-?

    Abstract

    We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

    View details for DOI 10.1038/ng.3043

    View details for Web of Science ID 000341579400013

    View details for PubMedID 25064009

  • Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance JOURNAL OF MEDICAL GENETICS Ramos, Y. F., Metrustry, S., Arden, N., Bay-Jensen, A. C., Beekman, M., de Craen, A. J., Cupples, L. A., Esko, T., Evangelou, E., Felson, D. T., Hart, D. J., Ioannidis, J. P., Karsdal, M., Kloppenburg, M., Lafeber, F., Metspalu, A., Panoutsopoulou, K., Slagboom, P. E., Spector, T. D., van Spil, E. W., Uitterlinden, A. G., Zhu, Y., Valdes, A. M., van Meurs, J. B., Meulenbelt, I. 2014; 51 (9): 596-604

    Abstract

    Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II).Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage.Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage.We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.

    View details for DOI 10.1136/jmedgenet-2014-102478

    View details for Web of Science ID 000340242400006

    View details for PubMedID 25057126

  • Changes of serum adhesion molecules and cytokines in post-ERCP pancreatitis Adhesion molecules and cytokines in acute pancreatitis CLINICAL BIOCHEMISTRY Sigounas, D. E., Christodoulou, D. K., Karamoutsios, A., Tatsioni, A., Dova, L., Vartholomatos, G., Kolaitis, N., Katsanos, K. H., Zervou, E., Ioannidis, J. P., Tsianos, E. V. 2014; 47 (13-14): 1245-1249

    Abstract

    To assess the early changes of soluble IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-α, TNF-β, IL-17A, IL-22, soluble (s) P-Selectin, sE-Selectin and sICAM-1 in post-ERCP pancreatitis (PEP).Single center, prospective study of 318 ERCP procedures. Serum samples were acquired from all patients prior to ERCP, 6hours and 24hours after the procedure. For every PEP case, another patient was chosen as a control, matched for gender, age and time period in which ERCP took place.Totally, 28 cases and 28 controls were studied. Except for significantly higher IL-1b levels in cases at baseline, no significant differences were observed between cases and controls after Bonferroni corrections. An increase in IL-6 was noted between baseline and 6h in cases alone (p=0.016). There was a significant fall in sP-selectin levels at 6 and 24hours compared to baseline in all patients (corrected p=0.008 and 0.016 for cases and 0.016 and 0.048 for controls respectively). An increase of sE-selectin in cases was observed between 6 and 24hours post-ERCP (corrected p=0.03).Soluble forms of cytokines and adhesion molecules studied seem not to play a major role in PEP.

    View details for DOI 10.1016/j.clinbiochem.2014.05.007

    View details for Web of Science ID 000341329000014

    View details for PubMedID 24845714

  • Assessing Value in Biomedical Research The PQRST of Appraisal and Reward JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A., Khoury, M. J. 2014; 312 (5): 483–84

    View details for DOI 10.1001/jama.2014.6932

    View details for Web of Science ID 000339808600013

    View details for PubMedID 24911291

    View details for PubMedCentralID PMC4687964

  • Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example FRONTIERS IN GENETICS Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5

    Abstract

    Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

    View details for DOI 10.3389/fgene.2014.00254

    View details for Web of Science ID 000347445200001

  • Design and Analysis of Metabolomics Studies in Epidemiologic Research: A Primer on -Omic Technologies AMERICAN JOURNAL OF EPIDEMIOLOGY Tzoulaki, I., Ebbels, T. M., Valdes, A., Elliott, P., Ioannidis, J. P. 2014; 180 (2): 129-139

    Abstract

    Metabolomics is the field of "-omics" research concerned with the comprehensive characterization of the small low-molecular-weight metabolites in biological samples. In epidemiology, it represents an emerging technology and an unprecedented opportunity to measure environmental and other exposures with improved precision and far less measurement error than with standard epidemiologic methods. Advances in the application of metabolomics in large-scale epidemiologic research are now being realized through a combination of improved sample preparation and handling, automated laboratory and processing methods, and reduction in costs. The number of epidemiologic studies that use metabolic profiling is still limited, but it is fast gaining popularity in this area. In the present article, we present a roadmap for metabolomic analyses in epidemiologic studies and discuss the various challenges these data pose to large-scale studies. We discuss the steps of data preprocessing, univariate and multivariate data analysis, correction for multiplicity of comparisons with correlated data, and finally the steps of cross-validation and external validation. As data from metabolomic studies accumulate in epidemiology, there is a need for large-scale replication and synthesis of findings, increased availability of raw data, and a focus on good study design, all of which will highlight the potential clinical impact of metabolomics in this field.

    View details for DOI 10.1093/aje/kwu143

    View details for Web of Science ID 000339808700002

    View details for PubMedID 24966222

  • Design and Analysis for Studying microRNAs in Human Disease: A Primer on -Omic Technologies AMERICAN JOURNAL OF EPIDEMIOLOGY Nair, V. S., Pritchard, C. C., Tewari, M., Ioannidis, J. P. 2014; 180 (2): 140-152

    Abstract

    microRNAs (miRNAs) are fundamental to cellular biology. Although only approximately 22 bases long, miRNAs regulate complex processes in health and disease, including human cancer. Because miRNAs are highly stable in circulation when compared with several other classes of nucleic acids, they have generated intense interest as clinical biomarkers in diverse epidemiologic studies. As with other molecular biomarker fields, however, miRNA research has become beleaguered by pitfalls related to terminology and classification; procedural, assay, and study cohort heterogeneity; and methodological inconsistencies. Together, these issues have led to both false-positive and potentially false-negative miRNA associations. In this review, we summarize the biological rationale for studying miRNAs in human disease with a specific focus on circulating miRNAs, which highlight some of the most challenging topics in the field to date. Examples from lung cancer are used to illustrate the potential utility and some of the pitfalls in contemporary miRNA research. Although the field is in its infancy, several important lessons have been learned relating to cohort development, sample preparation, and statistical analysis that should be considered for future studies. The goal of this primer is to equip epidemiologists and clinical researchers with sound principles of study design and analysis when using miRNAs.

    View details for DOI 10.1093/aje/kwu135

    View details for Web of Science ID 000339808700003

    View details for PubMedID 24966218

    View details for PubMedCentralID PMC4082346

  • Engaging Patients and Stakeholders in Research Proposal Review: The Patient-Centered Outcomes Research Institute ANNALS OF INTERNAL MEDICINE Fleurence, R. L., Forsythe, L. P., Lauer, M., Rotter, J., Ioannidis, J. P., Beal, A., Frank, L., Selby, J. V. 2014; 161 (2): 122-?

    Abstract

    The inaugural round of merit review for the Patient-Centered Outcomes Research Institute (PCORI) in November 2012 included patients and other stakeholders, as well as scientists. This article examines relationships among scores of the 3 reviewer types, changes in scoring after in-person discussion, and the effect of inclusion of patient and stakeholder reviewers on the review process. In the first phase, 363 scientists scored 480 applications. In the second phase, 59 scientists, 21 patients, and 31 stakeholders provided a "prediscussion" score and a final "postdiscussion" score after an in-person meeting for applications. Bland-Altman plots were used to characterize levels of agreement among and within reviewer types before and after discussion. Before discussion, there was little agreement among average scores given by the 4 lead scientific reviewers and patient and stakeholder reviewers. After discussion, the 4 primary reviewers showed mild convergence in their scores, and the 21-member panel came to a much stronger agreement. Of the 25 awards with the best (and lowest) scores after phase 2, only 13 had ranked in the top 25 after the phase 1 review by scientists. Five percent of the 480 proposals submitted were funded. The authors conclude that patient and stakeholder reviewers brought different perspectives to the review process but that in-person discussion led to closer agreement among reviewer types. It is not yet known whether these conclusions are generalizable to future rounds of peer review. Future work would benefit from additional data collection for evaluation purposes and from long-term evaluation of the effect on the funded research.

    View details for DOI 10.7326/M13-2412

    View details for Web of Science ID 000339764600021

    View details for PubMedID 25023251

  • How to Read a Systematic Review and Meta-analysis and Apply the Results to Patient Care Users' Guides to the Medical Literature JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Murad, M. H., Montori, V. M., Ioannidis, J. P., Jaeschke, R., Devereaux, P. J., Prasad, K., Neumann, I., Carrasco-Labra, A., Agoritsas, T., Hatala, R., Meade, M. O., Wyer, P., Cook, D. J., Guyatt, G. 2014; 312 (2): 171-179

    Abstract

    Clinical decisions should be based on the totality of the best evidence and not the results of individual studies. When clinicians apply the results of a systematic review or meta-analysis to patient care, they should start by evaluating the credibility of the methods of the systematic review, ie, the extent to which these methods have likely protected against misleading results. Credibility depends on whether the review addressed a sensible clinical question; included an exhaustive literature search; demonstrated reproducibility of the selection and assessment of studies; and presented results in a useful manner. For reviews that are sufficiently credible, clinicians must decide on the degree of confidence in the estimates that the evidence warrants (quality of evidence). Confidence depends on the risk of bias in the body of evidence; the precision and consistency of the results; whether the results directly apply to the patient of interest; and the likelihood of reporting bias. Shared decision making requires understanding of the estimates of magnitude of beneficial and harmful effects, and confidence in those estimates.

    View details for DOI 10.1001/jama.2014.5559

    View details for Web of Science ID 000338511200023

    View details for PubMedID 25005654

  • Evidence of reporting biases in voxel-based morphometry (VBM) studies of psychiatric and neurological disorders. Human brain mapping Fusar-Poli, P., Radua, J., Frascarelli, M., Mechelli, A., Borgwardt, S., Di Fabio, F., Biondi, M., Ioannidis, J. P., David, S. P. 2014; 35 (7): 3052-3065

    Abstract

    To evaluate whether biases may influence the findings of whole-brain structural imaging literature.Forty-seven whole-brain voxel-based meta-analyses including voxel-based morphometry (VBM) studies in neuropsychiatric conditions were included, for a total of 324 individual VBM studies. The total sample size, the overall number of foci, and different moderators were extracted both at the level of the individual studies and at the level of the meta-analyses.Sample size ranged from 12 to 545 (median n = 47) per VBM study. The median number of reported foci per study was six. VBM studies with larger sample sizes reported only slightly more abnormalities than smaller studies (2% increase in the number of foci per 10-patients increase in sample size). A similar pattern was seen in several analyses according to different moderator variables with some possible modulating evidence for the statistical threshold employed, publication year and number of coauthors. Whole-brain meta-analyses (median sample size n = 534) found fewer foci (median = 3) than single studies and overall they showed no significant increase in the number of foci with increasing sample size. Meta-analyses with ≥10 VBM studies reported a median of three foci and showed a significant increase with increasing sample size, while there was no relationship between sample size and number of foci (median = 5) in meta-analyses with <10 VBM studies.The number of foci reported in small VBM studies and even in meta-analyses with few studies may often be inflated. This picture is consistent with reporting biases affecting small studies. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.22384

    View details for PubMedID 24123491

  • Inferior vena cava filters and postoperative outcomes in patients undergoing bariatric surgery: a meta-analysis SURGERY FOR OBESITY AND RELATED DISEASES Kaw, R., Pasupuleti, V., Overby, D. W., Deshpande, A., Coleman, C. I., Ioannidis, J. P., Hernandez, A. V. 2014; 10 (4): 725-733

    View details for DOI 10.1016/j.soard.2014.04.008

    View details for Web of Science ID 000342329800036

    View details for PubMedID 25224168

  • Diagnostic tests often fail to lead to changes in patient outcomes. Journal of clinical epidemiology Siontis, K. C., Siontis, G. C., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2014; 67 (6): 612-621

    Abstract

    To evaluate the effects of diagnostic testing on patient outcomes in a large sample of diagnostic randomized controlled trials (D-RCTs) and to examine whether the effects for patient outcomes correlate with the effects on management and with diagnostic accuracy.We considered D-RCTs that evaluated diagnostic interventions for any condition and reported effectiveness data on one or more patient outcomes. We calculated odds ratios for patient outcomes and outcomes pertaining to the use of further diagnostic and therapeutic interventions and the diagnostic odds ratio (DOR) for the accuracy of experimental tests.One hundred forty trials (153 comparisons) were eligible. Patient outcomes were significantly improved in 28 comparisons (18%). There was no concordance in significance and direction of effects between the patient outcome and outcomes for use of further diagnostic or therapeutic interventions (weighted κ 0.02 and 0.09, respectively). The effect size for the patient outcome did not correlate with the effect sizes for use of further diagnostic (r = 0.05; P = 0.78) or therapeutic interventions (r = 0.18; P = 0.08) or the experimental intervention DOR in the same trial (r = -0.24; P = 0.51).Few tests have well-documented benefits on patient outcomes. Diagnostic performance or the effects on management decisions are not necessarily indicative of patient benefits.

    View details for DOI 10.1016/j.jclinepi.2013.12.008

    View details for PubMedID 24679598

  • Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses INTENSIVE CARE MEDICINE Tonelli, A. R., Zein, J., Adams, J., Ioannidis, J. P. 2014; 40 (6): 769-787

    Abstract

    Multiple interventions have been tested in acute respiratory distress syndrome (ARDS). We examined the entire agenda of published randomized controlled trials (RCTs) in ARDS that reported on mortality and of respective meta-analyses.We searched PubMed, the Cochrane Library, and Web of Knowledge until July 2013. We included RCTs in ARDS published in English. We excluded trials of newborns and children; and those on short-term interventions, ARDS prevention, or post-traumatic lung injury. We also reviewed all meta-analyses of RCTs in this field that addressed mortality. Treatment modalities were grouped in five categories: mechanical ventilation strategies and respiratory care, enteral or parenteral therapies, inhaled/intratracheal medications, nutritional support, and hemodynamic monitoring.We identified 159 published RCTs of which 93 had overall mortality reported (n = 20,671 patients)-44 trials (14,426 patients) reported mortality as a primary outcome. A statistically significant survival benefit was observed in eight trials (seven interventions) and two trials reported an adverse effect on survival. Among RCTs with more than 50 deaths in at least one treatment arm (n = 21), two showed a statistically significant mortality benefit of the intervention (lower tidal volumes and prone positioning), one showed a statistically significant mortality benefit only in adjusted analyses (cisatracurium), and one (high-frequency oscillatory ventilation) showed a significant detrimental effect. Across 29 meta-analyses, the most consistent evidence was seen for low tidal volumes and prone positioning in severe ARDS.There is limited supportive evidence that specific interventions can decrease mortality in ARDS. While low tidal volumes and prone positioning in severe ARDS seem effective, most sporadic findings of interventions suggesting reduced mortality are not corroborated consistently in large-scale evidence including meta-analyses.

    View details for DOI 10.1007/s00134-014-3272-1

    View details for Web of Science ID 000336281100001

    View details for PubMedID 24667919

    View details for PubMedCentralID PMC4031289

  • Diagnostic tests often fail to lead to changes in patient outcomes JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, K. C., Siontis, G. C., Contopoutos-Ioannidis, D. G., Ioannidis, J. P. 2014; 67 (6): 612-621

    Abstract

    To evaluate the effects of diagnostic testing on patient outcomes in a large sample of diagnostic randomized controlled trials (D-RCTs) and to examine whether the effects for patient outcomes correlate with the effects on management and with diagnostic accuracy.We considered D-RCTs that evaluated diagnostic interventions for any condition and reported effectiveness data on one or more patient outcomes. We calculated odds ratios for patient outcomes and outcomes pertaining to the use of further diagnostic and therapeutic interventions and the diagnostic odds ratio (DOR) for the accuracy of experimental tests.One hundred forty trials (153 comparisons) were eligible. Patient outcomes were significantly improved in 28 comparisons (18%). There was no concordance in significance and direction of effects between the patient outcome and outcomes for use of further diagnostic or therapeutic interventions (weighted κ 0.02 and 0.09, respectively). The effect size for the patient outcome did not correlate with the effect sizes for use of further diagnostic (r = 0.05; P = 0.78) or therapeutic interventions (r = 0.18; P = 0.08) or the experimental intervention DOR in the same trial (r = -0.24; P = 0.51).Few tests have well-documented benefits on patient outcomes. Diagnostic performance or the effects on management decisions are not necessarily indicative of patient benefits.

    View details for DOI 10.1016/j.jclinepi.2013.12.008

    View details for Web of Science ID 000335610000003

  • Study design and the drug development process--reply. JAMA Ioannidis, J. P., Hozo, I., Djulbegovic, B. 2014; 311 (19): 2023-2024

    View details for DOI 10.1001/jama.2014.3829

    View details for PubMedID 24846045

  • Prevention and control of neglected tropical diseases: overview of randomized trials, systematic reviews and meta-analyses. Bulletin of the World Health Organization Kappagoda, S., Ioannidis, J. P. 2014; 92 (5): 356-366C

    Abstract

    To analyse evidence from randomized controlled trials (RCTs) on the prevention and control of neglected tropical diseases (NTDs) and to identify areas where evidence is lacking.The Cochrane Central Register of Controlled Trials and PubMed were searched for RCTs and the Cochrane Database of Systematic Reviews and PubMed were searched for meta-analyses and systematic reviews, both from inception to 31 December 2012.Overall, 258 RCTs were found on American trypanosomiasis, Buruli ulcer, dengue, geohelminth infection, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis or trachoma. No RCTs were found on cysticercosis, dracunculiasis, echinococcosis, foodborne trematodes, or human African trypanosomiasis. The most studied diseases were geohelminth infection (51 RCTs) and leishmaniasis (46 RCTs). Vaccines, chemoprophylaxis and interventions targeting insect vectors were evaluated in 113, 99 and 39 RCTs, respectively. Few addressed how best to deliver preventive chemotherapy, such as the choice of dosing interval (10) or target population (4), the population coverage needed to reduce transmission (2) or the method of drug distribution (1). Thirty-one publications containing 32 systematic reviews (16 with and 16 without meta-analyses) were found on American trypanosomiasis, dengue, geohelminths, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis or trachoma. Together, they included only 79 of the 258 published RCTs (30.6%). Of 36 interventions assessed, 8 were judged effective in more than one review.Few RCTs on the prevention or control of the principal NTDs were found. Trials on how best to deliver preventive chemotherapy were particularly rare.

    View details for DOI 10.2471/BLT.13.129601

    View details for PubMedID 24839325

  • Mapping the expanded often inappropriate use of the Framingham Risk Score in the medical literature. Journal of clinical epidemiology Tzoulaki, I., Seretis, A., Ntzani, E. E., Ioannidis, J. P. 2014; 67 (5): 571-577

    Abstract

    To systematically evaluate the use of Framingham Risk Score (FRS) in the medical literature and specifically examine the use of FRS in different populations and settings and for different outcomes than the ones originally developed for.We identified all the citations to the article by Wilson et al. (1998), in which FRS was originally described through ISI Web of Science until April 2011. We selected studies that stated in their abstract that they calculated or used the FRS for any reason and extracted information on publication date, population studied, outcome, or disease risk factor with which FRS was associated and study design.We identified 375 eligible articles corresponding to 471 analyses using the FRS in cohort (n = 141), case-control (n = 16), or cross-sectional (n = 314) settings. Only a minority of the cohort studies had as a primary aim to externally validate the FRS (n = 45). The studied population was different (from general or healthy) in 35 (25%) and 133 (42%) of the cohort and cross-sectional analyses, respectively. All case-control studies examined healthy controls. The studied outcome was different (from coronary heart disease) in 79 (56%) of the cohort analyses and 10 (63%) of the case-control studies. Overall, only 46 (33%) of the 141 cohort analyses examined the same outcome and population as FRS was originally developed for.A large number of studies use FRS in populations and for outcomes other than the ones it has been developed for and therefore for which its performance is unknown and nonvalidated.

    View details for DOI 10.1016/j.jclinepi.2013.10.021

    View details for PubMedID 24513280

  • Publication and other reporting biases in cognitive sciences: detection, prevalence, and prevention TRENDS IN COGNITIVE SCIENCES Ioannidis, J. P., Munafo, M. R., Fusar-Poli, P., Nosek, B. A., David, S. P. 2014; 18 (5): 235-241

    Abstract

    Recent systematic reviews and empirical evaluations of the cognitive sciences literature suggest that publication and other reporting biases are prevalent across diverse domains of cognitive science. In this review, we summarize the various forms of publication and reporting biases and other questionable research practices, and overview the available methods for probing into their existence. We discuss the available empirical evidence for the presence of such biases across the neuroimaging, animal, other preclinical, psychological, clinical trials, and genetics literature in the cognitive sciences. We also highlight emerging solutions (from study design to data analyses and reporting) to prevent bias and improve the fidelity in the field of cognitive science research.

    View details for DOI 10.1016/j.tics.2014.02.010

    View details for Web of Science ID 000336113400007

    View details for PubMedID 24656991

  • Scientific reporting is suboptimal for aspects that characterize genetic risk prediction studies: a review of published articles based on the Genetic RIsk Prediction Studies statement JOURNAL OF CLINICAL EPIDEMIOLOGY Iglesias, A. I., Mihaescu, R., Ioannidis, J. P., Khoury, M. J., Little, J., van Duijn, C. M., Janssens, A. C. 2014; 67 (5): 487-499

    Abstract

    Our main objective was to raise awareness of the areas that need improvements in the reporting of genetic risk prediction articles for future publications, based on the Genetic RIsk Prediction Studies (GRIPS) statement.We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted.Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as genetic risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the risk model.Completeness of reporting in genetic risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize genetic risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of genetic risk prediction models.

    View details for DOI 10.1016/j.jclinepi.2013.10.006

    View details for Web of Science ID 000334974900002

    View details for PubMedID 24411311

  • Prevention and control of neglected tropical diseases; overview of randomized trials, systematic reviews and meta-analyses BULLETIN OF THE WORLD HEALTH ORGANIZATION Kappagoda, S., Ioannidis, J. P. 2014; 92 (5): 356-366

    Abstract

    To analyse evidence from randomized controlled trials (RCTs) on the prevention and control of neglected tropical diseases (NTDs) and to identify areas where evidence is lacking.The Cochrane Central Register of Controlled Trials and PubMed were searched for RCTs and the Cochrane Database of Systematic Reviews and PubMed were searched for meta-analyses and systematic reviews, both from inception to 31 December 2012.Overall, 258 RCTs were found on American trypanosomiasis, Buruli ulcer, dengue, geohelminth infection, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis or trachoma. No RCTs were found on cysticercosis, dracunculiasis, echinococcosis, foodborne trematodes, or human African trypanosomiasis. The most studied diseases were geohelminth infection (51 RCTs) and leishmaniasis (46 RCTs). Vaccines, chemoprophylaxis and interventions targeting insect vectors were evaluated in 113, 99 and 39 RCTs, respectively. Few addressed how best to deliver preventive chemotherapy, such as the choice of dosing interval (10) or target population (4), the population coverage needed to reduce transmission (2) or the method of drug distribution (1). Thirty-one publications containing 32 systematic reviews (16 with and 16 without meta-analyses) were found on American trypanosomiasis, dengue, geohelminths, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis or trachoma. Together, they included only 79 of the 258 published RCTs (30.6%). Of 36 interventions assessed, 8 were judged effective in more than one review.Few RCTs on the prevention or control of the principal NTDs were found. Trials on how best to deliver preventive chemotherapy were particularly rare.

    View details for DOI 10.2471/BLT.13.129601

    View details for Web of Science ID 000336478400015

    View details for PubMedCentralID PMC4007126

  • Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. Human molecular genetics Gordon, A. S., Tabor, H. K., Johnson, A. D., Snively, B. M., Assimes, T. L., Auer, P. L., Ioannidis, J. P., Peters, U., Robinson, J. G., Sucheston, L. E., Wang, D., Sotoodehnia, N., Rotter, J. I., Psaty, B. M., Jackson, R. D., Herrington, D. M., O'Donnell, C. J., Reiner, A. P., Rich, S. S., Rieder, M. J., Bamshad, M. J., Nickerson, D. A. 2014; 23 (8): 1957-1963

    Abstract

    The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

    View details for DOI 10.1093/hmg/ddt588

    View details for PubMedID 24282029

  • Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset HUMAN MOLECULAR GENETICS Gordon, A. S., Tabor, H. K., Johnson, A. D., Snively, B. M., Assimes, T. L., Auer, P. L., Ioannidis, J. P., Peters, U., Robinson, J. G., Sucheston, L. E., Wang, D., Sotoodehnia, N., Rotter, J. I., Psaty, B. M., Jackson, R. D., Herrington, D. M., ODonnell, C. J., Reiner, A. P., Rich, S. S., Rieder, M. J., Bamshad, M. J., Nickerson, D. A. 2014; 23 (8): 1957-1963

    Abstract

    The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

    View details for DOI 10.1093/hmg/ddt588

    View details for Web of Science ID 000333269400001

  • Network geometry shows evidence sequestration for medical vs. surgical practices: treatments for basal cell carcinoma. Journal of clinical epidemiology Kim, D. D., Tang, J. Y., Ioannidis, J. P. 2014; 67 (4): 391-400

    Abstract

    Basal cell carcinoma (BCC) is the most common cancer with 2 million treatments per year with little evidence-based guidelines for treatment. There are three classes of interventions (surgical, destructive, and topical) for BCC, and this study aimed to determine whether there are preferences or avoidances in comparisons of different types of treatments for BCC in randomized controlled trials (RCTs).PubMed, Cochrane Central Registry of Clinical Trials, and ClinicalTrials.Gov were used to identify eligible published and registered ongoing RCTs.Fifty-five trials (42 published and 13 registered trials) were identified. Only one unpublished registered trial compared a topical vs. a surgical intervention, and only one trial compared a topical vs. a destructive intervention. Conversely, 44 of the 55 trials compared interventions within the same treatment class and 9 of 55 trials compared surgical vs. destructive interventions. In most trials, selection of same-class comparators was not necessitated by the type of BCC lesions (nonaggressive superficial or nodular vs. aggressive, infiltrative, morpheic BCCs, P = 0.155) or their location (face vs. nonfacial, P = 0.137).This is the first time that an evaluation of network geometry is applied to address issues of comparisons between different families of interventions that belong to different specialties and practices (medical vs. surgical). Previous evaluations of homophily have addressed different families of interventions, in which all interventions are medical (drugs) and performed in the same health-care settings. The noncommunicating bodies of evidence between medical and surgical interventions that we document highlight a problem of unnecessary sequestration of the evidence and the corresponding health-care practices.

    View details for DOI 10.1016/j.jclinepi.2013.10.015

    View details for PubMedID 24491794

  • Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis & rheumatology (Hoboken, N.J.) Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garcés Aletá, C. M., Gomez-Reino Carnota, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2014; 66 (4): 940-949

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24757145

  • Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis & rheumatology Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garcés Aletá, C. M., Gomez-Reino Carnota, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2014; 66 (4): 940-949

    Abstract

    To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24757145

  • Research: increasing value, reducing waste - Authors' reply. Lancet Glasziou, P., Macleod, M., Chalmers, I., Ioannidis, J. P., Al-Shahi Salman, R., Chan, A. 2014; 383 (9923): 1126-1127

    View details for DOI 10.1016/S0140-6736(14)60563-8

    View details for PubMedID 24679627

  • Clinical interpretation and implications of whole-genome sequencing. JAMA Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

    Abstract

    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

    View details for PubMedCentralID PMC4119063

  • Clinical interpretation and implications of whole-genome sequencing. JAMA : the journal of the American Medical Association Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

    Abstract

    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

    View details for PubMedCentralID PMC4119063

  • Safety of medical interventions in children versus adults. Pediatrics Lathyris, D., Panagiotou, O. A., Baltogianni, M., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2014; 133 (3): e666-73

    Abstract

    Compare the risk of harm from pharmacologic interventions in pediatric versus adult randomized controlled trials (RCTs).We used systematic reviews from the Cochrane Database of Systematic Reviews. We considered separately 7 categories of harms/harm-related end points: severe harms, withdrawals due to harms, any harm, organ system-level harms, specific harms, withdrawals for any reason, and mortality. Systematic reviews with quantitative synthesis from at least 1 adult and 1 pediatric RCT for any of those end points were eligible. We calculated the summary odds ratio (experimental versus control intervention) in adult and pediatric trials/meta-analysis; the relative odds ratio (ROR) in adults versus children per meta-analysis; and the summary ROR (sROR) across all meta-analyses for each end point. ROR <1 means that the experimental intervention fared worse in children than adults.We identified 176 meta-analyses for 52 types of harms/harm-related end points with 669 adult and 184 pediatric RCTs. Of those, 165 had sufficient data for ROR estimation. sRORs showed statistically significant discrepancy between adults and children only for headache (sROR 0.82; 95% confidence interval 0.70-0.96). Nominally significant discrepancies for specific harms were identified in 12 of 165 meta-analyses (RORs <1 in 7, ROR >1 in 5). In 36% of meta-analyses, the ROR estimates suggested twofold or greater differences between children and adults, and the 95% confidence intervals could exclude twofold differences only in 18% of meta-analyses.Available evidence on harms/harm-related end points from pharmacologic interventions has large uncertainty. Extrapolation of evidence from adults to children may be tenuous. Some clinically important discrepancies were identified.

    View details for DOI 10.1542/peds.2013-3128

    View details for PubMedID 24567023

  • Safety of medical interventions in children versus adults. Pediatrics Lathyris, D., Panagiotou, O. A., Baltogianni, M., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2014; 133 (3): e666-73

    View details for DOI 10.1542/peds.2013-3128

    View details for PubMedID 24567023

  • Making Prospective Registration of Observational Research a Reality SCIENCE TRANSLATIONAL MEDICINE Dal-Re, R., Ioannidis, J. P., Bracken, M. B., Buffler, P. A., Chan, A., Franco, E. L., La Vecchia, C., Weiderpass, E. 2014; 6 (224)

    Abstract

    The vast majority of health-related observational studies are not prospectively registered and the advantages of registration have not been fully appreciated. Nonetheless, international standards require approval of study protocols by an independent ethics committee before the study can begin. We suggest that there is an ethical and scientific imperative to publicly preregister key information from newly approved protocols, which should be required by funders. Ultimately, more complete information may be publicly available by disclosing protocols, analysis plans, data sets, and raw data.

    View details for DOI 10.1126/scitranslmed.3007513

    View details for Web of Science ID 000331476700002

    View details for PubMedID 24553383

  • Reply to Nuijten et al.: Reanalyses actually confirm that US studies overestimate effects in softer research PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Ioannidis, J. P. 2014; 111 (7): E714-E715

    View details for DOI 10.1073/pnas.1322565111

    View details for Web of Science ID 000331396500002

    View details for PubMedID 24693543

    View details for PubMedCentralID PMC3932901

  • Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol. American journal of human genetics Lange, L. A., Hu, Y., Zhang, H., Xue, C., Schmidt, E. M., Tang, Z., Bizon, C., Lange, E. M., Smith, J. D., Turner, E. H., Jun, G., Kang, H. M., Peloso, G., Auer, P., Li, K., Flannick, J., Zhang, J., Fuchsberger, C., Gaulton, K., Lindgren, C., Locke, A., Manning, A., Sim, X., Rivas, M. A., Holmen, O. L., Gottesman, O., Lu, Y., Ruderfer, D., Stahl, E. A., Duan, Q., Li, Y., Durda, P., Jiao, S., Isaacs, A., Hofman, A., Bis, J. C., Correa, A., Griswold, M. E., Jakobsdottir, J., Smith, A. V., Schreiner, P. J., Feitosa, M. F., Zhang, Q., Huffman, J. E., Crosby, J., Wassel, C. L., Do, R., Franceschini, N., Martin, L. W., Robinson, J. G., Assimes, T. L., Crosslin, D. R., Rosenthal, E. A., Tsai, M., Rieder, M. J., Farlow, D. N., Folsom, A. R., Lumley, T., Fox, E. R., Carlson, C. S., Peters, U., Jackson, R. D., van Duijn, C. M., Uitterlinden, A. G., Levy, D., Rotter, J. I., Taylor, H. A., Gudnason, V., Siscovick, D. S., Fornage, M., Borecki, I. B., Hayward, C., Rudan, I., Chen, Y. E., Bottinger, E. P., Loos, R. J., Sætrom, P., Hveem, K., Boehnke, M., Groop, L., McCarthy, M., Meitinger, T., Ballantyne, C. M., Gabriel, S. B., O'Donnell, C. J., Post, W. S., North, K. E., Reiner, A. P., Boerwinkle, E., Psaty, B. M., Altshuler, D., Kathiresan, S., Lin, D., Jarvik, G. P., Cupples, L. A., Kooperberg, C., Wilson, J. G., Nickerson, D. A., Abecasis, G. R., Rich, S. S., Tracy, R. P., Willer, C. J. 2014; 94 (2): 233-245

    Abstract

    Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

    View details for DOI 10.1016/j.ajhg.2014.01.010

    View details for PubMedID 24507775

  • A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. Journal of medical genetics Oei, L., Hsu, Y., Styrkarsdottir, U., Eussen, B. H., de Klein, A., Peters, M. J., Halldorsson, B., Liu, C., Alonso, N., Kaptoge, S. K., Thorleifsson, G., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Kruk, M., Lewis, J. R., Patel, M. S., Scollen, S., Svensson, O., Trompet, S., van Schoor, N. M., Zhu, K., Buckley, B. M., Cooper, C., Ford, I., Goltzman, D., González-Macías, J., Langdahl, B. L., Leslie, W. D., Lips, P., Lorenc, R. S., Olmos, J. M., Pettersson-Kymmer, U., Reid, D. M., Riancho, J. A., Slagboom, P. E., Garcia-Ibarbia, C., Ingvarsson, T., Johannsdottir, H., Luben, R., Medina-Gómez, C., Arp, P., Nandakumar, K., Palsson, S. T., Sigurdsson, G., van Meurs, J. B., Zhou, Y., Hofman, A., Jukema, J. W., Pols, H. A., Prince, R. L., Cupples, L. A., Marshall, C. R., Pinto, D., Sato, D., Scherer, S. W., Reeve, J., Thorsteinsdottir, U., Karasik, D., Richards, J. B., Stefansson, K., Uitterlinden, A. G., Ralston, S. H., Ioannidis, J. P., Kiel, D. P., Rivadeneira, F., Estrada, K. 2014; 51 (2): 122-131

    Abstract

    Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.To identify CNVs associated with osteoporotic bone fracture risk.We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

    View details for DOI 10.1136/jmedgenet-2013-102064

    View details for PubMedID 24343915

  • Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus BONE Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gomez, C., Vandenput, L., Kim, G. S., Lee, S. H., Castano-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellstrom, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, O., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2014; 59: 20-27

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for DOI 10.1016/j.bone.2013.10.015

    View details for Web of Science ID 000329558600004

    View details for PubMedID 24516880

    View details for PubMedCentralID PMC4102322

  • Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses. Clinical microbiology and infection Kanters, S., Mills, E. J., Thorlund, K., Bucher, H. C., Ioannidis, J. P. 2014; 20 (2): 114-122

    Abstract

    There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

    View details for DOI 10.1111/1469-0691.12475

    View details for PubMedID 24274661

  • Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gómez, C., Vandenput, L., Kim, G. S., Hun Lee, S., Castaño-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellström, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, Ö., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2014; 59: 20-27

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for PubMedID 24516880

    View details for PubMedCentralID PMC4102322

  • Improving the drug development process: more not less randomized trials. JAMA Djulbegovic, B., Hozo, I., Ioannidis, J. P. 2014; 311 (4): 355-356

    View details for DOI 10.1001/jama.2013.283742

    View details for PubMedID 24449311

  • How to Use a Subgroup Analysis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Sun, X., Ioannidis, J. P., Agoritsas, T., Alba, A. C., Guyatt, G. 2014; 311 (4): 405-411

    Abstract

    Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

    View details for DOI 10.1001/jama.2013.285063

    View details for Web of Science ID 000329939300026

  • How to use a subgroup analysis: users' guide to the medical literature. JAMA Sun, X., Ioannidis, J. P., Agoritsas, T., Alba, A. C., Guyatt, G. 2014; 311 (4): 405-411

    Abstract

    Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

    View details for DOI 10.1001/jama.2013.285063

    View details for PubMedID 24449319

  • Increasing value and reducing waste in research design, conduct, and analysis. Lancet Ioannidis, J. P., Greenland, S., Hlatky, M. A., Khoury, M. J., Macleod, M. R., Moher, D., Schulz, K. F., Tibshirani, R. 2014; 383 (9912): 166-175

    Abstract

    Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

    View details for DOI 10.1016/S0140-6736(13)62227-8

    View details for PubMedID 24411645

  • How to increase value and reduce waste when research priorities are set. Lancet Chalmers, I., Bracken, M. B., Djulbegovic, B., Garattini, S., Grant, J., Gülmezoglu, A. M., Howells, D. W., Ioannidis, J. P., Oliver, S. 2014; 383 (9912): 156-165

    Abstract

    The increase in annual global investment in biomedical research--reaching US$240 billion in 2010--has resulted in important health dividends for patients and the public. However, much research does not lead to worthwhile achievements, partly because some studies are done to improve understanding of basic mechanisms that might not have relevance for human health. Additionally, good research ideas often do not yield the anticipated results. As long as the way in which these ideas are prioritised for research is transparent and warranted, these disappointments should not be deemed wasteful; they are simply an inevitable feature of the way science works. However, some sources of waste cannot be justified. In this report, we discuss how avoidable waste can be considered when research priorities are set. We have four recommendations. First, ways to improve the yield from basic research should be investigated. Second, the transparency of processes by which funders prioritise important uncertainties should be increased, making clear how they take account of the needs of potential users of research. Third, investment in additional research should always be preceded by systematic assessment of existing evidence. Fourth, sources of information about research that is in progress should be strengthened and developed and used by researchers. Research funders have primary responsibility for reductions in waste resulting from decisions about what research to do.

    View details for DOI 10.1016/S0140-6736(13)62229-1

    View details for PubMedID 24411644

  • Biomedical research: increasing value, reducing waste. Lancet Macleod, M. R., Michie, S., Roberts, I., Dirnagl, U., Chalmers, I., Ioannidis, J. P., Al-Shahi Salman, R., Chan, A., Glasziou, P. 2014; 383 (9912): 101-104

    View details for DOI 10.1016/S0140-6736(13)62329-6

    View details for PubMedID 24411643

  • A vision for chronic disease prevention intervention research: Report from a workshop. Canadian journal of public health = Revue canadienne de santé publique Ashbury, F. D., Little, J., Ioannidis, J. P., Kreiger, N., Palmer, L. J., Relton, C., Taylor, P. 2014; 105 (2): e150–3

    Abstract

    The Population Studies Research Network of Cancer Care Ontario hosted a strategic planning workshop to establish an agenda for a prevention intervention research program in Ontario, including priority topics for investigation and design considerations. The two-day workshop included: presentations on background papers developed to facilitate participants' preparation for and discussions in the workshop; keynote presentations on intervention research concerning primary prevention of chronic diseases, design and study implementation considerations; a dedicated session on critical and creative thinking to stimulate participation and discussion topics; breakout groups to identify, discuss and present study ideas, designs, implementation considerations; and a consensus process to discuss and identify recommendations for research priorities and next steps. The retreat yielded the following recommendations: 1) develop an intervention research agenda that includes working with existing large-scale cohorts; 2) develop an intervention research agenda that includes novel research designs that could target individuals or groups; and 3) develop an intervention research agenda in which studies collect data on costs, define stakeholders, and ensure clear strategies for stakeholder engagement and knowledge transfer. The Population Studies Research Network will develop options from these recommendations and release a call for proposals in 2014 for intervention research pilot projects that reflect these recommendations. Pilot projects will be evaluated based on their fit with the retreat's recommendations, and their potential to scale up to full studies and application in practice.

    View details for PubMedID 24886853

  • The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiology of aging Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., Auburger, G., Bacon, J. A., Boczarska-Jedynak, M., Bozi, M., Brighina, L., Chartier-Harlin, M., Dardiotis, E., Destée, A., Ferrarese, C., Ferraris, A., Fiske, B., Gispert, S., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lin, C., Lohmann, K., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Opala, G., Park, S. S., Petrucci, S., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Tomiyama, H., Uitti, R. J., Valente, E. M., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J., Ross, O. A. 2014; 35 (1): 266 e5-266 e14

    View details for DOI 10.1016/j.neurobiolaging.2013.07.013

    View details for PubMedID 23962496

  • The diagnostic accuracy of the Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-8 (PHQ-8), and Patient Health Questionnaire-9 (PHQ-9) for detecting major depression: protocol for a systematic review and individual patient data meta-analyses. Systematic reviews Thombs, B. D., Benedetti, A., Kloda, L. A., Levis, B., Nicolau, I., Cuijpers, P., Gilbody, S., Ioannidis, J. P., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C. 2014; 3: 124-?

    Abstract

    Major depressive disorder (MDD) may be present in 10%-20% of patients in medical settings. Routine depression screening is sometimes recommended to improve depression management. However, studies of the diagnostic accuracy of depression screening tools have typically used data-driven, exploratory methods to select optimal cutoffs. Often, these studies report results from a small range of cutoff points around whatever cutoff score is most accurate in that given study. When published data are combined in meta-analyses, estimates of accuracy for different cutoff points may be based on data from different studies, rather than data from all studies for each possible cutoff point. As a result, traditional meta-analyses may generate exaggerated estimates of accuracy. Individual patient data (IPD) meta-analyses can address this problem by synthesizing data from all studies for each cutoff score to obtain diagnostic accuracy estimates. The nine-item Patient Health Questionnaire-9 (PHQ-9) and the shorter PHQ-2 and PHQ-8 are commonly recommended for depression screening. Thus, the primary objectives of our IPD meta-analyses are to determine the diagnostic accuracy of the PHQ-9, PHQ-8, and PHQ-2 to detect MDD among adults across all potentially relevant cutoff scores. Secondary analyses involve assessing accuracy accounting for patient factors that may influence accuracy (age, sex, medical comorbidity).Data sources will include MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. We will include studies that included a Diagnostic and Statistical Manual or International Classification of Diseases diagnosis of MDD based on a validated structured or semi-structured clinical interview administered within 2 weeks of the administration of the PHQ. Two reviewers will independently screen titles and abstracts, perform full article review, and extract study data. Disagreements will be resolved by consensus. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cutoff values.The proposed IPD meta-analyses will allow us to obtain estimates of the diagnostic accuracy of the PHQ-9, PHQ-8, and PHQ-2.PROSPERO CRD42014010673.

    View details for DOI 10.1186/2046-4053-3-124

    View details for PubMedID 25348422

  • Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5: 254-?

    Abstract

    Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

    View details for DOI 10.3389/fgene.2014.00254

    View details for PubMedID 25136350

  • Estimates of the continuously publishing core in the scientific workforce. PloS one Ioannidis, J. P., Boyack, K. W., Klavans, R. 2014; 9 (7)

    Abstract

    The ability of a scientist to maintain a continuous stream of publication may be important, because research requires continuity of effort. However, there is no data on what proportion of scientists manages to publish each and every year over long periods of time.Using the entire Scopus database, we estimated that there are 15,153,100 publishing scientists (distinct author identifiers) in the period 1996-2011. However, only 150,608 (<1%) of them have published something in each and every year in this 16-year period (uninterrupted, continuous presence [UCP] in the literature). This small core of scientists with UCP are far more cited than others, and they account for 41.7% of all papers in the same period and 87.1% of all papers with >1000 citations in the same period. Skipping even a single year substantially affected the average citation impact. We also studied the birth and death dynamics of membership in this influential UCP core, by imputing and estimating UCP-births and UCP-deaths. We estimated that 16,877 scientists would qualify for UCP-birth in 1997 (no publication in 1996, UCP in 1997-2012) and 9,673 scientists had their UCP-death in 2010. The relative representation of authors with UCP was enriched in Medical Research, in the academic sector and in Europe/North America, while the relative representation of authors without UCP was enriched in the Social Sciences and Humanities, in industry, and in other continents.The proportion of the scientific workforce that maintains a continuous uninterrupted stream of publications each and every year over many years is very limited, but it accounts for the lion's share of researchers with high citation impact. This finding may have implications for the structure, stability and vulnerability of the scientific workforce.

    View details for DOI 10.1371/journal.pone.0101698

    View details for PubMedID 25007173

    View details for PubMedCentralID PMC4090124

  • Authors' reply to Boucher. BMJ (Clinical research ed.) Theodoratou, E., Ioannidis, J. P. 2014; 348: g2927-?

    View details for DOI 10.1136/bmj.g2927

    View details for PubMedID 24780520

  • What Is Wrong with Clinical Proteomics? Clinical chemistry Meo, A. D., Diamandis, E. P., Rodriguez, H., Hoofnagle, A. N., Ioannidis, J., Lopez, M. 2014

    View details for DOI 10.1373/clinchem.2014.225185

    View details for PubMedID 24831563

  • Studying the elusive environment in large scale. JAMA : the journal of the American Medical Association Patel, C. J., Ioannidis, J. P. 2014; 311 (21): 2173–74

    View details for DOI 10.1001/jama.2014.4129

    View details for PubMedID 24893084

  • The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC medical research methodology Inthout, J., Ioannidis, J. P., Borm, G. F. 2014; 14: 25-?

    Abstract

    The DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results.We evaluated the performance of the HKSJ versus DL approach in simulated meta-analyses of 2-20 trials with varying sample sizes and between-study heterogeneity, and allowing trials to have various sizes, e.g. 25% of the trials being 10-times larger than the smaller trials. We also compared the number of "positive" (statistically significant at p < 0.05) findings using empirical data of recent meta-analyses with > = 3 studies of interventions from the Cochrane Database of Systematic Reviews.The simulations showed that the HKSJ method consistently resulted in more adequate error rates than the DL method. When the significance level was 5%, the HKSJ error rates at most doubled, whereas for DL they could be over 30%. DL, and, far less so, HKSJ had more inflated error rates when the combined studies had unequal sizes and between-study heterogeneity. The empirical data from 689 meta-analyses showed that 25.1% of the significant findings for the DL method were non-significant with the HKSJ method. DL results can be easily converted into HKSJ results.Our simulations showed that the HKSJ method consistently results in more adequate error rates than the DL method, especially when the number of studies is small, and can easily be applied routinely in meta-analyses. Even with the HKSJ method, extra caution is needed when there are = <5 studies of very unequal sizes.

    View details for DOI 10.1186/1471-2288-14-25

    View details for PubMedID 24548571

    View details for PubMedCentralID PMC4015721

  • Non-publication and delayed publication of randomized trials on vaccines: survey. BMJ (Clinical research ed.) Manzoli, L., Flacco, M. E., D'Addario, M., Capasso, L., De Vito, C., Marzuillo, C., Villari, P., Ioannidis, J. P. 2014; 348: g3058-?

    Abstract

    To evaluate the extent of non-publication or delayed publication of registered randomized trials on vaccines, and to investigate potential determinants of delay to publication.Survey.Trials registry websites, Scopus, PubMed, Google.Randomized controlled trials evaluating the safety or the efficacy or immunogenicity of human papillomavirus (HPV), pandemic A/H1N1 2009 influenza, and meningococcal, pneumococcal, and rotavirus vaccines that were registered in ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, Clinical Study Register, or Indian, Australian-New Zealand, and Chinese trial registries in 2006-12. Electronic databases were searched up to February 2014 to identify published manuscripts containing trial results. These were reviewed and classified as positive, mixed, or negative. We also reviewed the results available in ClinicalTrials.gov.Publication status of trial results and time from completion to publication in peer reviewed journals.Cox proportional hazards regression was used to evaluate potential predictors of publication delay.We analysed 384 trials (85% sponsored by industry). Of 355 trials (404 758 participants) that were completed, 176 (n=151 379) had been published in peer reviewed journals. Another 42 trials (total sample 62 765) remained unpublished but reported results in ClinicalTrials.gov. The proportion of trials published 12, 24, 36, and 48 months after completion was 12%, 29%, 53%, and 73%, respectively. Including results posted in ClinicalTrials.gov, 48 months after study completion results were available for 82% of the trials and 90% of the participants. Delay to publication between non-industry and industry sponsored trials did not differ, but non-industry sponsored trials were 4.42-fold (P=0.008) more likely to report negative or mixed findings. Negative results were reported by only 2% of the published trials.Most vaccine trials are published eventually or the results posted in ClinicalTrials.gov, but delays to publication of several years are common. Actions should focus on the timely dissemination of data from vaccine trials to the public.

    View details for DOI 10.1136/bmj.g3058

    View details for PubMedID 24838102

  • Errors (my very own) and the fearful uncertainty of numbers. European journal of clinical investigation Ioannidis, J. P. 2014

    View details for DOI 10.1111/eci.12277

    View details for PubMedID 24785138

  • Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ (Clinical research ed.) Theodoratou, E., Tzoulaki, I., Zgaga, L., Ioannidis, J. P. 2014; 348: g2035-?

    Abstract

    To evaluate the breadth, validity, and presence of biases of the associations of vitamin D with diverse outcomes.Umbrella review of the evidence across systematic reviews and meta-analyses of observational studies of plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D concentrations and randomised controlled trials of vitamin D supplementation.Medline, Embase, and screening of citations and references.Three types of studies were eligible for the umbrella review: systematic reviews and meta-analyses that examined observational associations between circulating vitamin D concentrations and any clinical outcome; and meta-analyses of randomised controlled trials assessing supplementation with vitamin D or active compounds (both established and newer compounds of vitamin D).107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people.Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.

    View details for DOI 10.1136/bmj.g2035

    View details for PubMedID 24690624

    View details for PubMedCentralID PMC3972415

  • John P. A. Ioannidis. Nature reviews. Drug discovery Ioannidis, J. P., Mullard, A. 2014; 13 (5): 328–29

    View details for DOI 10.1038/nrd4317

    View details for PubMedID 24751817

  • Attention to local health burden and the global disparity of health research. PloS one Evans, J. A., Shim, J., Ioannidis, J. P. 2014; 9 (4)

    Abstract

    Most studies on global health inequality consider unequal health care and socio-economic conditions but neglect inequality in the production of health knowledge relevant to addressing disease burden. We demonstrate this inequality and identify likely causes. Using disability-adjusted life years (DALYs) for 111 prominent medical conditions, assessed globally and nationally by the World Health Organization, we linked DALYs with MEDLINE articles for each condition to assess the influence of DALY-based global disease burden, compared to the global market for treatment, on the production of relevant MEDLINE articles, systematic reviews, clinical trials and research using animal models vs. humans. We then explored how DALYs, wealth, and the production of research within countries correlate with this global pattern. We show that global DALYs for each condition had a small, significant negative relationship with the production of each type of MEDLINE articles for that condition. Local processes of health research appear to be behind this. Clinical trials and animal studies but not systematic reviews produced within countries were strongly guided by local DALYs. More and less developed countries had very different disease profiles and rich countries publish much more than poor countries. Accordingly, conditions common to developed countries garnered more clinical research than those common to less developed countries. Many of the health needs in less developed countries do not attract attention among developed country researchers who produce the vast majority of global health knowledge--including clinical trials--in response to their own local needs. This raises concern about the amount of knowledge relevant to poor populations deficient in their own research infrastructure. We recommend measures to address this critical dimension of global health inequality.

    View details for DOI 10.1371/journal.pone.0090147

    View details for PubMedID 24691431

    View details for PubMedCentralID PMC3972174

  • Registering Diagnostic and Prognostic Trials of Tests: Is it the Right Thing to Do? Clinical chemistry Rifai, N., Bossuyt, P. M., Ioannidis, J. P., Bray, K. R., McShane, L. M., Golub, R. M., Hooft, L. 2014

    View details for DOI 10.1373/clinchem.2014.226100

    View details for PubMedID 24855278

  • Discussion: Why "An estimate of the science-wise false discovery rate and application to the top medical literature" is false BIOSTATISTICS Ioannidis, J. P. 2014; 15 (1): 28-36

    Abstract

    Jager and Leek have tried to estimate a false-discovery rate (FDR) in abstracts of articles published in five medical journals during 2000-2010. Their approach is flawed in sampling, calculations, and conclusions. It uses a tiny portion of select papers in highly select journals. Randomized controlled trials and systematic reviews (designs with the lowest anticipated false-positive rates) are 52% of the analyzed papers, while these designs account for only 4% in PubMed in the same period. The FDR calculations consider the entire published literature as equivalent to a single genomic experiment where all performed analyses are reported without selection or distortion. However, the data used are the P-values reported in the abstracts of published papers; these P-values are a highly distorted, highly select sample. Besides selective reporting biases, all other biases, in particular confounding in observational studies, are also ignored, while these are often the main drivers for high false-positive rates in the biomedical literature. A reproducibility check of the raw data shows that much of the data Jager and Leek used are either wrong or make no sense: most of the usable data were missed by their script, 94% of the abstracts that reported ≥2 P-values had high correlation/overlap between reported outcomes, and only a minority of P-values corresponded to relevant primary outcomes. The Jager and Leek paper exemplifies the dreadful combination of using automated scripts with wrong methods and unreliable data. Sadly, this combination is common in the medical literature.

    View details for DOI 10.1093/biostatistics/kxt036

    View details for Web of Science ID 000328286700006

    View details for PubMedID 24068251

  • There are no randomized controlled trials that support the United States Preventive Services Task Force guideline on screening for depression in primary care: a systematic review. BMC medicine Thombs, B. D., Ziegelstein, R. C., Roseman, M., Kloda, L. A., Ioannidis, J. P. 2014; 12 (1): 13-?

    Abstract

    The United States Preventive Services Task Force (USPSTF) recommends screening adults for depression in primary care settings when staff-assisted depression management programs are available. This recommendation, however, is based on evidence from depression management programs conducted with patients already identified as depressed, even though screening is intended to identify depressed patients not already recognized or treated. The objective of this systematic review was to evaluate whether there is evidence from randomized controlled trials (RCTs) that depression screening benefits patients in primary care, using an explicit definition of screening.We re-evaluated RCTs included in the 2009 USPSTF evidence review on depression screening, including only trials that compared depression outcomes between screened and non-screened patients and met the following three criteria: determined patient eligibility and randomized prior to screening; excluded patients already diagnosed with a recent episode of depression or already being treated for depression; and provided the same level of depression treatment services to patients identified as depressed in the screening and non-screening trial arms. We also reviewed studies included in a recent Cochrane systematic review, but not the USPSTF review; conducted a focused search to update the USPSTF review; and reviewed trial registries.Of the nine RCTs included in the USPSTF review, four fulfilled none of three criteria for a test of depression screening, four fulfilled one of three criteria, and one fulfilled two of three criteria. There were two additional RCTs included only in the Cochrane review, and each fulfilled one of three criteria. No eligible RCTs were found via the updated review.The USPSTF recommendation to screen adults for depression in primary care settings when staff-assisted depression management programs are available is not supported by evidence from any RCTs that are directly relevant to the recommendation. The USPSTF should re-evaluate this recommendation.Registration: PROSPERO (#CRD42013004276).

    View details for DOI 10.1186/1741-7015-12-13

    View details for PubMedID 24472580

  • Potential increased risk of cancer from commonly used medications: an umbrella review of meta-analyses. Annals of oncology Ioannidis, J. P., Zhou, Y., Chang, C. Q., Schully, S. D., Khoury, M. J., Freedman, A. N. 2014; 25 (1): 16-23

    Abstract

    Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearman's correlation coefficient = -0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.

    View details for DOI 10.1093/annonc/mdt372

    View details for PubMedID 24310915

    View details for PubMedCentralID PMC3868319

  • Association between pediatric clinical trials and global burden of disease. Pediatrics Bourgeois, F. T., Olson, K. L., Ioannidis, J. P., Mandl, K. D. 2014; 133 (1): 78-87

    Abstract

    The allocation of research resources should favor conditions responsible for the greatest disease burden. This is particularly important in pediatric populations, which have been underrepresented in clinical research. Our aim was to measure the association between the focus of pediatric clinical trials and burden of disease and to identify neglected clinical domains.We performed a cross-sectional study of clinical trials by using trial records in ClinicalTrials.gov. All trials started in 2006 or after and studying patient-level interventions in pediatric populations were included. Age-specific measures of disease burden were obtained for 21 separate conditions for high-, middle-, and low-income countries. We measured the correlation between number of pediatric clinical trials and disease burden for each condition.Neuropsychiatric conditions and infectious diseases were the most studied conditions globally in terms of number of trials (874 and 847 trials, respectively), while intentional injuries (5 trials) and maternal conditions (4 trials) were the least studied. Clinical trials were only moderately correlated with global disease burden (r = 0.58, P = .006). Correlations were also moderate within each of the country income levels, but lowest in low-income countries (r = .47, P = .03). Globally, the conditions most understudied relative to disease burden were injuries (-260 trials for unintentional injuries and -160 trials for intentional injuries), nutritional deficiencies (-175 trials), and respiratory infections (-171 trials).Pediatric clinical trial activity is only moderately associated with pediatric burden of disease, and least associated in low-income countries. The mismatch between clinical trials and disease burden identifies key clinical areas for focus and investment.

    View details for DOI 10.1542/peds.2013-2567

    View details for PubMedID 24344112

    View details for PubMedCentralID PMC3876184

  • Evidence-based de-implementation for contradicted, unproven, and aspiring healthcare practices. Implementation science Prasad, V., Ioannidis, J. P. 2014; 9 (1): 1-?

    Abstract

    Abandoning ineffective medical practices and mitigating the risks of untested practices are important for improving patient health and containing healthcare costs. Historically, this process has relied on the evidence base, societal values, cultural tensions, and political sway, but not necessarily in that order. We propose a conceptual framework to guide and prioritize this process, shifting emphasis toward the principles of evidence-based medicine, acknowledging that evidence may still be misinterpreted or distorted by recalcitrant proponents of entrenched practices and other biases.

    View details for DOI 10.1186/1748-5908-9-1

    View details for PubMedID 24398253

    View details for PubMedCentralID PMC3892018

  • Research accomplishments that are too good to be true: reply to Ting. Intensive care medicine Ioannidis, J. P. 2014

    View details for DOI 10.1007/s00134-014-3220-0

    View details for PubMedID 24477457

  • Research accomplishments that are too good to be true INTENSIVE CARE MEDICINE Ioannidis, J. P. 2014; 40 (1): 99-101

    View details for DOI 10.1007/s00134-013-3100-z

    View details for Web of Science ID 000328198600013

    View details for PubMedID 24129497

  • Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiology of aging Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., Auburger, G., Bacon, J. A., Boczarska-Jedynak, M., Bozi, M., Brighina, L., Chartier-Harlin, M., Dardiotis, E., Destée, A., Ferrarese, C., Ferraris, A., Fiske, B., Gispert, S., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lin, C., Lohmann, K., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Opala, G., Park, S. S., Petrucci, S., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Tomiyama, H., Uitti, R. J., Valente, E. M., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J., Ross, O. A. 2014; 35 (1): 266 e5-14

    Abstract

    The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

    View details for DOI 10.1016/j.neurobiolaging.2013.07.013

    View details for PubMedID 23962496

  • Guidelines for cardiovascular risk assessment and cholesterol treatment--reply. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2014; 311 (21): 2235–36

    View details for DOI 10.1001/jama.2014.4075

    View details for PubMedID 24893099

  • Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation A Randomized Clinical Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Katritsis, D. G., Pokushalov, E., Romanov, A., Giazitzoglou, E., Siontis, G. C., Po, S. S., Camm, A. J., Ioannidis, J. P. 2013; 62 (24): 2318-2325

    Abstract

    The aim of this study was to investigate whether the combination of conventional pulmonary vein isolation (PVI) by circumferential antral ablation with ganglionated plexi (GP) modification in a single ablation procedure, yields higher success rates than PVI or GP ablation alone, in patients with paroxysmal atrial fibrillation (PAF).Conventional PVI transects the major left atrial GP, and it is possible that autonomic denervation by inadvertent GP ablation plays a central role in the efficacy of PVI.A total of 242 patients with symptomatic PAF were recruited and randomized as follows: 1) circumferential PVI (n = 78); 2) anatomic ablation of the main left atrial GP (n = 82); or 3) circumferential PVI followed by anatomic ablation of the main left atrial GP (n = 82). The primary endpoint was freedom from atrial fibrillation (AF) or other sustained atrial tachycardia (AT), verified by monthly visits, ambulatory electrocardiographic monitoring, and implantable loop recorders, during a 2-year follow-up period.Freedom from AF or AT was achieved in 44 (56%), 39 (48%), and 61 (74%) patients in the PVI, GP, and PVI+GP groups, respectively (p = 0.004 by log-rank test). PVI+GP ablation strategy compared with PVI alone yielded a hazard ratio of 0.53 (95% confidence interval: 0.31 to 0.91; p = 0.022) for recurrence of AF or AT. Fluoroscopy duration was 16 ± 3 min, 20 ± 5 min, and 23 ± 5 min for PVI, GP, and PVI+GP groups, respectively (p < 0.001). Post-ablation atrial flutter did not differ between groups: 5.1% in PVI, 4.9% in GP, and 6.1% in PVI+GP. No serious adverse procedure-related events were encountered.Addition of GP ablation to PVI confers a significantly higher success rate compared with either PVI or GP alone in patients with PAF.

    View details for DOI 10.1016/j.jacc.2013.06.053

    View details for Web of Science ID 000328073300012

    View details for PubMedID 23973694

  • Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 185 (18): E827-37

    Abstract

    Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality.We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes.We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes.In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.

    View details for DOI 10.1503/cmaj.130430

    View details for PubMedID 24144601

  • Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality CANADIAN MEDICAL ASSOCIATION JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 185 (18): E827-E837

    Abstract

    Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality.We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes.We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes.In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.

    View details for DOI 10.1503/cmaj.130430

    View details for Web of Science ID 000327902600014

    View details for PubMedID 24144601

    View details for PubMedCentralID PMC3855143

  • Joint Linkage and Association Analysis with Exome Sequence Data Implicates SLC25A40 in Hypertriglyceridemia. American journal of human genetics Rosenthal, E. A., Ranchalis, J., Crosslin, D. R., Burt, A., Brunzell, J. D., Motulsky, A. G., Nickerson, D. A., Wijsman, E. M., Jarvik, G. P. 2013; 93 (6): 1035-1045

    Abstract

    Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.

    View details for DOI 10.1016/j.ajhg.2013.10.019

    View details for PubMedID 24268658

  • Narrow band imaging to differentiate neoplastic and non-neoplastic colorectal polyps in real time: a meta-analysis of diagnostic operating characteristics GUT Mcgill, S. K., Evangelou, E., Ioannidis, J. P., Soetikno, R. M., Kaltenbach, T. 2013; 62 (12): 1704-1713

    Abstract

    PURPOSE: Many studies have reported on the use of narrow band imaging (NBI) colonoscopy to differentiate neoplastic from non-neoplastic colorectal polyps. It has potential to replace pathological diagnosis of diminutive polyps. We aimed to perform a systematic review and meta-analysis on the real-time diagnostic operating characteristics of NBI colonoscopy. METHODS: We searched PubMed, SCOPUS and Cochrane databases and abstracts. We used a two-level bivariate meta-analysis following a random effects model to summarise the data and fit hierarchical summary receiver-operating characteristic (HSROC) curves. The area under the HSROC curve serves as an indicator of the diagnostic test strength. We calculated summary sensitivity, specificity and negative predictive value (NPV). We assessed agreement of surveillance interval recommendations based on endoscopic diagnosis compared to pathology. RESULTS: For NBI diagnosis of colorectal polyps, the area under the HSROC curve was 0.92 (95% CI 0.90 to 0.94), based on 28 studies involving 6280 polyps in 4053 patients. The overall sensitivity was 91.0% (95% CI 87.6% to 93.5%) and specificity was 82.6% (95% CI 79.0% to 85.7%). In eight studies (n=2146 polyps) that used high-confidence diagnostic predictions, sensitivity was 93.8% and specificity was 83.3%. The NPVs exceeded 90% when 60% or less of all polyps were neoplastic. Surveillance intervals based on endoscopic diagnosis agreed with those based on pathology in 92.6% of patients (95% CI 87.9% to 96.3%). CONCLUSIONS: NBI diagnosis of colorectal polyps is highly accurate-the area under the HSROC curve exceeds 0.90. High-confidence predictions provide >90% sensitivity and NPV. It shows high potential for real-time endoscopic diagnosis.

    View details for DOI 10.1136/gutjnl-2012-303965

    View details for Web of Science ID 000326877200007

    View details for PubMedID 23300139

  • WHAT'S TO KNOW ABOUT THE CREDIBILITY OF EMPIRICAL ECONOMICS? JOURNAL OF ECONOMIC SURVEYS Ioannidis, J., Doucouliagos, C. 2013; 27 (5): 997–1004

    View details for DOI 10.1111/joes.12032

    View details for Web of Science ID 000325148400008

  • Empirical evidence for low reproducibility indicates low pre-study odds. Nature reviews. Neuroscience Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafò, M. R. 2013; 14 (12): 877-?

    View details for DOI 10.1038/nrn3475-c6

    View details for PubMedID 24149186

  • Collaborative cancer epidemiology in the 21st century: the model of cancer consortia. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Burgio, M. R., Ioannidis, J. P., Kaminski, B. M., Derycke, E., Rogers, S., Khoury, M. J., Seminara, D. 2013; 22 (12): 2148-2160

    Abstract

    During the last two decades, epidemiology has undergone a rapid evolution toward collaborative research. The proliferation of multi-institutional, interdisciplinary consortia has acquired particular prominence in cancer research. Herein, we describe the characteristics of a network of 49 established cancer epidemiology consortia (CEC) currently supported by the Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI). This collection represents the largest disease-based research network for collaborative cancer research established in population sciences. We describe the funding trends, geographic distribution, and areas of research focus. The CEC have been partially supported by 201 grants and yielded 3,876 publications between 1995 and 2011. We describe this output in terms of interdisciplinary collaboration and translational evolution. We discuss challenges and future opportunities in the establishment and conduct of large-scale team science within the framework of CEC, review future prospects for this approach to large-scale, interdisciplinary cancer research, and describe a model for the evolution of an integrated Network of Cancer Consortia optimally suited to address and support 21st-century epidemiology.

    View details for DOI 10.1158/1055-9965.EPI-13-0591

    View details for PubMedID 24045926

  • Geometry of the Randomized Evidence for Treatments of Pulmonary Hypertension CARDIOVASCULAR THERAPEUTICS Tonelli, A. R., Zein, J., Ioannidis, J. P. 2013; 31 (6): E138-E146

    Abstract

    We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication.We searched MEDLINE, Embase and Cochrane Library Databases for published studies. We queried clinicaltrials.gov and WHO International Clinical Trials Registry platform for non-published studies.We found 75 randomized trials (41 published [n = 4136 participants] and 34 registered unpublished [planned n = 3470 participants]). Of the published randomized studies, all used placebo as the comparator arm except for two nonindustry-sponsored comparisons between phosphodiestearase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERA), and one study comparing two different regimens of treprostinil. Similarly, only five unpublished/ongoing trials used an active PH treatment as comparator (PDE-5 inhibitors versus ERA (n = 3), different doses of sildenafil (n = 1) and two formulations of epoprostenol (n = 1). Of the 75 trials, 47 were sponsored by the manufacturer of the tested active product(s), and only two trials were sponsored by two companies comparing their products.The relative merits of different treatment options are not directly known, as there are very few head-to-head comparisons. A limited number of ongoing studies are using active FDA-approved PH-treatments for comparison. This lack of information can be overcome by carefully designing comparative effectiveness trials.

    View details for DOI 10.1111/1755-5922.12050

    View details for Web of Science ID 000327423800012

    View details for PubMedID 24112824

  • A list of highly influential biomedical researchers, 1996-2011. European journal of clinical investigation Boyack, K. W., Klavans, R., Sorensen, A. A., Ioannidis, J. P. 2013; 43 (12): 1339-1365

    Abstract

    We have generated a list of highly influential biomedical researchers based on Scopus citation data from the period 1996-2011. Of the 15,153,100 author identifiers in Scopus, approximately 1% (n=149,655) have an h-index >=20. Of those, we selected 532 authors who belonged to the 400 with highest total citation count (>=25,142 citations) and/or the 400 with highest h-index (>=76). Of those, we selected the top-400 living core biomedical researchers based on a normalized score combining total citations and h-index. Another 62 authors whose focus is outside biomedicine had a normalized score that was at least as high as the score of the 400th core biomedical researcher. We provide information on the profile of these most influential authors, including the most common Medical Subject Heading terms in their articles that are also specific to their work, most common journals where they publish, number of papers with over 100 citations that they have published as first/single, last, or middle authors, and impact score adjusted for authorship positions, given that crude citation indices and authorship positions are almost totally orthogonal. We also show for each researcher the distribution of their papers across 4 main levels (basic-to-applied) of research. We discuss technical issues, limitations and caveats, comparisons against other lists of highly-cited researchers, and potential uses of this resource.

    View details for DOI 10.1111/eci.12171

    View details for PubMedID 24134636

  • Raw data from clinical trials: within reach? Trends in pharmacological sciences Doshi, P., Goodman, S. N., Ioannidis, J. P. 2013; 34 (12): 645-647

    Abstract

    Making raw data from clinical trials widely publically available should reduce selective reporting biases and enhance the reproducibility of and trust in clinical research. The optimal procedures for data sharing are hotly debated. Some of the caveats and limitations in proposed data-sharing policies are potentially restrictive, and we argue in favor of more widespread availability of data from clinical research.

    View details for DOI 10.1016/j.tips.2013.10.006

    View details for PubMedID 24295825

  • Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States National Health and Nutrition Examination Survey. International journal of epidemiology Patel, C. J., Rehkopf, D. H., Leppert, J. T., Bortz, W. M., Cullen, M. R., Chertow, G. M., Ioannidis, J. P. 2013; 42 (6): 1795-1810

    Abstract

    Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.

    View details for DOI 10.1093/ije/dyt208

    View details for PubMedID 24345851

    View details for PubMedCentralID PMC3887569

  • Endgame: engaging the tobacco industry in its own elimination. European journal of clinical investigation Ioannidis, J. P., Henriksen, L., Prochaska, J. J. 2013; 43 (12): 1366-1370

    Abstract

    A billion deaths from tobacco are expected by 2100. Many policy interventions such as increased taxation, restrictions on advertisement, smoking bans, as well as behavioral interventions, such as pharmacological and psychological treatments for smoking cessation, decrease tobacco use, but they reach their limits. Endgame scenarios focusing on tobacco supply rather than demand are increasingly discussed, but meet with resistance by the industry and even by many tobacco control experts. A main stumbling block that requires more attention is what to do with the tobacco industry in endgame scenarios. This industry has employed notoriously talented experts in law, business, organization, marketing, advertising, strategy, policy, and statistics and has tremendous lobbying power. Performance-based regulatory approaches can pose a legal obligation on manufacturers to decrease - and eventually - eliminate tobacco products according to specified schedules. Penalties and rewards can make such plans both beneficial for public health and attractive to the companies that do the job well. We discuss caveats and reality checks of engaging the tobacco industry to eliminate its current market and change focus. Brainstorming is warranted to entice the industry to abandon tobacco for other profit goals. To get the dialogue started, we propose the wild possibility of hiring former tobacco companies to reduce the costs of healthcare, thereby addressing concurrently two major challenges to public health.

    View details for DOI 10.1111/eci.12172

    View details for PubMedID 24117211

  • Implausible results in human nutrition research BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. P. 2013; 347

    View details for DOI 10.1136/bmj.f6698

    View details for Web of Science ID 000327155000004

    View details for PubMedID 24231028

  • Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nature reviews. Rheumatology Ioannidis, J. P., Karassa, F. B., Druyts, E., Thorlund, K., Mills, E. J. 2013; 9 (11): 665-673

    Abstract

    Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.

    View details for DOI 10.1038/nrrheum.2013.134

    View details for PubMedID 23999553

  • ADHERENCE INTERVENTIONS TO IMPROVE ADHERENCE TO ANTIRETROVIRAL THERAPY IN LOW INCOME SETTINGS: AN INDIVIDUAL PATIENT DATA NETWORK META-ANALYSIS Mills, E. J., Nachega, J., Lester, R., Thorlund, K., Ioannidis, J., Linnemayr, S., Gross, R., Calderone, Y., Amico, R., Thirumurthy, H., Pearson, C., Remien, R., Mbuagbaw, L., Thabane, L., Chung, M., Wilson, Liu, A., Uthman, O., Ford, N. ELSEVIER SCIENCE INC. 2013: A361

    View details for DOI 10.1016/j.jval.2013.08.223

    View details for Web of Science ID 000326247600211

  • Prevention and management of non-communicable disease: the IOC consensus statement, Lausanne 2013 BRITISH JOURNAL OF SPORTS MEDICINE Matheson, G. O., Kluegl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Borjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 47 (16): 1003-U56

    Abstract

    Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology and design thinking. The purpose of this paper is to summarise the results of a consensus meeting on NCD prevention sponsored by the IOC in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within healthcare systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: (1) Focus on behavioural change as the core component of all clinical programmes for the prevention and management of chronic disease. (2) Establish actual centres to design, implement, study and improve preventive programmes for chronic disease. (3) Use human-centred design in the creation of prevention programmes with an inclination to action, rapid prototyping and multiple iterations. (4) Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programmes for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. (5) Mobilise resources and leverage networks to scale and distribute programmes of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programmes within healthcare. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.

    View details for DOI 10.1136/bjsports-2013-093034

    View details for Web of Science ID 000325530900002

    View details for PubMedID 24115479

  • Prevention and Management of Non-Communicable Disease: The IOC Consensus Statement, Lausanne 2013. Sports medicine Matheson, G. O., Klügl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Börjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 43 (11): 1075-1088

    Abstract

    Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April, 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioural change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centres to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad-hoc Working Group charged with the responsibility of moving this agenda forward.

    View details for DOI 10.1007/s40279-013-0104-3

    View details for PubMedID 24129783

  • Prevention and Management of Noncommunicable Disease: The IOC Consensus Statement, Lausanne 2013 CLINICAL JOURNAL OF SPORT MEDICINE Matheson, G. O., Kluegl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Boerjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 23 (6): 419-429

    View details for DOI 10.1097/JSM.0000000000000038

    View details for Web of Science ID 000326732800003

  • Genome-wide Association Study for Radiographic Vertebral Fractures: A Potential Role for the 16q24 BMD Locus versus Lessons Learned from Challenging Phenotype Definition. Bone Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gómez, C., Vandenput, L., Kim, G. S., Lee, S. H., Castaño-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellström, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, O., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2013

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2,666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at P<5x10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6 x 10(-8). However, the association was not significant across 5,720 cases and 21,791 controls from 14 studies. Fixed-effects meta analyses summary estimate was 1.06 (95% CI: 0.98-1.14; P=0.17), displaying high degree of heterogeneity (I(2)=57%; Qhet p= 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (P=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions are needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for DOI 10.1016/j.bone.2013.10.015

    View details for PubMedID 24513584

  • Mortality in persons with mental disorders is substantially overestimated using inpatient psychiatric diagnoses. Journal of psychiatric research Crump, C., Ioannidis, J. P., Sundquist, K., Winkleby, M. A., Sundquist, J. 2013; 47 (10): 1298-1303

    Abstract

    Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N = 7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001-2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85-5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08-5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (∼20-30%) or excluded (∼25-40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies.

    View details for DOI 10.1016/j.jpsychires.2013.05.034

    View details for PubMedID 23806577

  • Clarifications on the application and interpretation of the test for excess significance and its extensions JOURNAL OF MATHEMATICAL PSYCHOLOGY Ioannidis, J. A. 2013; 57 (5): 184–87

    View details for DOI 10.1016/j.jmp.2013.03.002

    View details for Web of Science ID 000326903100006

  • Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD) consortium. Movement disorders Heckman, M. G., Soto-Ortolaza, A. I., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Carr, J., Chartier-Harlin, M., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., Fiske, B., Gibson, J. M., Gibson, R., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Boczarska-Jedynak, M., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lesage, S., Lin, C., Lynch, T., Maraganore, D. M., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Park, S. S., Petrucci, S., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Theuns, J., Tomiyama, H., Uitti, R. J., Valente, E. M., Van Broeckhoven, C., van de Loo, S., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Hentati, F., Farrer, M. J., Ross, O. A. 2013; 28 (12): 1740-1744

    Abstract

    Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society.

    View details for DOI 10.1002/mds.25600

    View details for PubMedID 23913756

  • In reply II-Reversal of Medical Practices MAYO CLINIC PROCEEDINGS Ioannidis, J. P. 2013; 88 (10): 1184-1184

    View details for DOI 10.1016/j.mayocp.2013.08.014

    View details for Web of Science ID 000325470800029

    View details for PubMedID 24079693

  • Mining the human phenome using allelic scores that index biological intermediates. PLoS genetics Evans, D. M., Brion, M. J., Paternoster, L., Kemp, J. P., McMahon, G., Munafò, M., Whitfield, J. B., Medland, S. E., Montgomery, G. W., Timpson, N. J., St Pourcain, B., Lawlor, D. A., Martin, N. G., Dehghan, A., Hirschhorn, J., Davey Smith, G. 2013; 9 (10)

    Abstract

    It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.

    View details for DOI 10.1371/journal.pgen.1003919

    View details for PubMedID 24204319

  • A common biological basis of obesity and nicotine addiction TRANSLATIONAL PSYCHIATRY Thorgeirsson, T. E., Gudbjartsson, D. F., Sulem, P., Besenbacher, S., Styrkarsdottir, U., Thorleifsson, G., Walters, G. B., Furberg, H., Sullivan, P. F., Marchini, J., McCarthy, M. I., Steinthorsdottir, V., Thorsteinsdottir, U., Stefansson, K. 2013; 3

    Abstract

    Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

    View details for DOI 10.1038/tp.2013.81

    View details for Web of Science ID 000327472800001

    View details for PubMedID 24084939

  • Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study BMJ-BRITISH MEDICAL JOURNAL Naci, H., Ioannidis, J. P. 2013; 347

    Abstract

    To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes.Metaepidemiological study.Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care).Medline and Cochrane Database of Systematic Reviews, May 2013.Mortality.We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11, 1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant.Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

    View details for DOI 10.1136/bmj.f5577

    View details for Web of Science ID 000325426300002

    View details for PubMedID 24473061

  • US studies may overestimate effect sizes in softer research PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Ioannidis, J. P. 2013; 110 (37): 15031-15036

    Abstract

    Many biases affect scientific research, causing a waste of resources, posing a threat to human health, and hampering scientific progress. These problems are hypothesized to be worsened by lack of consensus on theories and methods, by selective publication processes, and by career systems too heavily oriented toward productivity, such as those adopted in the United States (US). Here, we extracted 1,174 primary outcomes appearing in 82 meta-analyses published in health-related biological and behavioral research sampled from the Web of Science categories Genetics & Heredity and Psychiatry and measured how individual results deviated from the overall summary effect size within their respective meta-analysis. We found that primary studies whose outcome included behavioral parameters were generally more likely to report extreme effects, and those with a corresponding author based in the US were more likely to deviate in the direction predicted by their experimental hypotheses, particularly when their outcome did not include additional biological parameters. Nonbehavioral studies showed no such "US effect" and were subject mainly to sampling variance and small-study effects, which were stronger for non-US countries. Although this latter finding could be interpreted as a publication bias against non-US authors, the US effect observed in behavioral research is unlikely to be generated by editorial biases. Behavioral studies have lower methodological consensus and higher noise, making US researchers potentially more likely to express an underlying propensity to report strong and significant findings.

    View details for DOI 10.1073/pnas.1302997110

    View details for Web of Science ID 000324125100053

    View details for PubMedID 23980165

    View details for PubMedCentralID PMC3773789

  • The effects of excluding treatments from network meta-analyses: survey BMJ-BRITISH MEDICAL JOURNAL Mills, E. J., Kanters, S., Thorlund, K., Chaimani, A., Veroniki, A., Ioannidis, J. P. 2013; 347

    Abstract

    To examine whether the exclusion of individual treatment comparators, including placebo/no treatment, affects the results of network meta-analysis.Survey of networks with individual trial data.PubMed and communication with authors of network meta-analyses.We included networks that had five or more treatments, contained at least two closed loops, had at least twice as many studies as treatments, and had trial level data available. Investigators abstracted information about study design, participants, outcomes, network geometry, and the exclusion of eligible treatments.Among 18 eligible networks involving 757 randomised controlled trials with 750 possible treatment comparisons, 11 had upfront decided not to consider all treatment comparators and only 10 included placebo/no treatment nodes. In 7/18 networks, there was at least one node whose removal caused a more than 1.10-fold average relative change in the estimated treatments effects, and switches in the top three treatments were observed in 9/18 networks. Removal of placebo/no treatment caused large relative changes of the treatment effects (average change 1.16-3.10-fold) for four of the 10 networks that had originally included placebo/no treatment nodes. Exclusion of current uncommonly used drugs resulted in substantial changes of the treatment effects (average 1.21-fold) in one of three networks on systemic treatments for advanced malignancies.Excluding treatments in network meta-analyses sometimes can have important effects on their results and can diminish the usefulness of the research to clinicians if important comparisons are missing.

    View details for DOI 10.1136/bmj.f5195

    View details for Web of Science ID 000324216500001

    View details for PubMedID 24009242

    View details for PubMedCentralID PMC3763846

  • Association Between Obesity and Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Operations: A Systematic Review and Meta-Analysis ANNALS OF THORACIC SURGERY Hernandez, A. V., Kaw, R., Pasupuleti, V., Bina, P., Ioannidis, J. P., Bueno, H., Boersma, E., Gillinov, M. 2013; 96 (3): 1104-1116

    Abstract

    In a systematic review and random-effects meta-analysis, we evaluated whether obesity is associated with postoperative atrial fibrillation (POAF) in patients undergoing cardiac operations. We selected 18 observational studies until December 2011 that excluded patients with preoperative AF (n=36,147). Obese patients had a modest higher risk of POAF compared with nonobese (odds ratio, 1.12; 95% confidence interval, 1.04 to 1.21; p=0.002). The association between obesity and POAF did not vary substantially by type of cardiac operation, study design, or year of publication. POAF was significantly associated with a higher risk of stroke, respiratory failure, and operative death.

    View details for DOI 10.1016/j.athoracsur.2013.04.029

    View details for Web of Science ID 000323940200076

    View details for PubMedID 23932258

  • Optimal type I and type II error pairs when the available sample size is fixed JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Hozo, I., Djulbegovic, B. 2013; 66 (8): 903-910

    Abstract

    OBJECTIVE: To model how to select the optimal pair of type I and type II errors that maximize study value when there are constrains on the available study sample size. STUDY DESIGN AND SETTING: Correct inferences [true positives (TPs) and true negatives (TNs)] increase and wrong inferences (false positives and false negatives) decrease the value of a study. We model the composite value of a study based on these four inferences, their relative importance, and relative frequency using multiplicative and additive models. Numerical examples are presented for randomized trials, epidemiologic studies, and agnostic omics investigations with massive testing and variable sample size constraints. RESULTS: The optimal choice of type I and type II errors varies a lot according to the available sample size and the plausible effect sizes in each field. We show how equations can be streamlined for special applications: when the value of all four inferences is considered equal, when the identification of TNs carries no value, and when a study carries no value unless at least one TP is discovered. CONCLUSION: The proposed optimization equations can be used to guide the selection of the optimal type I and type II errors of future studies in which sample size is constrained.

    View details for DOI 10.1016/j.jclinepi.2013.03.002

    View details for Web of Science ID 000322207300013

    View details for PubMedID 23664493

  • To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies Have Pharmacogenomics Failed, or Do They Just Need Larger-Scale Evidence and More Replication? CIRCULATION-CARDIOVASCULAR GENETICS Ioannidis, J. P. 2013; 6 (4): 413-418

    View details for DOI 10.1161/CIRCGENETICS.113.000106

    View details for Web of Science ID 000323542700014

    View details for PubMedID 23963161

  • Confidence and precision increase with high statistical power. Nature reviews. Neuroscience Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafò, M. R. 2013; 14 (8): 585-586

    View details for DOI 10.1038/nrn3475-c4

    View details for PubMedID 23820778

  • Expressing Death Risk as Condensed Life Experience and Death Intensity MEDICAL DECISION MAKING Ioannidis, J. P. 2013; 33 (6): 853-859

    Abstract

    Some risk exposures, including many medical and surgical procedures, typically carry hazards of death that are difficult to convey and appreciate in absolute terms. I propose presenting the death risk as a condensed life experience (i.e., the equivalent amount of life T that would carry the same cumulative mortality hazard for a person of the same age and sex based on life tables). For example, if the risk of death during an elective 1-hour procedure is 0.01%, and same-age and same-sex people have a 0.01% death risk over 1 month, one can inform the patient that "this procedure carries the same death risk as living 1 month of normal life." Comparative standards from other risky activities or from a person with the same disease at the same stage and same predictive profile could also be used. A complementary metric that may be useful to consider is the death intensity. The death intensity λ is the hazard function that shows the fold-risk estimate of dying compared with the reference person. The death intensity can vary substantially for different phases of the event, operation, or procedure (e.g., intraoperative, early postoperative, late postoperative), and this variability may also be useful to convey. T will vary depending on the time window for which it is computed. I present examples for calculating T and λ using literature data on accidents, ascent to Mount Everest, and medical and surgical procedures.

    View details for DOI 10.1177/0272989X13484389

    View details for Web of Science ID 000327813000010

    View details for PubMedID 23579043

  • Overlapping meta-analyses on the same topic: survey of published studies BMJ-BRITISH MEDICAL JOURNAL Siontis, K. C., Hernandez-Boussard, T., Ioannidis, J. P. 2013; 347

    Abstract

    To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic.Survey of published meta-analyses.PubMed.Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013.Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses.While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.

    View details for DOI 10.1136/bmj.f4501

    View details for Web of Science ID 000322247400002

    View details for PubMedID 23873947

    View details for PubMedCentralID PMC3716360

  • Practices and impact of primary outcome adjustment in randomized controlled trials: meta-epidemiologic study BMJ-BRITISH MEDICAL JOURNAL Saquib, N., Saquib, J., Ioannidis, J. P. 2013; 347

    Abstract

    To assess adjustment practices for primary outcomes of randomized controlled trials and their impact on the results.Meta-epidemiologic study.25 biomedical journals with the highest impact factor according to Journal Citation Reports 2009.Randomized controlled trials published in print in 2009 that reported primary outcomes. The search yielded 684 eligible papers of randomized controlled trials, of which 200 were randomly selected.Two researchers independently extracted data on study population, intervention, primary outcome, and the adjustment plan for primary outcomes. They also recorded the magnitude and statistical significance of the intervention effect with and without adjustments, and estimated whether adjustment made a difference in the level of nominal significance. They also compared the analysis plan for model adjustment in the published trial versus the trial protocol with information on the protocol collected from registries, design papers, and communication with all corresponding authors.54% of the trials used stratified randomization, 96% presented baseline characteristics in the compared arms, and 46% also evaluated differences in baseline factors with statistical testing. Half of the trials performed adjusted analyses for the main outcome, as the sole analysis (29%) or along with unadjusted analyses (21%). Adjustment for stratification variables and for baseline variables was performed in 39% (42/108) and 42% (84/199) of the trials, respectively. Among 40 comparisons with both adjusted and unadjusted analyses, 43% had statistically significant effects, 40% had non-significant effects, and 18% had significant effects with only one of the two analyses, but not with the other. Information on analysis plan regarding model adjustment was available in 6% (9/162) of trial registry entries, 78% (21/27) of design papers, and 74% (40/54) of protocols obtained from authors. The analysis plan disagreed between the published trial and the registry, protocol, or design paper in 47% (28/60) of the studies.There is large diversity on whether and how analyses of primary outcomes are adjusted in randomized controlled trials and these choices can sometimes change the nominal significance of the results. Registered protocols should explicitly specify adjustments plans for main outcomes and analysis should follow these plans.

    View details for DOI 10.1136/bmj.f4313

    View details for Web of Science ID 000321895300001

    View details for PubMedID 23851720

    View details for PubMedCentralID PMC3709831

  • Evaluation of excess significance bias in animal studies of neurological diseases. PLoS biology Tsilidis, K. K., Panagiotou, O. A., Sena, E. S., Aretouli, E., Evangelou, E., Howells, D. W., Al-Shahi Salman, R., Macleod, M. R., Ioannidis, J. P. 2013; 11 (7)

    Abstract

    Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10(-9)). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.

    View details for DOI 10.1371/journal.pbio.1001609

    View details for PubMedID 23874156

  • Evaluation of Excess Significance Bias in Animal Studies of Neurological Diseases PLOS BIOLOGY Tsilidis, K. K., Panagiotou, O. A., Sena, E. S., Aretouli, E., Evangelou, E., Howells, D. W., Salman, R. A., Macleod, M. R., Ioannidis, J. P. 2013; 11 (7)

    Abstract

    Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10(-9)). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.

    View details for DOI 10.1371/journal.pbio.1001609

    View details for Web of Science ID 000322592700013

    View details for PubMedCentralID PMC3712913

  • The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males. Annals of the rheumatic diseases Evangelou, E., Valdes, A. M., Castano-Betancourt, M. C., Doherty, M., Doherty, S., Esko, T., Ingvarsson, T., Ioannidis, J. P., Kloppenburg, M., Metspalu, A., Ntzani, E. E., Panoutsopoulou, K., Slagboom, P. E., Southam, L., Spector, T. D., Styrkarsdottir, U., Stefanson, K., Uitterlinden, A. G., wheeler, M., Zeggini, E., Meulenbelt, I., van Meurs, J. B. 2013; 72 (7): 1264-1265

    View details for DOI 10.1136/annrheumdis-2012-203182

    View details for PubMedID 23505243

  • Meta-analysis methods for genome-wide association studies and beyond. Nature reviews. Genetics Evangelou, E., Ioannidis, J. P. 2013; 14 (6): 379-389

    Abstract

    Meta-analysis of genome-wide association studies (GWASs) has become a popular method for discovering genetic risk variants. Here, we overview both widely applied and newer statistical methods for GWAS meta-analysis, including issues of interpretation and assessment of sources of heterogeneity. We also discuss extensions of these meta-analysis methods to complex data. Where possible, we provide guidelines for researchers who are planning to use these methods. Furthermore, we address special issues that may arise for meta-analysis of sequencing data and rare variants. Finally, we discuss challenges and solutions surrounding the goals of making meta-analysis data publicly available and building powerful consortia.

    View details for DOI 10.1038/nrg3472

    View details for PubMedID 23657481

  • JOINT EULAR/ERA-EDTA RECOMMENDATIONS FOR THE MANAGEMENT OF ADULT AND PEDIATRIC LUPUS NEPHRITIS Bertsias, G., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J., Boletis, J., Cervera, R., Doerner, T., Doria, A., Ferrario, F., Floege, J., Houssiau, F., Ioannidis, J. P., Isenberg, D., Kallenberg, C. G., Lightstone, L., Marks, S., Martini, A., Moroni, G., Neumann, I., Niaudet, P., Praga, M., Schneider, M., Tesar, V., Vasconcelos, C., van Vollenhoven, R., Zakharova, E., Haubitz, M., Gordon, C., Jayne, D., Boumpas, D. BMJ PUBLISHING GROUP. 2013: 74–75

    View details for DOI 10.1136/annrheumdis-2012-eular.1747

    View details for Web of Science ID 000208898500273

  • Systematic identification of interaction effects between genome- and environment-wide associations in type 2 diabetes mellitus HUMAN GENETICS Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 132 (5): 495-508

    Abstract

    Diseases such as type 2 diabetes (T2D) result from environmental and genetic factors, and risk varies considerably in the population. T2D-related genetic loci discovered to date explain only a small portion of the T2D heritability. Some heritability may be due to gene-environment interactions. However, documenting these interactions has been difficult due to low availability of concurrent genetic and environmental measures, selection bias, and challenges in controlling for multiple hypothesis testing. Through genome-wide association studies (GWAS), investigators have identified over 90 single nucleotide polymorphisms (SNPs) associated to T2D. Using a method analogous to GWAS [environment-wide association study (EWAS)], we found five environmental factors associated with the disease. By focusing on risk factors that emerge from GWAS and EWAS, it is possible to overcome difficulties in uncovering gene-environment interactions. Using data from the National Health and Nutrition Examination Survey (NHANES), we screened 18 SNPs and 5 serum-based environmental factors for interaction in association to T2D. We controlled for multiple hypotheses using false discovery rate (FDR) and Bonferroni correction and found four interactions with FDR <20 %. The interaction between rs13266634 (SLC30A8) and trans-β-carotene withstood Bonferroni correction (corrected p = 0.006, FDR <1.5 %). The per-risk-allele effect sizes in subjects with low levels of trans-β-carotene were 40 % greater than the marginal effect size [odds ratio (OR) 1.8, 95 % CI 1.3-2.6]. We hypothesize that impaired function driven by rs13266634 increases T2D risk when combined with serum levels of nutrients. Unbiased consideration of environmental and genetic factors may help identify larger and more relevant effect sizes for disease associations.

    View details for DOI 10.1007/s00439-012-1258-z

    View details for Web of Science ID 000317691100002

    View details for PubMedID 23334806

    View details for PubMedCentralID PMC3625410

  • Undue industry influences that distort healthcare research, strategy, expenditure and practice: a review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Stamatakis, E., Weiler, R., Ioannidis, J. P. 2013; 43 (5): 469-475

    Abstract

    Expenditure on industry products (mostly drugs and devices) has spiraled over the last 15 years and accounts for substantial part of healthcare expenditure. The enormous financial interests involved in the development and marketing of drugs and devices may have given excessive power to these industries to influence medical research, policy, and practice.Review of the literature and analysis of the multiple pathways through which the industry has directly or indirectly infiltrated the broader healthcare systems. We present the analysis of the industry influences at the following levels: (i) evidence base production, (ii) evidence synthesis, (iii) understanding of safety and harms issues, (iv) cost-effectiveness evaluation, (v) clinical practice guidelines formation, (vi) healthcare professional education, (vii) healthcare practice, (viii) healthcare consumer's decisions.We located abundance of consistent evidence demonstrating that the industry has created means to intervene in all steps of the processes that determine healthcare research, strategy, expenditure, practice and education. As a result of these interferences, the benefits of drugs and other products are often exaggerated and their potential harms are downplayed, and clinical guidelines, medical practice, and healthcare expenditure decisions are biased.To serve its interests, the industry masterfully influences evidence base production, evidence synthesis, understanding of harms issues, cost-effectiveness evaluations, clinical practice guidelines and healthcare professional education and also exerts direct influences on professional decisions and health consumers. There is an urgent need for regulation and other action towards redefining the mission of medicine towards a more objective and patient-, population- and society-benefit direction that is free from conflict of interests.

    View details for DOI 10.1111/eci.12074

    View details for Web of Science ID 000317983300005

    View details for PubMedID 23521369

  • Pancreatitis Potentially Associated Drugs as a Risk Factor for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis A Prospective Cohort Study PANCREAS Sigounas, D. E., Christodoulou, D. K., Tatsioni, A., Katsanos, K. H., Baltayiannis, G., Kappas, A., Ioannidis, J. P., Tsianos, E. V. 2013; 42 (4): 601-606

    Abstract

    The aim of this study was to assess the role of known risk factors and specifically evaluate the role of pancreatitis potentially associated drugs as potential risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).This was a prospective, single-center cohort study conducted in a tertiary university hospital. All eligible ERCP procedures within a 16-month period were evaluated, and all interventions, patient characteristics, and medications used were documented. The association of potential risk factor with PEP was investigated with univariable analyses. Those statistically significant were entered in a multivariable regression model.Three hundred eighteen ERCP procedures were studied. Post-ERCP pancreatitis occurred in 28 patients (8.8%). Twenty-three potential risk factors were studied in univariable analyses, and 3 of them were found to be nominally statistically significant. These 3 factors were independently associated with PEP in the multivariable model and included the use of pancreatitis potentially associated drugs, belonging to Badalov classes I or II, during the last month before ERCP (odds ratio [OR], 4.39; 95% confidence interval [CI], 1.70-5.47; P = 0.003), more than 1 guide-wire insertions in the pancreatic duct (OR, 5.00; 95% CI, 1.97-12.81; P = 0.001) and bile duct stone extraction (OR, 0.12; CI, 0.05-0.32; P < 0.001).Pancreatitis potentially associated drugs used before ERCP seem to increase the risk for PEP.

    View details for DOI 10.1097/MPA.0b013e31827309fd

    View details for Web of Science ID 000317655200007

    View details for PubMedID 23548878

  • Power failure: why small sample size undermines the reliability of neuroscience NATURE REVIEWS NEUROSCIENCE Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafo, M. R. 2013; 14 (5): 365-376

    Abstract

    A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.

    View details for DOI 10.1038/nrn3475

    View details for Web of Science ID 000317913900012

    View details for PubMedID 23571845

  • Mega-Randomized Clinical Trials for Blockbuster Drugs Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (16): 1683-1683

    View details for Web of Science ID 000317906700018

    View details for PubMedID 23613069

  • Bias in associations of emerging biomarkers with cardiovascular disease. JAMA internal medicine Tzoulaki, I., Siontis, K. C., Evangelou, E., Ioannidis, J. P. 2013; 173 (8): 664-671

    Abstract

    IMPORTANCE Numerous cardiovascular biomarkers are proposed as potential predictors of cardiovascular risk. OBJECTIVE To evaluate whether there is evidence for biases favoring statistically significant results and inflating associations in this literature. DESIGN AND SETTING PubMed search for meta-analyses of cardiovascular biomarkers that are not part of the Framingham Risk Score. MAIN OUTCOME MEASURES We estimated summary effects and between-study heterogeneity (considered "very large" for I2 > 75%). We evaluated whether large studies had significantly more conservative results than smaller studies (small-study effects) and whether there were too many studies with statistically significant results compared with what would be expected on the basis of the findings of the largest study in each meta-analysis. RESULTS Of 56 eligible meta-analyses, 49 had statistically significant results. Very large heterogeneity and small-study effects were seen in 9 and 13 meta-analyses, respectively. In 29 meta-analyses (52%), there was a significant excess of studies with statistically significant results. Only 13 of the statistically significant meta-analyses had more than 1000 cases and no hints of large heterogeneity, small-study effects, or excess significance. These included the associations of glomerular filtration rate and albumin to creatinine ratio in general and high-risk populations with cardiovascular disease mortality and of non-high-density lipoprotein cholesterol, serum albumin, Chlamydia pneumoniae IgG, glycosylated hemoglobin, nonfasting insulin, apolipoprotein B/AI ratio, erythrocyte sedimentation rate, and lipoprotein-associated phospholipase mass or activity with coronary heart disease. CONCLUSIONS AND RELEVANCE Selective reporting biases may be common in the evidence on emerging cardiovascular biomarkers. Most of the proposed associations of these biomarkers may be inflated.

    View details for DOI 10.1001/jamainternmed.2013.3018

    View details for PubMedID 23529078

  • Are Mortality Differences Detected by Administrative Data Reliable and Actionable? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (13): 1410-1411

    View details for Web of Science ID 000316934500032

    View details for PubMedID 23549588

  • Seven new loci associated with age-related macular degeneration. Nature genetics Fritsche, L. G., Chen, W., Schu, M., Yaspan, B. L., Yu, Y., Thorleifsson, G., Zack, D. J., Arakawa, S., Cipriani, V., Ripke, S., Igo, R. P., Buitendijk, G. H., Sim, X., Weeks, D. E., Guymer, R. H., Merriam, J. E., Francis, P. J., Hannum, G., Agarwal, A., Armbrecht, A. M., Audo, I., Aung, T., Barile, G. R., Benchaboune, M., Bird, A. C., Bishop, P. N., Branham, K. E., Brooks, M., Brucker, A. J., Cade, W. H., Cain, M. S., Campochiaro, P. A., Chan, C., Cheng, C., Chew, E. Y., Chin, K. A., Chowers, I., Clayton, D. G., Cojocaru, R., Conley, Y. P., Cornes, B. K., Daly, M. J., Dhillon, B., Edwards, A. O., Evangelou, E., Fagerness, J., Ferreyra, H. A., Friedman, J. S., Geirsdottir, A., George, R. J., Gieger, C., Gupta, N., Hagstrom, S. A., Harding, S. P., Haritoglou, C., Heckenlively, J. R., Holz, F. G., Hughes, G., Ioannidis, J. P., Ishibashi, T., Joseph, P., Jun, G., Kamatani, Y., Katsanis, N., N Keilhauer, C., Khan, J. C., Kim, I. K., Kiyohara, Y., Klein, B. E., Klein, R., Kovach, J. L., Kozak, I., Lee, C. J., Lee, K. E., Lichtner, P., Lotery, A. J., Meitinger, T., Mitchell, P., Mohand-Saïd, S., Moore, A. T., Morgan, D. J., Morrison, M. A., Myers, C. E., Naj, A. C., Nakamura, Y., Okada, Y., Orlin, A., Ortube, M. C., Othman, M. I., Pappas, C., Park, K. H., Pauer, G. J., Peachey, N. S., Poch, O., Priya, R. R., Reynolds, R., Richardson, A. J., Ripp, R., Rudolph, G., Ryu, E., Sahel, J., Schaumberg, D. A., Scholl, H. P., Schwartz, S. G., Scott, W. K., Shahid, H., Sigurdsson, H., Silvestri, G., Sivakumaran, T. A., Smith, R. T., Sobrin, L., Souied, E. H., Stambolian, D. E., Stefansson, H., Sturgill-Short, G. M., Takahashi, A., Tosakulwong, N., Truitt, B. J., Tsironi, E. E., Uitterlinden, A. G., van Duijn, C. M., Vijaya, L., Vingerling, J. R., Vithana, E. N., Webster, A. R., Wichmann, H., Winkler, T. W., Wong, T. Y., Wright, A. F., Zelenika, D., Zhang, M., Zhao, L., Zhang, K., Klein, M. L., Hageman, G. S., Lathrop, G. M., Stefansson, K., Allikmets, R., Baird, P. N., Gorin, M. B., Wang, J. J., Klaver, C. C., Seddon, J. M., Pericak-Vance, M. A., Iyengar, S. K., Yates, J. R., Swaroop, A., Weber, B. H., Kubo, M., DeAngelis, M. M., Léveillard, T., Thorsteinsdottir, U., Haines, J. L., Farrer, L. A., Heid, I. M., Abecasis, G. R. 2013; 45 (4): 433-?

    Abstract

    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

    View details for DOI 10.1038/ng.2578

    View details for PubMedID 23455636

  • Seven new loci associated with age-related macular degeneration NATURE GENETICS Fritsche, L. G., Chen, W., Schu, M., Yaspan, B. L., Yu, Y., Thorleifsson, G., Zack, D. J., Arakawa, S., Cipriani, V., Ripke, S., Igo, R. P., Buitendijk, G. H., Sim, X., Weeks, D. E., Guymer, R. H., Merriam, J. E., Francis, P. J., Hannum, G., Agarwal, A., Armbrecht, A. M., Audo, I., Aung, T., Barile, G. R., Benchaboune, M., Bird, A. C., Bishop, P. N., Branham, K. E., Brooks, M., Brucker, A. J., Cade, W. H., Cain, M. S., Campochiaroll, P. A., Chan, C., Cheng, C., Chew, E. Y., Chin, K. A., Chowers, I., Clayton, D. G., Cojocaru, R., Conley, Y. P., Cornes, B. K., Daly, M. J., Dhillon, B., Edwards, A., Evangelou, E., Fagemess, J., Ferreyra, H. A., Friedman, J. S., Geirsdottir, A., George, R. J., Gieger, C., Gupta, N., Hagstrom, S. A., Harding, S. P., Haritoglou, C., Heckenlively, J. R., Hoz, F. G., Hughes, G., Ioannidis, J. P., Ishibashi, T., Joseph, P., Jun, G., Kamatani, Y., Katsanis, N., Keilhauer, C. N., Khan, J. C., Kim, I. K., Kiyohara, Y., Klein, B. E., Klein, R., Kovach, J. L., Kozak, I., Lee, C. J., Lee, K. E., Lichtner, P., Lotery, A. J., Meitinger, T., Mitchell, P., Mohand-Saied, S., Moore, A. T., Morgan, D. J., Morrison, M. A., Myers, C. E., Naj, A. C., Nakamura, Y., Okada, Y., Orlin, A., Ortube, M. C., Othman, M. I., Pappas, C., Park, K. H., Pauer, G. J., Peachey, N. S., Poch, O., Priya, R. R., Reynolds, R., Richardson, A. J., Ripp, R., Rudolph, G., Ryu, E., Sahel, J., Schaumberg, D. A., Scholl, H. P., Schwartz, S. G., Scott, W. K., Shahid, H., Sigurdsson, H., Silvestri, G., Sivakumaran, T. A., Smith, R. T., Sobrin, L., Souied, E. H., Stambolian, D. E., Stefansson, H., Sturgill-Short, G. M., Takahashi, A., Tosakulwong, N., Truitt, B. J., Tsironi, E. E., Uitterlinden, A. G., van Duijn, C. M., Vijaya, L., Vingerling, J. R., Vithana, E. N., Webster, A. R., Wichmann, H., Winkler, T. W., Wong, T. Y., Wright, A. F., Zelenika, D., Zhang, M., Zhao, L., Zhang, K., Klein, M. L., Hageman, G. S., Lathrop, G. M., Stefansson, K., Allikmets, R., Baird, P. N., Gorin, M. B., Wang, J. J., Klaver, C. C., Seddon, J. M., Pericak-Vance, M. A., Iyengar, S. K., Yates, J. R., Swaroop, A., Weber, B. H., Kubo, M., DeAngelis, M. M., Leveillard, T., Thorsteinsdottir, U., Haines, J. L., Farrer, L. A., Heid, I. M., Abecasis, G. R. 2013; 45 (4): 433-439

    Abstract

    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

    View details for DOI 10.1038/ng.2578

    View details for Web of Science ID 000316840600015

    View details for PubMedID 23455636

  • Technical aspects and inter-laboratory variability in native peptide profiling: The CE-MS experience CLINICAL BIOCHEMISTRY Mischak, H., Vlahou, A., Ioannidis, J. P. 2013; 46 (6): 432-443

    Abstract

    Mass spectrometry platforms have attracted a lot of interest in the last 2 decades as profiling tools for native peptides and proteins with clinical potential. However, limitations associated with reproducibility and analytical robustness, especially pronounced with the initial SELDI systems, hindered the application of such platforms in biomarker qualification and clinical implementation. The scope of this article is to give a short overview on data available on performance and on analytical robustness of the different platforms for peptide profiling. Using the CE-MS platform as a paradigm, data on analytical performance are described including reproducibility (short-term and intermediate repeatability), stability, interference, quantification capabilities (limits of detection), and inter-laboratory variability. We discuss these issues by using as an example our experience with the development of a 273-peptide marker for chronic kidney disease. Finally, we discuss pros and cons and means for improvement and emphasize the need to test in terms of comparative clinical performance and impact, different platforms that pass reasonably well analytical validation tests.

    View details for DOI 10.1016/j.clinbiochem.2012.09.025

    View details for Web of Science ID 000317155800005

    View details for PubMedID 23041249

  • Transforming Epidemiology for 21st Century Medicine and Public Health CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Khoury, M. J., Lam, T. K., Ioannidis, J. P., Hartge, P., Spitz, M. R., Buring, J. E., Chanock, S. J., Croyle, R. T., Goddard, K. A., Ginsburg, G. S., Herceg, Z., Hiatt, R. A., Hoover, R. N., Hunter, D. J., Kramer, B. S., Lauer, M. S., Meyerhardt, J. A., Olopade, O. I., Palmer, J. R., Sellers, T. A., Seminara, D., Ransohoff, D. F., Rebbeck, T. R., Tourassi, G., Winn, D. M., Zauber, A., Schully, S. D. 2013; 22 (4): 508-516

    Abstract

    In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.

    View details for DOI 10.1158/1055-9965.EPI-13-0146

    View details for Web of Science ID 000317960900005

    View details for PubMedID 23462917

    View details for PubMedCentralID PMC3625652

  • Limitations of Medical Research and Evidence at the Patient-Clinician Encounter Scale CHEST Morris, A. H., Ioannidis, J. P. 2013; 143 (4): 1127-1135

    Abstract

    We explore some philosophical and scientific underpinnings of clinical research and evidence at the patient-clinician encounter scale. Insufficient evidence and a common failure to use replicable and sound research methods limit us. Both patients and health care may be, in part, complex nonlinear chaotic systems, and predicting their outcomes is a challenge. When trustworthy (credible) evidence is lacking, making correct clinical choices is often a low-probability exercise. Thus, human (clinician) error and consequent injury to patients appear inevitable. Individual clinician decision-makers operate under the philosophical influence of Adam Smith's "invisible hand" with resulting optimism that they will eventually make the right choices and cause health benefits. The presumption of an effective "invisible hand" operating in health-care delivery has supported a model in which individual clinicians struggle to practice medicine, as they see fit based on their own intuitions and preferences (and biases) despite the obvious complexity, errors, noise, and lack of evidence pervading the system. Not surprisingly, the "invisible hand" does not appear to produce the desired community health benefits. Obtaining a benefit at the patient-clinician encounter scale requires human (clinician) behavior modification. We believe that serious rethinking and restructuring of the clinical research and care delivery systems is necessary to assure the profession and the public that we continue to do more good than harm. We need to evaluate whether, and how, detailed decision-support tools may enable reproducible clinician behavior and beneficial use of evidence.

    View details for DOI 10.1378/chest.12-1908

    View details for Web of Science ID 000317871500037

    View details for PubMedID 23546485

    View details for PubMedCentralID PMC3616682

  • Most meta-analyses of drug interventions have narrow scopes and many focus on specific agents JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A., Pilalas, D., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 66 (4): 371-378

    Abstract

    To assess the extent to which meta-analysis publications of drugs and biologics focus on specific named agents or even only a single agent, and identify characteristics associated with such focus.We evaluated 499 articles with meta-analyses published in 2010 and estimated how many did not cover all the available comparisons of tested interventions for a given condition (not all-inclusive); focused on specific named agent(s), or focused strictly on comparisons of only one specific active agent vs. placebo/no treatment or different doses/schedules.Of 499 eligible articles, 403 (80.8%) were not all-inclusive, 214 (42.9%) covered only specific named agent(s), and 74 (14.8%) examined only comparisons with one active agent vs. placebo/no treatment or different doses/schedules. Only 39 articles (7.8%) covered all possible indications for the examined agent(s). After adjusting for type of treatment/field, focus on specific named agent(s) was associated with publication in journal venues (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.17-3.26) vs. Cochrane, industry sponsoring (OR: 3.94; 95% CI: 1.66-10.66), and individual patient data analyses (OR: 6.59; 95% CI: 2.24-19.39). Individual patient data analyses primarily (29/34) focused on specific named agent(s).The scope of meta-analysis publications frequently is narrow and shaped to serve particular agents.

    View details for DOI 10.1016/j.jclinepi.2012.10.014

    View details for Web of Science ID 000315935100006

    View details for PubMedID 23384590

  • Informed Consent, Big Data, and the Oxymoron of Research That Is Not Research AMERICAN JOURNAL OF BIOETHICS Ioannidis, J. P. 2013; 13 (4): 40-42

    View details for DOI 10.1080/15265161.2013.768864

    View details for Web of Science ID 000316391200014

    View details for PubMedID 23514395

  • Observational studies often make clinical practice recommendations: an empirical evaluation of authors' attitudes JOURNAL OF CLINICAL EPIDEMIOLOGY Prasad, V., Jorgenson, J., Ioannidis, J. P., Cifu, A. 2013; 66 (4): 361-366

    Abstract

    Although observational studies provide useful descriptive and correlative information, their role in the evaluation of medical interventions remains contentious. There has been no systematic evaluation of authors' attitudes toward their own nonrandomized studies and how often they recommend specific medical practices.We reviewed all original articles of nonrandomized studies published in 2010 in New England Journal of Medicine, Lancet, Journal of the American Medical Association, and Annals of Internal Medicine. We classified articles based on whether authors recommend a medical practice and whether they state that a randomized trial is needed to support their recommendation. We also examined the types of logical extrapolations used by authors who did advance recommendations.Of the 631 original articles published in 2010, 298 (47%) articles were eligible observational studies. In 167 (56%) of 298 studies, authors recommended a medical practice based on their results. Only 24 (14%) of 167 studies stated that a randomized controlled trial (RCT) should be done to validate the recommendation, whereas the other 143 articles made a total of 149 logical extrapolations to recommend specific medical practices. Recommendations without a call for a randomized trial were most common in studies of modifiable factors (59%), but they were also common in studies reporting incidence or prevalence (51%), studies examining novel tests (41%), and association studies of nonmodifiable factors (32%).The authors of observational studies often extrapolate their results to make recommendations concerning a medical practice, typically without first calling for a RCT.

    View details for DOI 10.1016/j.jclinepi.2012.11.005

    View details for Web of Science ID 000315935100004

    View details for PubMedID 23384591

  • Patient safety strategies targeted at diagnostic errors: a systematic review. Annals of internal medicine McDonald, K. M., Matesic, B., Contopoulos-Ioannidis, D. G., Lonhart, J., Schmidt, E., Pineda, N., Ioannidis, J. P. 2013; 158 (5): 381-389

    Abstract

    Missed, delayed, or incorrect diagnosis can lead to inappropriate patient care, poor patient outcomes, and increased cost. This systematic review analyzed evaluations of interventions to prevent diagnostic errors. Searches used MEDLINE (1966 to October 2012), the Agency for Healthcare Research and Quality's Patient Safety Network, bibliographies, and prior systematic reviews. Studies that evaluated any intervention to decrease diagnostic errors in any clinical setting and with any study design were eligible, provided that they addressed a patient-related outcome. Two independent reviewers extracted study data and rated study quality. There were 109 studies that addressed 1 or more intervention categories: personnel changes (n = 6), educational interventions (n = 11), technique (n = 23), structured process changes (n = 27), technology-based systems interventions (n = 32), and review methods (n = 38). Of 14 randomized trials, which were rated as having mostly low to moderate risk of bias, 11 reported interventions that reduced diagnostic errors. Evidence seemed strongest for technology-based systems (for example, text message alerting) and specific techniques (for example, testing equipment adaptations). Studies provided no information on harms, cost, or contextual application of interventions. Overall, the review showed a growing field of diagnostic error research and categorized and identified promising interventions that warrant evaluation in large studies across diverse settings.

    View details for DOI 10.7326/0003-4819-158-5-201303051-00004

    View details for PubMedID 23460094

  • Patient Safety Strategies Targeted at Diagnostic Errors A Systematic Review ANNALS OF INTERNAL MEDICINE McDonald, K. M., Matesic, B., Contopoulos-Ioannidis, D. G., Lonhart, J., Schmidt, E., Pineda, N., Ioannidis, J. P. 2013; 158 (5): 381-?

    Abstract

    Missed, delayed, or incorrect diagnosis can lead to inappropriate patient care, poor patient outcomes, and increased cost. This systematic review analyzed evaluations of interventions to prevent diagnostic errors. Searches used MEDLINE (1966 to October 2012), the Agency for Healthcare Research and Quality's Patient Safety Network, bibliographies, and prior systematic reviews. Studies that evaluated any intervention to decrease diagnostic errors in any clinical setting and with any study design were eligible, provided that they addressed a patient-related outcome. Two independent reviewers extracted study data and rated study quality. There were 109 studies that addressed 1 or more intervention categories: personnel changes (n = 6), educational interventions (n = 11), technique (n = 23), structured process changes (n = 27), technology-based systems interventions (n = 32), and review methods (n = 38). Of 14 randomized trials, which were rated as having mostly low to moderate risk of bias, 11 reported interventions that reduced diagnostic errors. Evidence seemed strongest for technology-based systems (for example, text message alerting) and specific techniques (for example, testing equipment adaptations). Studies provided no information on harms, cost, or contextual application of interventions. Overall, the review showed a growing field of diagnostic error research and categorized and identified promising interventions that warrant evaluation in large studies across diverse settings.

    View details for Web of Science ID 000316058600004

    View details for PubMedID 23460094

  • Emergence of Large Treatment Effects From Small Trials Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Pereira, T. V., Horwitz, R. I. 2013; 309 (8): 768-769

    View details for Web of Science ID 000315332200015

    View details for PubMedID 23443435

  • Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment BRITISH MEDICAL JOURNAL Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Rehnborg, C. F. 2013; 346

    Abstract

    To compare treatment effects from randomised trials conducted in more developed versus less developed countries.Meta-epidemiological study.Cochrane Database of Systematic Reviews (August 2012).Meta-analyses with mortality outcomes including data from at least one randomised trial conducted in a less developed country and one in a more developed country. Relative risk estimates of more versus less developed countries were compared by calculating the relative relative risks for each topic and the summary relative relative risks across all topics. Similar analyses were performed for the primary binary outcome of each topic.139 meta-analyses with mortality outcomes were eligible. No nominally significant differences between more developed and less developed countries were found for 128 (92%) meta-analyses. However, differences were beyond chance in 11 (8%) cases, always showing more favourable treatment effects in trials from less developed countries. The summary relative relative risk was 1.12 (95% confidence interval 1.06 to 1.18; P<0.001; I(2)=0%), suggesting significantly more favourable mortality effects in trials from less developed countries. Results were similar for meta-analyses with nominally significant treatment effects for mortality (1.15), meta-analyses with recent trials (1.14), and when excluding trials from less developed countries that subsequently became more developed (1.12). For the primary binary outcomes (127 meta-analyses), 20 topics had differences in treatment effects beyond chance (more favourable in less developed countries in 15/20 cases).Trials from less developed countries in a few cases show significantly more favourable treatment effects than trials in more developed countries and, on average, treatment effects are more favourable in less developed countries. These discrepancies may reflect biases in reporting or study design as well as genuine differences in baseline risk or treatment implementation and should be considers when generalising evidence across different settings.

    View details for DOI 10.1136/bmj.f707

    View details for Web of Science ID 000315087700003

    View details for PubMedID 23403829

    View details for PubMedCentralID PMC3570069

  • Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study PLOS ONE Stefanaki, I., Panagiotou, O. A., Kodela, E., Gogas, H., Kypreou, K. P., Chatzinasiou, F., Nikolaou, V., Plaka, M., Kalfa, I., Antoniou, C., Ioannidis, J. P., Evangelou, E., Stratigos, A. J. 2013; 8 (2)

    Abstract

    Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982--SLC45A2, rs12203592--IRF4, rs258322--CDK10, rs1805007--MC1R, rs1805008--MC1R, rs910873--PIGU, rs17305573--PIGU, and rs1885120--MTAP) and higher for one SNP (rs6001027--PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22-2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34-0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03-9.43; P = 2×10⁻⁵). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66).Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.

    View details for DOI 10.1371/journal.pone.0055712

    View details for Web of Science ID 000314692800051

    View details for PubMedID 23393597

    View details for PubMedCentralID PMC3564929

  • Assessment of systematic effects of methodological characteristics on candidate genetic associations HUMAN GENETICS Aljasir, B., Ioannidis, J. P., Yurkiewich, A., Moher, D., Higgins, J. P., Arora, P., Little, J. 2013; 132 (2): 167-178

    Abstract

    Candidate genetic association studies have been found to have a low replication rate in the past. Here, we aimed to assess whether aspects of reported methodological characteristics in genetic association studies may be related to the magnitude of effects observed. An observational, literature-based investigation of 511 case-control studies of genetic association studies indexed in 2007, was undertaken. Meta-regression analyses were used to assess the relationship between 23 reported methodological characteristics and the magnitude of genetic associations. The 511 studies had been conducted in 52 countries and were published in 220 journals (median impact factor 5.1). The multivariate meta-regression model of methodological characteristics plus disease category accounted for 17.2 % of the between-study variance in the magnitude of the reported genetic associations. Our findings are consistent with the view that better conducted and better reported genetic association research may lead to less inflated results.

    View details for DOI 10.1007/s00439-012-1237-4

    View details for Web of Science ID 000313518900006

    View details for PubMedID 23095857

  • The genetic basis of cross-phenotype correlation with bone fracture risk: the GEFOS consortium Oei, L., Nordstrom, P., Ntzani, E., Zheng, H., Estrada, K., Duncan, E., Medina-Gomez, C., Kaptoge, S., Hsu, Y., Yang, J., Nielson, C., Styrkarsdottir, U., Ridker, P., Garcia, M., Aragaki, A., Enneman, A., Lehtimaki, T., Esko, T., Trompet, S., Eriksson, J., Amin, N., Kung, A., Tsilidis, K., Thorleifsson, G., Rose, L., Zmuda, J., Liu, C., Vernon-Smith, A., Srikanth, P., Wilson, S., Clark, G., Viikari, J., Mihailov, E., Moayyeri, A., Li, G., Kammerer, C., Lorentzon, M., Rivera, N., Xiao, S., Tranah, G., Evans, D., Siggeirsdottir, K., Oei, E., Stefansson, K., Aalto, V., Willner, D., Wareham, N., Minster, R., Bis, J., van Duijn, C., Boyle, A., Snyder, M., Herrera, L., Cupples, L., Aspelund, T., Raitakari, O., Leo, P., Khaw, K., Robbins, J., Liu, Y., Breda, S., Luben, R., Cauley, J., Arnold, A., Reppe, S., Hibbs, M., Stolk, L., Pasco, J., Grundberg, E., Gautvik, K., Ackert-Bicknell, C., Yadav, V., Choi, K., van de Peppel, J., Van Leeuwen, J., Pols, H., Hofman, A., Shen, J., van Meurs, J., Atanasovska, B., Sham, P., Ohlsson, C., Psaty, B., Harris, T., Reeve, J., Jukema, J., Metspalu, A., Kahonen, M., van der Velde, N., Brown, M., Gudnason, V., Ioannidis, J., Uitterlinden, A., Cummings, S., Spector, T., Kiel, D., Jackson, R., Thorsteinsdottir, U., Chasman, D., Orwoll, E., Karasik, D., Zillikens, M., Evangelou, E., Richards, B., Visscher, P., Michaelsson, K., Rivadeneira, F. WILEY-BLACKWELL. 2013

    View details for Web of Science ID 000332035801175

  • Functional characterization of GWAS loci associated with fracture risk Oei, L., Reppe, S., Ntzani, E., Hibbs, M., Choi, K., Zheng, H., Estrada, K., van de Peppel, J., Nielson, C., Styrkarsdottir, U., Ridker, P., Hsu, Y., Garcia, M., Aragaki, A., Duncan, E., Enneman, A., Lehtimaki, T., Esko, T., Trompet, S., Kaptoge, S., Eriksson, J., Amin, N., Kung, A., Medina-Gomez, C., Tsilidis, K., Thorleifsson, G., Rose, L., Zmuda, J., Liu, C., Vernon-Smith, A., Srikanth, P., Wilson, S., Clark, G., Viikari, J., Mihailov, E., Moayyeri, A., Li, G., Kammerer, C., Lorentzon, M., Rivera, N., Xiao, S., Yang, J., Visscher, P., Tranah, G., Evans, D., Karasik, D., Siggeirsdottir, K., Oei, E., Stefansson, K., Aalto, V., Willner, D., Wareham, N., Minster, R., Bis, J., van Duijn, C., Boyle, A., Snyder, M., Herrera, L., Cupples, L., Aspelund, T., Raitakari, O., Leo, P., Khaw, K., Robbins, J., Liu, Y., Breda, S., Luben, R., Cauley, J., Arnold, A., Stolk, L., Pols, H., Hofman, A., Shen, J., Van Meurs, J., Sham, P., Zillikens, M., Ohlsson, C., Psaty, B., Harris, T., Reeve, J., Jukema, J., Metspalu, A., Kahonen, M., van der Velde, N., Brown, M., Gudnason, V., Ioannidis, J., Uitterlinden, A., Cummings, S., Spector, T., Kiel, D., Jackson, R., Thorsteinsdottir, U., Chasman, D., Orwoll, E., Yadav, V., Van Leeuwen, J., Evangelou, E., Grundberg, E., Richards, B., Gautvik, K., Rivadeneira, F., Ackert-Bicknell, C., GEFOS Consortium WILEY-BLACKWELL. 2013

    View details for Web of Science ID 000332035803064

  • Distinguishing true from false positives in genomic studies: p values EUROPEAN JOURNAL OF EPIDEMIOLOGY Broer, L., Lill, C. M., Schuur, M., Amin, N., Roehr, J. T., Bertram, L., Ioannidis, J. P., van Duijn, C. M. 2013; 28 (2): 131-138

    Abstract

    Distinguishing true from false positive findings is a major challenge in human genetic epidemiology. Several strategies have been devised to facilitate this, including the positive predictive value (PPV) and a set of epidemiological criteria, known as the "Venice" criteria. The PPV measures the probability of a true association, given a statistically significant finding, while the Venice criteria grade the credibility based on the amount of evidence, consistency of replication and protection from bias. A vast majority of journals use significance thresholds to identify the true positive findings. We studied the effect of p value thresholds on the PPV and used the PPV and Venice criteria to define usable thresholds of statistical significance. Theoretical and empirical analyses of data published on AlzGene show that at a nominal p value threshold of 0.05 most "positive" findings will turn out to be false if the prior probability of association is below 0.10 even if the statistical power of the study is higher than 0.80. However, in underpowered studies (0.25) with a low prior probability of 1 × 10(-3), a p value of 1 × 10(-5) yields a high PPV (>96 %). Here we have shown that the p value threshold of 1 × 10(-5) gives a very strong evidence of association in almost all studies. However, in the case of a very high prior probability of association (0.50) a p value threshold of 0.05 may be sufficient, while for studies with very low prior probability of association (1 × 10(-4); genome-wide association studies for instance) 1 × 10(-7) may serve as a useful threshold to declare significance.

    View details for DOI 10.1007/s10654-012-9755-x

    View details for Web of Science ID 000316638900003

    View details for PubMedID 23371043

  • Effect of left ventricular ejection fraction and QRS duration on the survival benefit of implantable cardioverter-defibrillators: Meta-analysis of primary prevention trials HEART RHYTHM Katritsis, D. G., Siontis, K. C., Bigger, J. T., Kadish, A. H., Steinman, R., Zareba, W., Siontis, G. C., Bardy, G. H., Ioannidis, J. P. 2013; 10 (2): 200-206

    Abstract

    Implantable cardioverter-defibrillators (ICDs) are recommended for the primary prevention of sudden cardiac death in patients with left ventricular dysfunction, but it is unclear whether treatment benefits are diminished in patients with very low baseline left ventricular ejection fraction (LVEF) (<25%) or increased in those with prolonged QRS duration (>120 ms).To study the effects of very low LVEF and prolonged QRS duration on the mortality benefits of ICD therapy.We performed a meta-analysis of primary prevention randomized controlled trials comparing ICD and standard medical therapy. All-cause mortality hazard ratios (HRs) in subgroups according to thresholds of 25% for LVEF and 120 ms for QRS duration were extracted from published reports or contributed by trial investigators and synthesized.There was no significant difference of ICD effectiveness in LVEF subgroups of 25%-35% (random effects HR 0.81; 95% confidence interval [CI] 0.70-0.94) vs<25% (HR 0.71; 95% CI 0.55-0.93). Results were also similar in the narrow and wide QRS subgroups (HR 0.78; 95% CI 0.68-0.90 and HR 0.70; 95% CI 0.51-0.95, respectively). Within the LVEF<25% and wide QRS subgroups, there was large heterogeneity driven by the Defibrillator in Acute Myocardial Infarction Trial that included patients with early post-myocardial infarction and its results (HR 1.49; 95% CI 0.84-2.68 and HR 1.51; 95% CI 0.83-2.83, respectively) differed significantly from other trials (P = .008 and P = .01, respectively).LVEF values and QRS duration do not appear to directly modify the survival benefit of ICD in patients with baseline LVEF<35%. However, patients with a recent myocardial infarction do not benefit from ICD, especially when they have LVEF<25% and/or wide QRS.

    View details for DOI 10.1016/j.hrthm.2012.10.039

    View details for Web of Science ID 000315110500014

    View details for PubMedID 23107652

  • Opportunities and Challenges for Selected Emerging Technologies in Cancer Epidemiology: Mitochondrial, Epigenomic, Metabolomic, and Telomerase Profiling CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Verma, M., Khoury, M. J., Ioannidis, J. P. 2013; 22 (2): 189-200

    Abstract

    Remarkable progress has been made in the last decade in new methods for biologic measurements using sophisticated technologies that go beyond the established genome, proteome, and gene expression platforms. These methods and technologies create opportunities to enhance cancer epidemiologic studies. In this article, we describe several emerging technologies and evaluate their potential in epidemiologic studies. We review the background, assays, methods, and challenges and offer examples of the use of mitochondrial DNA and copy number assessments, epigenomic profiling (including methylation, histone modification, miRNAs, and chromatin condensation), metabolite profiling (metabolomics), and telomere measurements. We map the volume of literature referring to each one of these measurement tools and the extent to which efforts have been made at knowledge integration (e.g., systematic reviews and meta-analyses). We also clarify strengths and weaknesses of the existing platforms and the range of type of samples that can be tested with each of them. These measurement tools can be used in identifying at-risk populations and providing novel markers of survival and treatment response. Rigorous analytic and validation standards, transparent availability of massive data, and integration in large-scale evidence are essential in fulfilling the potential of these technologies.

    View details for DOI 10.1158/1055-9965.EPI-12-1263

    View details for Web of Science ID 000314700800002

    View details for PubMedID 23242141

    View details for PubMedCentralID PMC3565041

  • Mega-Trials for Blockbusters JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (3): 239-240

    View details for Web of Science ID 000313546800020

    View details for PubMedID 23321760

  • Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants NATURE Fu, W., O'Connor, T. D., Jun, G., Kang, H. M., Abecasis, G., Leal, S. M., Gabriel, S., Altshuler, D., Shendure, J., Nickerson, D. A., Bamshad, M. J., Akey, J. M. 2013; 493 (7431): 216-220

    Abstract

    Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

    View details for DOI 10.1038/nature11690

    View details for Web of Science ID 000313259600038

    View details for PubMedID 23201682

  • NIH funding: the critics respond NATURE Ioannidis, J. P., Nicholson, J. M. 2013; 493 (7430): 26-26

    View details for Web of Science ID 000312933800016

    View details for PubMedID 23282353

  • This I believe in genetics: discovery can be a nuisance, replication is science, implementation matters. Frontiers in genetics Ioannidis, J. P. 2013; 4: 33-?

    View details for DOI 10.3389/fgene.2013.00033

    View details for PubMedID 23505393

    View details for PubMedCentralID PMC3596761

  • Ensuring the integrity of clinical practice guidelines: a tool for protecting patients. BMJ (Clinical research ed.) Lenzer, J., Hoffman, J. R., Furberg, C. D., Ioannidis, J. P. 2013; 347: f5535-?

    View details for DOI 10.1136/bmj.f5535

    View details for PubMedID 24046286

  • Assessment of osteoarthritis candidate genes in a meta-analysis of 9 genome-wide association studies. Arthritis and rheumatism Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garces, C. M., Gomez-Reino, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2013

    Abstract

    Objectives: To assess osteoarthritis (OA) candidate genes for identification of promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods: 199 published candidate genes for OA were obtained from the HuGe Navigator. All their SNPs with allele frequency >5% were assessed with fixed effect meta-analysis of 9 genome-wide association studies (GWAS) including 5 636 knee OA patients and 16 972 controls, and 4 349 hip OA patients and 17 836 controls of European ancestry. Additional 5 921 individuals were studied for top SNPs in the meta-analysis. Significance was corrected for the number of independent tests at p < 1.58 x 10(-5) . Results: SNPs at only two of the 199 candidate genes were associated with OA in the meta-analysis. They were associated with hip OA, COL11A1 showing two independent associations in the combined analysis (rs4907986, p = 1.29 x 10(-5) , OR = 1.12; 95 % CI = 1.06-1.17; and rs1241164, p = 1.47 x 10(-5) , OR = 0.82, CI = 0.74-0.89) and a SNP in linkage disequilibrium with rs4907986 in the female-specific analysis (rs4908291, p = 1.29 x 10(-5) , OR = 0.87, CI = 0.82-0.92), and VEGF associated in male-specific analysis (rs833058, p = 1.35 x 10(-5) , OR = 0.85, CI = 0.79-0.91). After genotyping additional samples, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion: Two candidate genes were significantly associated with OA in this focused meta-analysis COL11A1 and VEGF. The remaining candidate genes were not associated. © 2013 American College of Rheumatology.

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24338622

  • Potential reporting bias in FMRI studies of the brain. PloS one David, S. P., Ware, J. J., Chu, I. M., Loftus, P. D., Fusar-Poli, P., Radua, J., Munafò, M. R., Ioannidis, J. P. 2013; 8 (7)

    Abstract

    Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants.After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher's z transformation.There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies.These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.

    View details for DOI 10.1371/journal.pone.0070104

    View details for PubMedID 23936149

    View details for PubMedCentralID PMC3723634

  • More Than a Billion People Taking Statins?: Potential Implications of the New Cardiovascular Guidelines. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2013

    View details for DOI 10.1001/jama.2013.284657

    View details for PubMedID 24296612

  • Is everything we eat associated with cancer? A systematic cookbook review AMERICAN JOURNAL OF CLINICAL NUTRITION Schoenfeld, J. D., Loannidis, J. P. 2013; 97 (1): 127-134

    Abstract

    Nutritional epidemiology is a highly prolific field. Debates on associations of nutrients with disease risk are common in the literature and attract attention in public media.We aimed to examine the conclusions, statistical significance, and reproducibility in the literature on associations between specific foods and cancer risk.We selected 50 common ingredients from random recipes in a cookbook. PubMed queries identified recent studies that evaluated the relation of each ingredient to cancer risk. Information regarding author conclusions and relevant effect estimates were extracted. When >10 articles were found, we focused on the 10 most recent articles.Forty ingredients (80%) had articles reporting on their cancer risk. Of 264 single-study assessments, 191 (72%) concluded that the tested food was associated with an increased (n = 103) or a decreased (n = 88) risk; 75% of the risk estimates had weak (0.05 > P ≥ 0.001) or no statistical (P > 0.05) significance. Statistically significant results were more likely than nonsignificant findings to be published in the study abstract than in only the full text (P < 0.0001). Meta-analyses (n = 36) presented more conservative results; only 13 (26%) reported an increased (n = 4) or a decreased (n = 9) risk (6 had more than weak statistical support). The median RRs (IQRs) for studies that concluded an increased or a decreased risk were 2.20 (1.60, 3.44) and 0.52 (0.39, 0.66), respectively. The RRs from the meta-analyses were on average null (median: 0.96; IQR: 0.85, 1.10).Associations with cancer risk or benefits have been claimed for most food ingredients. Many single studies highlight implausibly large effects, even though evidence is weak. Effect sizes shrink in meta-analyses.

    View details for DOI 10.3945/ajcn.112.047142

    View details for Web of Science ID 000313135600018

    View details for PubMedID 23193004

  • Systematic identification of interaction effects between validated genome- and environment-wide associations on Type 2 Diabetes Mellitus. AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 2013: 135-?

    View details for PubMedID 24303322

  • Appropriate vs Clinically Useful Diagnostic Tests. JAMA internal medicine Ioannidis, J. P. 2013

    View details for DOI 10.1001/jamainternmed.2013.6582

    View details for PubMedID 23877418

  • Overlapping meta-analyses on the same topic: survey of published studies. BMJ (Clinical research ed.) Siontis, K. C., Hernandez-Boussard, T., Ioannidis, J. P. 2013; 347: f4501-?

    Abstract

    To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic.Survey of published meta-analyses.PubMed.Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013.Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses.While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.

    View details for DOI 10.1136/bmj.f4501

    View details for PubMedID 23873947

  • Demystifying trial networks and network meta-analysis. BMJ (Clinical research ed.) Mills, E. J., Thorlund, K., Ioannidis, J. P. 2013; 346: f2914-?

    View details for DOI 10.1136/bmj.f2914

    View details for PubMedID 23674332

  • Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment. BMJ (Clinical research ed.) Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 346: f707-?

    Abstract

    To compare treatment effects from randomised trials conducted in more developed versus less developed countries.Meta-epidemiological study.Cochrane Database of Systematic Reviews (August 2012).Meta-analyses with mortality outcomes including data from at least one randomised trial conducted in a less developed country and one in a more developed country. Relative risk estimates of more versus less developed countries were compared by calculating the relative relative risks for each topic and the summary relative relative risks across all topics. Similar analyses were performed for the primary binary outcome of each topic.139 meta-analyses with mortality outcomes were eligible. No nominally significant differences between more developed and less developed countries were found for 128 (92%) meta-analyses. However, differences were beyond chance in 11 (8%) cases, always showing more favourable treatment effects in trials from less developed countries. The summary relative relative risk was 1.12 (95% confidence interval 1.06 to 1.18; P<0.001; I(2)=0%), suggesting significantly more favourable mortality effects in trials from less developed countries. Results were similar for meta-analyses with nominally significant treatment effects for mortality (1.15), meta-analyses with recent trials (1.14), and when excluding trials from less developed countries that subsequently became more developed (1.12). For the primary binary outcomes (127 meta-analyses), 20 topics had differences in treatment effects beyond chance (more favourable in less developed countries in 15/20 cases).Trials from less developed countries in a few cases show significantly more favourable treatment effects than trials in more developed countries and, on average, treatment effects are more favourable in less developed countries. These discrepancies may reflect biases in reporting or study design as well as genuine differences in baseline risk or treatment implementation and should be considers when generalising evidence across different settings.

    View details for DOI 10.1136/bmj.f707

    View details for PubMedID 23403829

  • Are randomized trials obsolete or more important than ever in the genomic era? Genome medicine Ioannidis, J. P., Khoury, M. J. 2013; 5 (4): 32

    View details for DOI 10.1186/gm436

    View details for PubMedID 23673134

  • Trends in citations to books on epidemiological and statistical methods in the biomedical literature. PloS one Porta, M., Vandenbroucke, J. P., Ioannidis, J. P., Sanz, S., Fernandez, E., Bhopal, R., Morabia, A., Victora, C., Lopez, T. 2013; 8 (5)

    Abstract

    There are no analyses of citations to books on epidemiological and statistical methods in the biomedical literature. Such analyses may shed light on how concepts and methods changed while biomedical research evolved. Our aim was to analyze the number and time trends of citations received from biomedical articles by books on epidemiological and statistical methods, and related disciplines.The data source was the Web of Science. The study books were published between 1957 and 2010. The first year of publication of the citing articles was 1945. We identified 125 books that received at least 25 citations. Books first published in 1980-1989 had the highest total and median number of citations per year. Nine of the 10 most cited texts focused on statistical methods. Hosmer & Lemeshow's Applied logistic regression received the highest number of citations and highest average annual rate. It was followed by books by Fleiss, Armitage, et al., Rothman, et al., and Kalbfleisch and Prentice. Fifth in citations per year was Sackett, et al., Evidence-based medicine. The rise of multivariate methods, clinical epidemiology, or nutritional epidemiology was reflected in the citation trends. Educational textbooks, practice-oriented books, books on epidemiological substantive knowledge, and on theory and health policies were much less cited. None of the 25 top-cited books had the theoretical or sociopolitical scope of works by Cochrane, McKeown, Rose, or Morris.Books were mainly cited to reference methods. Books first published in the 1980s continue to be most influential. Older books on theory and policies were rooted in societal and general medical concerns, while the most modern books are almost purely on methods.

    View details for DOI 10.1371/journal.pone.0061837

    View details for PubMedID 23667447

    View details for PubMedCentralID PMC3646840

  • The Power of Meta-Analysis in Genome-Wide Association Studies ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 14 Panagiotou, O. A., Willer, C. J., Hirschhorn, J. N., Ioannidis, J. P. 2013; 14: 441-465

    Abstract

    Meta-analysis of multiple genome-wide association (GWA) studies has become common practice over the past few years. The main advantage of this technique is the maximization of power to detect subtle genetic effects for common traits. Moreover, one can use meta-analysis to probe and identify heterogeneity in the effect sizes across the combined studies. In this review, we systematically appraise and evaluate the characteristics of GWA meta-analyses with 10,000 or more subjects published up to June 2012. We provide an overview of the current landscape of variants discovered by GWA meta-analyses, and we discuss and assess with extrapolations from empirical data the value of larger meta-analyses for the discovery of additional genetic associations and new biology in the future. Finally, we discuss some emerging logistical and practical issues related to the conduct of meta-analysis of GWA studies. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

    View details for DOI 10.1146/annurev-genom-091212-153520

    View details for Web of Science ID 000326658500020

    View details for PubMedID 23724904

  • Evaluating Health System Processes With Randomized Controlled Trials. JAMA internal medicine Ioannidis, J. P., Prasad, V. 2013: 1–2

    View details for DOI 10.1001/jamainternmed.2013.1044

    View details for PubMedID 23689271

  • The geometric increase in meta-analyses from china in the genomic era. PloS one Ioannidis, J. P., Chang, C. Q., Lam, T. K., Schully, S. D., Khoury, M. J. 2013; 8 (6)

    Abstract

    Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses.

    View details for DOI 10.1371/journal.pone.0065602

    View details for PubMedID 23776510

    View details for PubMedCentralID PMC3680482

  • Meta-analyses of hydroxyethyl starch for volume resuscitation. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2013; 309 (21): 2209

    View details for DOI 10.1001/jama.2013.5817

    View details for PubMedID 23736722

  • Biomarker Failures CLINICAL CHEMISTRY Ioannidis, J. P. 2013; 59 (1): 202-204

    View details for DOI 10.1373/clinchem.2012.185801

    View details for Web of Science ID 000313535100033

    View details for PubMedID 22997282

  • How Many Contemporary Medical Practices Are Worse Than Doing Nothing or Doing Less? Mayo Clinic proceedings. Mayo Clinic Ioannidis, J. P. 2013

    View details for DOI 10.1016/j.mayocp.2013.05.010

    View details for PubMedID 23871231

  • Knowledge Integration in Cancer: Current Landscape and Future Prospects CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ioannidis, J. P., Schully, S. D., Lam, T. K., Khoury, M. J. 2013; 22 (1): 3-10

    Abstract

    Knowledge integration includes knowledge management, synthesis, and translation processes. It aims to maximize the use of collected scientific information and accelerate translation of discoveries into individual and population health benefits. Accumulated evidence in cancer epidemiology constitutes a large share of the 2.7 million articles on cancer in PubMed. We examine the landscape of knowledge integration in cancer epidemiology. Past approaches have mostly used retrospective efforts of knowledge management and traditional systematic reviews and meta-analyses. Systematic searches identify 2,332 meta-analyses, about half of which are on genetics and epigenetics. Meta-analyses represent 1:89-1:1162 of published articles in various cancer subfields. Recently, there are more collaborative meta-analyses with individual-level data, including those with prospective collection of measurements [e.g., genotypes in genome-wide association studies (GWAS)]; this may help increase the reliability of inferences in the field. However, most meta-analyses are still done retrospectively with published information. There is also a flurry of candidate gene meta-analyses with spuriously prevalent "positive" results. Prospective design of large research agendas, registration of datasets, and public availability of data and analyses may improve our ability to identify knowledge gaps, maximize and accelerate translational progress or-at a minimum-recognize dead ends in a more timely fashion.

    View details for DOI 10.1158/1055-9965.EPI-12-1144

    View details for Web of Science ID 000313531900001

    View details for PubMedID 23093546

  • Research grants: Conform and be funded. Nature Nicholson, J. M., Ioannidis, J. P. 2012; 492 (7427): 34-36

    View details for DOI 10.1038/492034a

    View details for PubMedID 23222591

  • Scientific inbreeding and same-team replication: Type D personality as an example JOURNAL OF PSYCHOSOMATIC RESEARCH Ioannidis, J. P. 2012; 73 (6): 408-410

    Abstract

    Replication is essential for validating correct results, sorting out false-positive early discoveries, and improving the accuracy and precision of estimated effects. However, some types of seemingly successful replication may foster a spurious notion of increased credibility, if they are performed by the same team and propagate or extend the same errors made by the original discoveries. Besides same-team replication, replication by other teams may also succumb to inbreeding, if it cannot fiercely maintain its independence. These patterns include obedient replication and obliged replication. I discuss these replication patterns in the context of associations and effects in the psychological sciences, drawing from the criticism of Coyne and de Voogd of the proposed association between type D personality and cardiovascular mortality and other empirical examples.

    View details for DOI 10.1016/j.jpsychores.2012.09.014

    View details for Web of Science ID 000311465500002

    View details for PubMedID 23148806

  • METRADISC-XL: A program for meta-analysis of multidimensional ranked discovery oriented datasets including microarrays COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE Zintzaras, E., Ioannidis, J. P. 2012; 108 (3): 1243-1246

    Abstract

    A comprehensive software for performing meta-analysis of ranked discovery oriented datasets, such as those derived from microarrays or other high throughput technologies, and for testing between-study heterogeneity for biological variables (gene expression, microRNA, proteomic, or other high-dimensional data) is presented. The software can identify biological probes that have either very high average ranks (e.g. consistently over-expressed genes) or very low average ranks (e.g. consistently under-expressed genes). The program tests each probe's average rank and the between-study heterogeneity of the study-specific ranks. Furthermore, it performs heterogeneity analyses restricted to probes with similar average ranks. The program allows both unweighted and weighted analysis. Statistical inferences are based on Monte Carlo permutation tests.

    View details for DOI 10.1016/j.cmpb.2012.08.001

    View details for Web of Science ID 000311976100033

    View details for PubMedID 22959629

  • Reproducibility concerns NATURE MEDICINE Ioannidis, J. P., Nosek, B., Iorns, E. 2012; 18 (12): 1736-1736

    View details for DOI 10.1038/nm.3020

    View details for Web of Science ID 000311999800011

    View details for PubMedID 23223056

  • Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Staines-Urias, E., Paez, M. C., Doyle, P., Dudbridge, F., Serrano, N. C., Ioannidis, J. P., Keating, B. J., Hingorani, A. D., Casas, J. P. 2012; 41 (6): 1764-1775

    Abstract

    Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies.To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia.For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models.Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43-2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31-2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99-1.40), AGT rs699 (OR = 1.26; 99% CI 1.00-1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96-1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations.To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype.

    View details for DOI 10.1093/ije/dys162

    View details for Web of Science ID 000313128000033

    View details for PubMedID 23132613

  • Perceived information gain from randomized trials correlates with publication in high-impact factor journals JOURNAL OF CLINICAL EPIDEMIOLOGY Evangelou, E., Siontis, K. C., Pfeiffer, T., Ioannidis, J. P. 2012; 65 (12): 1274-1281

    Abstract

    To examine whether perceived information gain (IG) drives the publication of randomized trials in high-impact factor (IF) journals.We estimated IG as the Kullback-Leibler divergence, quantifying how much a new finding changes established knowledge. We used 67 meta-analyses (964 randomized trials) that include one or more trials from any of the three highest IF general medical journals (NEJM, JAMA, and Lancet). We calculated IG for the presence of a non-null effect (IG(1)) and IG for the effect size magnitude (IG(2)).Across meta-analyses, the summary correlation coefficient of IF was 0.23 (95% confidence interval [CI]: 0.14, 0.31) for IG(1) and 0.35 (95% CI: 0.25, 0.46) for IG(2). IF also correlated with the P-value of the results (r=0.18), order of publication (r=-0.13), and number of events in the trial (r=0.36). Multivariate regression including IG, order of publication, P-value, and the number of events showed that IG is an independent correlate of IF. IG(2) explained a substantially larger proportion of the variance in IF than IG(1).Publication in journals with high IF is driven by how extensively the results of a study change prior perceptions of the evidence, independently of the statistical significance and size of the study.

    View details for DOI 10.1016/j.jclinepi.2012.06.009

    View details for Web of Science ID 000310669400009

    View details for PubMedID 22959593

  • Calculating additive treatment effects from multiple randomized trials provides useful estimates of combination therapies JOURNAL OF CLINICAL EPIDEMIOLOGY Mills, E. J., Thorlund, K., Ioannidis, J. P. 2012; 65 (12): 1282-1288

    Abstract

    Many clinicians and decision makers want to know the combined effects of treatments that have not been evaluated in combination. It is possible to determine such treatment effects by making assumptions about the additive effects. We discuss here the prerequisites and methods of applying additivity assumptions in synthesizing the evidence from randomized trials and multiple treatment meta-analyses.Using statistical approaches, we demonstrate the utility of additivity of both pairwise randomized trials and multiple treatment comparison meta-analyses.We present illustratively an example on estimating the treatment effects of drug combinations for chronic obstructive pulmonary disease. We confirm the additive treatment effects by comparing with direct combination treatment trial results.Additive effects may be a useful tool to estimate the effectiveness of treatment combinations.

    View details for DOI 10.1016/j.jclinepi.2012.07.012

    View details for Web of Science ID 000310669400010

    View details for PubMedID 22981250

  • Evaluation of Excess Statistical Significance in Meta-analyses of 98 Biomarker Associations with Cancer Risk JOURNAL OF THE NATIONAL CANCER INSTITUTE Tsilidis, K. K., Papatheodorou, S. I., Evangelou, E., Ioannidis, J. P. 2012; 104 (24): 1867-1878

    Abstract

    Numerous biomarkers have been associated with cancer risk. We assessed whether there is evidence for excess statistical significance in results of cancer biomarker studies, suggesting biases.We systematically searched PubMed for meta-analyses of nongenetic biomarkers and cancer risk. The number of observed studies with statistically significant results was compared with the expected number, based on the statistical power of each study under different assumptions for the plausible effect size. We also evaluated small-study effects using asymmetry tests. All statistical tests were two-sided.We included 98 meta-analyses with 847 studies. Forty-three meta-analyses (44%) found nominally statistically significant summary effects (random effects). The proportion of meta-analyses with statistically significant effects was highest for infectious agents (86%), inflammatory (67%), and insulin-like growth factor (IGF)/insulin system (52%) biomarkers. Overall, 269 (32%) individual studies observed nominally statistically significant results. A statistically significant excess of the observed over the expected number of studies with statistically significant results was seen in 20 meta-analyses. An excess of observed vs expected was observed in studies of IGF/insulin (P ≤ .04) and inflammation systems (P ≤ .02). Only 12 meta-analyses (12%) had a statistically significant summary effect size, more than 1000 case patients, and no hints of small-study effects or excess statistical significance; only four of them had large effect sizes, three of which pertained to infectious agents (Helicobacter pylori, hepatitis and human papilloma viruses).Most well-documented biomarkers of cancer risk without evidence of bias pertain to infectious agents. Conversely, an excess of statistically significant findings was observed in studies of IGF/insulin and inflammation systems, suggesting reporting biases.

    View details for DOI 10.1093/jnci/djs437

    View details for Web of Science ID 000312891200007

    View details for PubMedID 23090067

  • There is nothing personal-reply. Archives of internal medicine Ioannidis, J. P. 2012; 172 (21): 1691-1692

    View details for DOI 10.1001/2013.jamainternmed.13

    View details for PubMedID 23753076

  • There Is Nothing Personal reply ARCHIVES OF INTERNAL MEDICINE Ioannidis, J. A. 2012; 172 (21): 1692

    View details for Web of Science ID 000311513000028

  • A Nutrient-Wide Association Study on Blood Pressure CIRCULATION Tzoulaki, I., Patel, C. J., Okamura, T., Chan, Q., Brown, I. J., Miura, K., Ueshima, H., Zhao, L., Van Horn, L., Daviglus, M. L., Stamler, J., Butte, A. J., Ioannidis, J. P., Elliott, P. 2012; 126 (21): 2456-2464

    Abstract

    A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner.Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP.We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

    View details for DOI 10.1161/CIRCULATIONAHA.112.114058

    View details for Web of Science ID 000311342600010

    View details for PubMedID 23093587

  • Content area experts as authors: helpful or harmful for systematic reviews and meta-analyses? BRITISH MEDICAL JOURNAL Gotzsche, P. C., Ioannidis, J. P. 2012; 345

    View details for DOI 10.1136/bmj.e7031

    View details for Web of Science ID 000310779000003

    View details for PubMedID 23118303

  • Effectiveness and harms of seasonal and pandemic influenza vaccines in children, adults and elderly: a critical review and re-analysis of 15 meta-analyses Manzoli, L., Ioannidis, J. A., Flacco, M. E., De Vito, C., Villari, P. OXFORD UNIV PRESS. 2012: 57

    View details for Web of Science ID 000310370400135

  • Why Science Is Not Necessarily Self-Correcting PERSPECTIVES ON PSYCHOLOGICAL SCIENCE Ioannidis, J. P. 2012; 7 (6): 645-654

    Abstract

    The ability to self-correct is considered a hallmark of science. However, self-correction does not always happen to scientific evidence by default. The trajectory of scientific credibility can fluctuate over time, both for defined scientific fields and for science at-large. History suggests that major catastrophes in scientific credibility are unfortunately possible and the argument that "it is obvious that progress is made" is weak. Careful evaluation of the current status of credibility of various scientific fields is important in order to understand any credibility deficits and how one could obtain and establish more trustworthy results. Efficient and unbiased replication mechanisms are essential for maintaining high levels of scientific credibility. Depending on the types of results obtained in the discovery and replication phases, there are different paradigms of research: optimal, self-correcting, false nonreplication, and perpetuated fallacy. In the absence of replication efforts, one is left with unconfirmed (genuine) discoveries and unchallenged fallacies. In several fields of investigation, including many areas of psychological science, perpetuated and unchallenged fallacies may comprise the majority of the circulating evidence. I catalogue a number of impediments to self-correction that have been empirically studied in psychological science. Finally, I discuss some proposed solutions to promote sound replication practices enhancing the credibility of scientific results as well as some potential disadvantages of each of them. Any deviation from the principle that seeking the truth has priority over any other goals may be seriously damaging to the self-correcting functions of science.

    View details for DOI 10.1177/1745691612464056

    View details for Web of Science ID 000310852500018

  • Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J. H., Boletis, J., Cervera, R., Doerner, T., Doria, A., Ferrario, F., Floege, J., Houssiau, F. A., Ioannidis, J. P., Isenberg, D. A., Kallenberg, C. G., Lightstone, L., Marks, S. D., Martini, A., Moroni, G., Neumann, I., Praga, M., Schneider, M., Starra, A., Tesar, V., Vasconcelos, C., Van Vollenhoven, R. F., Zakharova, H., Haubitz, M., Gordon, C., Jayne, D., Boumpas, D. T. 2012; 71 (11): 1771-1782

    Abstract

    To develop recommendations for the management of adult and paediatric lupus nephritis (LN).The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

    View details for DOI 10.1136/annrheumdis-2012-201940

    View details for Web of Science ID 000309654900004

    View details for PubMedID 22851469

    View details for PubMedCentralID PMC3465859

  • To Correct or Not to Correct-and How EPIDEMIOLOGY Ioannidis, J. P., Yu, Y., Seddon, J. M. 2012; 23 (6): 912-913

    View details for DOI 10.1097/EDE.0b013e31826cc1b3

    View details for Web of Science ID 000309965800024

    View details for PubMedID 23038115

  • Correction of Phenotype Misclassification Based on High-Discrimination Genetic Predictive Risk Models EPIDEMIOLOGY Ioannidis, J. P., Yu, Y., Seddon, J. M. 2012; 23 (6): 902-909

    Abstract

    Misclassification of phenotype status can seriously affect accuracy in association studies, including studies of genetic risk factors. A common problem is the classification of participants as nondiseased because of insufficient diagnostic workup or because participants have not been followed up long enough to develop disease. Some validated predictive models may have high discrimination in predicting disease. We suggest that information from such models can be used to predict the risk that a nondiseased participant will eventually develop disease and to recode the status of participants predicted to be at highest risk. We evaluate conditions under which recoding results in a maximal net improvement in the accuracy of phenotype classification. Net improvement is expected only when the positive likelihood ratio of the predictive model is larger than the inverse of the odds of disease among apparently nondiseased controls. We conducted simulations to probe the impact of reclassification on the power to detect new risk factors under several scenarios of classification accuracy of the previously developed models. We also apply this framework to a validated model of progression to advanced age-related macular degeneration that uses genetic and nongenetic variables (area under the curve = 0.915). In the training cohort (n = 2,937) and a separate validation cohort (n = 1,227), 195-272 and 78-91 nonprogressor participants, respectively, were reclassified as progressors. Correction of phenotype misclassification based on highly informative predictive models may be helpful in identifying additional genetic and other risk factors, when there are validated risk factors that provide strong discriminating ability.

    View details for DOI 10.1097/EDE.0b013e31826c3129

    View details for Web of Science ID 000309965800022

    View details for PubMedID 23023008

  • A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants JOURNAL OF MEDICAL GENETICS Sharma, M., Ioannidis, J. P., Aasly, J. O., Annesi, G., Brice, A., Bertram, L., Bozi, M., Barcikowska, M., Crosiers, D., Clarke, C. E., Facheris, M. F., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilarino-Guell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., Jeon, B. S., Jamrozik, Z., Krygowska-Wajs, A., Lesage, S., Lill, C. M., Lin, J., Lynch, T., Lichtner, P., Lang, A. E., Libioulle, C., Murata, M., Mok, V., Jasinska-Myga, B., Mellick, G. D., Morrison, K. E., Meitnger, T., Zimprich, A., Opala, G., Pramstaller, P. P., Pichler, I., Park, S. S., Quattrone, A., Rogaeva, E., Ross, O. A., Stefanis, L., Stockton, J. D., Satake, W., Silburn, P. A., Strom, T. M., Theuns, J., Tan, E., Toda, T., Tomiyama, H., Uitti, R. J., Van Broeckhoven, C., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Yomono, H. S., Yueh, K., Zhao, Y., Gasser, T., Maraganore, D., Krueger, R. 2012; 49 (11): 721-726

    Abstract

    Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

    View details for DOI 10.1136/jmedgenet-2012-101155

    View details for Web of Science ID 000310632800008

    View details for PubMedID 23125461

    View details for PubMedCentralID PMC3488700

  • Empirical Evaluation of Very Large Treatment Effects of Medical Interventions JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pereira, T. V., Horwitz, R. I., Ioannidis, J. P. 2012; 308 (16): 1676-1684

    Abstract

    Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms.To evaluate the frequency and features of very large effects in medicine.Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7).We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], ≥5). We also sampled randomly 250 topics from each group for further in-depth evaluation.We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses.Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < .001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < .001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns).Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.

    View details for Web of Science ID 000310434100022

    View details for PubMedID 23093165

  • Neglected tropical diseases: survey and geometry of randomised evidence BRITISH MEDICAL JOURNAL Kappagoda, S., Ioannidis, J. P. 2012; 345

    Abstract

    To assess the quantity and distribution of evidence from randomised controlled trials for the treatment of the major neglected tropical diseases and to identify gaps in the evidence with network analysis.Systematic review and network analysis.Cochrane Central Register of Controlled Trials and PubMed from inception to 31 August 2011.Randomised controlled trials that examined treatment of 16 neglected tropical diseases or complications thereof published in English, French, Spanish, Portuguese, German, or Dutch.We identified 971 eligible randomised trials. Leishmaniasis (184 trials, 23,039 participants) and geohelminth infections; 160 trials, 46,887 participants) were the most studied, while dracunculiasis (nine trials, 798 participants) and Buruli ulcer (five trials, 337 participants) were least studied. Relative to its global burden of disease, lymphatic filariasis had the fewest trials and participants. Only 11% of trials were industry funded. Either a single trial or trials with fewer than 100 participants comprised the randomised evidence for first or second line treatments for Buruli ulcer, human African trypanosomiasis, American trypanosomiasis, cysticercosis, rabies, echinococcosis, New World cutaneous leishmaniasis, and each of the foodborne trematode infections. Among the 10 disease categories with more than 40 trials, five lacked sufficient head to head comparisons between first or second line treatments.There is considerable variation in the amount of evidence from randomised controlled trials for each of the 16 major neglected tropical diseases. Even in diseases with substantial evidence, such as leishmaniasis and geohelminth infections, some recommended treatments have limited supporting data and lack head to head comparisons.

    View details for DOI 10.1136/bmj.e6512

    View details for Web of Science ID 000310426900001

    View details for PubMedID 23089149

    View details for PubMedCentralID PMC3478233

  • Sex-specific differences in effect size estimates at established complex trait loci INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Orozco, G., Ioannidis, J. P., Morris, A., Zeggini, E. 2012; 41 (5): 1376-1382

    Abstract

    Genetic differences between men and women may contribute to sex differences in prevalence and progression of many common complex diseases. Using the WTCCC GWAS, we analysed whether there are sex-specific differences in effect size estimates at 142 established loci for seven complex diseases: rheumatoid arthritis, type 1 diabetes (T1D), Crohn's disease, type 2 diabetes (T2D), hypertension, coronary artery disease and bipolar disorder.For each Single nucleotide polymorphism (SNP), we calculated the per-allele odds ratio for each sex and the relative odds ratios (RORs; the effect size is higher in men with ROR greater than one). RORs were then meta-analysed across loci within each disease and across diseases.For each disease, summary RORs were not different from one, but there was between-SNP heterogeneity in the RORs for T1D and T2D. Four loci in T1D, three in Crohn's disease and three in T2D showed differences in the genetic effect between men and women (P<0.05). We probed these differences in additional independent replication samples for T1D and T2D. The differences remained for the T1D loci CTSH, 17q21 and 20p13 and the T2D locus BCL11A, when WTCCC data and replication data were meta-analysed. Only CTSH showed different genetic effect between men and women in the replication data alone.Our results exclude the presence of large and frequent differences in the effect size estimates between men and women for the established loci in the seven common diseases explored. Documenting small differences in genetic effects between men and women requires large studies and systematic evaluation.

    View details for DOI 10.1093/ije/dys104

    View details for Web of Science ID 000309922700023

    View details for PubMedID 22825589

    View details for PubMedCentralID PMC3465768

  • In-Depth Analysis of Diagnostic Operating Characteristics Shows that Narrow Band Imaging (NBI) Is an Excellent Test to Differentiate Neoplastic and Hyperplastic Colorectal Polyps McGill, S., Evangelou, E., Ioannidis, J., Soetikno, R., Kaltenbach, T. NATURE PUBLISHING GROUP. 2012: S206

    View details for Web of Science ID 000208839700497

  • Assessment of gene-by-sex interaction effect on bone mineral density JOURNAL OF BONE AND MINERAL RESEARCH Liu, C., Estrada, K., Yerges-Armstrong, L. M., Amin, N., Evangelou, E., Li, G., Minster, R. L., Carless, M. A., Kammerer, C. M., Oei, L., Zhou, Y., Alonso, N., Dailiana, Z., Eriksson, J., Garcia-Giralt, N., Giroux, S., Husted, L. B., Khusainova, R. I., Koromila, T., Kung, A. W., Lewis, J. R., Masi, L., Mencej-Bedrac, S., Nogues, X., Patel, M. S., Prezelj, J., Richards, J. B., Sham, P. C., Spector, T., Vandenput, L., Xiao, S., Zheng, H., Zhu, K., Balcells, S., Brandi, M. L., Frost, M., Goltzman, D., Gonzalez-Macias, J., Karlsson, M., Khusnutdinova, E. K., Kollia, P., Langdahl, B. L., Ljunggren, O., Lorentzon, M., Marc, J., Mellstroem, D., Ohlsson, C., Olmos, J. M., Ralston, S. H., Riancho, J. A., Rousseau, F., Urreizti, R., Van Hul, W., Zarrabeitia, M. T., Castano-Betancourt, M., Demissie, S., Grundberg, E., Herrera, L., Kwan, T., Medina-Gomez, C., Pastinen, T., Sigurdsson, G., Thorleifsson, G., Vanmeurs, J. B., Blangero, J., Hofman, A., Liu, Y., Mitchell, B. D., O'Connell, J. R., Oostra, B. A., Rotter, J. I., Stefansson, K., Streeten, E. A., Styrkarsdottir, U., Thorsteinsdottir, U., Tylavsky, F. A., Uitterlinden, A., Cauley, J. A., Harris, T. B., Ioannidis, J. P., Psaty, B. M., Robbins, J. A., Zillikens, M. C., Vanduijn, C. M., Prince, R. L., Karasik, D., Rivadeneira, F., Kiel, D. P., Cupples, L. A., Hsu, Y. 2012; 27 (10): 2051-2064

    Abstract

    Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

    View details for DOI 10.1002/jbmr.1679

    View details for Web of Science ID 000308925800003

    View details for PubMedID 22692763

    View details for PubMedCentralID PMC3447125

  • How to use an article reporting a multiple treatment comparison meta-analysis. JAMA : the journal of the American Medical Association Mills, E. J., Ioannidis, J. P., Thorlund, K., Schünemann, H. J., Puhan, M. A., Guyatt, G. H. 2012; 308 (12): 1246-1253

    Abstract

    Multiple treatment comparison (MTC) meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions. The methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex. Clinicians and others evaluating an MTC should be aware of the potential biases that can affect the interpretation of these analyses. Readers should consider whether the primary studies are sufficiently homogeneous to combine; whether the different interventions are sufficiently similar in their populations, study designs, and outcomes; and whether the direct evidence is sufficiently similar to the indirect evidence to consider combining. This article uses the existing Users' Guides format to address study validity, interpretation of results, and application to a patient scenario.

    View details for PubMedID 23011714

  • How to Use an Article Reporting a Multiple Treatment Comparison Meta-analysis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Mills, E. J., Ioannidis, J. P., Thorlund, K., Schuenemann, H. J., Puhan, M. A., Guyatt, G. H. 2012; 308 (12): 1246-1253

    Abstract

    Multiple treatment comparison (MTC) meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions. The methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex. Clinicians and others evaluating an MTC should be aware of the potential biases that can affect the interpretation of these analyses. Readers should consider whether the primary studies are sufficiently homogeneous to combine; whether the different interventions are sufficiently similar in their populations, study designs, and outcomes; and whether the direct evidence is sufficiently similar to the indirect evidence to consider combining. This article uses the existing Users' Guides format to address study validity, interpretation of results, and application to a patient scenario.

    View details for Web of Science ID 000309103600028

  • Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials ANNALS OF INTERNAL MEDICINE Savovic, J., Jones, H. E., Altman, D. G., Harris, R. J., Jueni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., Ioannidis, J. P., Schulz, K. F., Beynon, R., Welton, N. J., Wood, L., Moher, D., Deeks, J. J., Sterne, J. A. 2012; 157 (6): 429-U97

    Abstract

    Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.

    View details for Web of Science ID 000308912800017

    View details for PubMedID 22945832

  • Extrapolating from Animals to Humans SCIENCE TRANSLATIONAL MEDICINE Ioannidis, J. P. 2012; 4 (151)

    Abstract

    Because of a variety of caveats, the safety and effectiveness of interventions in human subjects can only be speculated from animal studies. Careful synthesis of data from multiple animal studies is needed to begin to assess the likelihood of successful cross-species translation (Fay et al., this issue).

    View details for DOI 10.1126/scitranslmed.3004631

    View details for Web of Science ID 000308806000002

    View details for PubMedID 22972841

  • Implementation of proteomic biomarkers: making it work EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Mischak, H., Ioannidis, J. P., Argiles, A., Attwood, T. K., Bongcam-Rudloff, E., Broenstrup, M., Charonis, A., Chrousos, G. P., Delles, C., Dominiczak, A., Dylag, T., Ehrich, J., Egido, J., Findeisen, P., Jankowski, J., Johnson, R. W., Julien, B. A., Lankisch, T., Leung, H. Y., Maahs, D., Magni, F., Manns, M. P., Manolis, E., Mayer, G., Navis, G., Novak, J., Ortiz, A., Persson, F., Peter, K., Riese, H. H., Rossing, P., Sattar, N., Spasovski, G., Thongboonkerd, V., Vanholder, R., Schanstra, J. P., Vlahou, A. 2012; 42 (9): 1027-1036

    Abstract

    While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.

    View details for DOI 10.1111/j.1365-2362.2012.02674.x

    View details for Web of Science ID 000307473300014

    View details for PubMedID 22519700

    View details for PubMedCentralID PMC3464367

  • Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study LANCET Zeggini, E., Panoutsopoulou, K., Southam, L., Rayner, N. W., Day-Williams, A. G., Lopes, M. C., Boraska, V., Esko, T., Evangelou, E., Hofman, A., Houwing-Duistermaat, J. J., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Kerkhof, H. J., Kloppenburg, M., Bos, S. D., Mangino, M., Metrustry, S., Slagboom, P. E., Thorleifsson, G., Raine, E. V., Ratnayake, M., Ricketts, M., Beazley, C., Blackburn, H., Bumpstead, S., Elliott, K. S., Hunt, S. E., Potter, S. C., Shin, S., Yadav, V. K., Zhai, G., Sherburn, K., Dixon, K., Arden, E., Aslam, N., Battley, P., Carluke, I., Doherty, S., Gordon, A., Joseph, J., Keen, R., Koller, N. C., Mitchell, S., O'Neill, F., Paling, E., Reed, M. R., Rivadeneira, F., Swift, D., Walker, K., Watkins, B., Wheeler, M., Birrell, F., Ioannidis, J. P., Meulenbelt, I., Metspalu, A., Rai, A., Salter, D., Stefansson, K., Styrkarsdottir, U., Uitterlinden, A. G., van Meurs, J. B., Chapman, K., Deloukas, P., Ollier, W. E., Wallis, G. A., Arden, N., Carr, A., Doherty, M., McCaskie, A., Wilkinson, J. M., Ralston, S. H., Valdes, A. M., Spector, T. D., Loughlin, J. 2012; 380 (9844): 815-823

    Abstract

    Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.arcOGEN was funded by a special purpose grant from Arthritis Research UK.

    View details for DOI 10.1016/S0140-6736(12)60681-3

    View details for Web of Science ID 000308396300030

    View details for PubMedCentralID PMC3443899

  • Replication and meta-analysis of TMEM132D gene variants in panic disorder TRANSLATIONAL PSYCHIATRY Erhardt, A., Akula, N., Schumacher, J., Czamara, D., Karbalai, N., Mueller-Myhsok, B., Mors, O., Borglum, A., Kristensen, A. S., Woldbye, D. P., Koefoed, P., Eriksson, E., Maron, E., Metspalu, A., Nurnberger, J., Philibert, R. A., Kennedy, J., Domschke, K., Reif, A., Deckert, J., Otowa, T., Kawamura, Y., Kaiya, H., Okazaki, Y., Tanii, H., Tokunaga, K., Sasaki, T., Ioannidis, J. P., McMahon, F. J., Binder, E. B. 2012; 2

    Abstract

    A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

    View details for DOI 10.1038/tp.2012.85

    View details for Web of Science ID 000312900000001

    View details for PubMedID 22948381

    View details for PubMedCentralID PMC3565207

  • Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-related Macular Degeneration Subtypes OPHTHALMOLOGY Sobrin, L., Ripke, S., Yu, Y., Fagerness, J., Bhangale, T. R., Tan, P. L., Souied, E. H., Buitendijk, G. H., Merriam, J. E., Richardson, A. J., Raychaudhuri, S., Reynolds, R., Chin, K. A., Lee, A. Y., Leveziel, N., Zack, D. J., Campochiaro, P., Smith, R. T., Barile, G. R., Hogg, R. E., Chakravarthy, U., Behrens, T. W., Uitterlinden, A. G., van Duijn, C. M., Vingerling, J. R., Brantley, M. A., Baird, P. N., Klaver, C. C., Allikmets, R., Katsanis, N., Graham, R. R., Ioannidis, J. P., Daly, M. J., Seddon, J. M. 2012; 119 (9): 1874-1885

    Abstract

    To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.Sibling correlation study and genome-wide association study (GWAS).For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

    View details for DOI 10.1016/j.ophtha.2012.03.014

    View details for Web of Science ID 000310581200023

    View details for PubMedID 22705344

  • Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies HEALTH TECHNOLOGY ASSESSMENT Savovic, J., Jones, H. E., Altman, D. G., Harris, R. J., Juni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., Ioannidis, J. P., Schulz, K. F., Beynon, R., Welton, N., Wood, L., Moher, D., Deeks, J. J., Sterne, J. A. 2012; 16 (35): 1-?

    Abstract

    The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent.To examine the influence of unclear or inadequate random sequence generation and allocation concealment, and unclear or absent double blinding, on intervention effect estimates and between-trial heterogeneity, and whether or not these influences vary with type of clinical area, intervention, comparison and outcome measure.Data were combined from seven contributing meta-epidemiological studies (collections of meta-analyses in which trial characteristics are assessed and results recorded). The resulting database was used to identify and remove overlapping meta-analyses. Outcomes were coded such that odds ratios < 1 correspond to beneficial intervention effects. Outcome measures were classified as mortality, other objective or subjective. We examined agreement between assessments of trial characteristics in trials assessed in more than one contributing study. We used hierarchical Bayesian bias models to estimate the effect of trial characteristics on average bias [quantified as ratios of odds ratios (RORs) with 95% credible intervals (CrIs) comparing trials with and without a characteristic] and in increasing between-trial heterogeneity.The analysis data set contained 1973 trials included in 234 meta-analyses. Median kappa statistics for agreement between assessments of trial characteristics were: sequence generation 0.60, allocation concealment 0.58 and blinding 0.87. Intervention effect estimates were exaggerated by an average 11% in trials with inadequate or unclear (compared with adequate) sequence generation (ROR 0.89, 95% CrI 0.82 to 0.96); between-trial heterogeneity was higher among such trials. Bias associated with inadequate or unclear sequence generation was greatest for subjective outcomes (ROR 0.83, 95% CrI 0.74 to 0.94) and the increase in heterogeneity was greatest for such outcomes [standard deviation (SD) 0.20, 95% CrI 0.03 to 0.32]. The effect of inadequate or unclear (compared with adequate) allocation concealment was greatest among meta-analyses with a subjectively assessed outcome intervention effect (ROR 0.85, 95% CrI 0.75 to 0.95), and the increase in between-trial heterogeneity was also greatest for such outcomes (SD 0.20, 95% CrI 0.02 to 0.33). Lack of, or unclear, double blinding (compared with double blinding) was associated with an average 13% exaggeration of intervention effects (ROR 0.87, 95% CrI 0.79 to 0.96), and between-trial heterogeneity was increased for such studies (SD 0.14, 95% CrI 0.02 to 0.30). Average bias (ROR 0.78, 95% CrI 0.65 to 0.92) and between-trial heterogeneity (SD 0.37, 95% CrI 0.19 to 0.53) were greatest for meta-analyses assessing subjective outcomes. Among meta-analyses with subjectively assessed outcomes, the effect of lack of blinding appeared greater than the effect of inadequate or unclear sequence generation or allocation concealment.Bias associated with specific reported study design characteristics leads to exaggeration of beneficial intervention effect estimates and increases in between-trial heterogeneity. For each of the three characteristics assessed, these effects were greatest for subjectively assessed outcomes. Assessments of the risk of bias in RCTs should account for these findings. Further research is needed to understand the effects of attrition bias, as well as the relative importance of blinding of patients, care-givers and outcome assessors, and thus separate the effects of performance and detection bias.National Institute for Health Research Health Technology Assessment programme.

    View details for DOI 10.3310/hta16350

    View details for Web of Science ID 000311662000001

    View details for PubMedID 22989478

  • STrengthening the Reporting of OBservational studies in Epidemiology: Molecular Epidemiology STROBE-ME. An extension of the STROBE statement JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 66 (9): 844-854

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility, and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as STrengthening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1136/jech-2011-200318

    View details for Web of Science ID 000307101800014

    View details for PubMedID 22025194

  • The Importance of Potential Studies That Have Not Existed and Registration of Observational Data Sets JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2012; 308 (6): 575-576

    View details for Web of Science ID 000307228400022

    View details for PubMedID 22871867

  • TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome NATURE GENETICS Boileau, C., Guo, D., Hanna, N., Regalado, E. S., Detaint, D., Gong, L., Varret, M., Prakash, S. K., Li, A. H., d'Indy, H., Braverman, A. C., Grandchamp, B., Kwartler, C. S., Gouya, L., Santos-Cortez, R. L., Abifadel, M., Leal, S. M., Muti, C., Shendure, J., Gross, M., Rieder, M. J., Vahanian, A., Nickerson, D. A., Michel, J. B., Jondeau, G., Milewicz, D. M. 2012; 44 (8): 916-?

    Abstract

    A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

    View details for DOI 10.1038/ng.2348

    View details for Web of Science ID 000306854700018

    View details for PubMedID 22772371

  • Large-scale replication and heterogeneity in Parkinson disease genetic loci NEUROLOGY Sharma, M., Ioannidis, J. P., Aasly, J. O., Annesi, G., Brice, A., Van Broeckhoven, C., Bertram, L., Bozi, M., Crosiers, D., Clarke, C., Facheris, M., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilarino-Gueell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., Jeon, B., Lesage, S., Lill, C. M., Lin, J., Lynch, T., Lichtner, P., Lang, A. E., Mok, V., Jasinska-Myga, B., Mellick, G. D., Morrison, K. E., Opala, G., Pramstaller, P. P., Pichler, I., Park, S. S., Quattrone, A., Rogaeva, E., Ross, O. A., Stefanis, L., Stockton, J. D., Satake, W., Silburn, P. A., Theuns, J., Tan, E., Toda, T., Tomiyama, H., Uitti, R. J., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Yueh, K., Zhao, Y., Gasser, T., Maraganore, D., Krueger, R. 2012; 79 (7): 659-667

    Abstract

    Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

    View details for Web of Science ID 000307475200013

    View details for PubMedID 22786590

    View details for PubMedCentralID PMC3414661

  • Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nature genetics Emond, M. J., Louie, T., Emerson, J., Zhao, W., Mathias, R. A., Knowles, M. R., Wright, F. A., Rieder, M. J., Tabor, H. K., Nickerson, D. A., Barnes, K. C., Gibson, R. L., Bamshad, M. J. 2012; 44 (8): 886-889

    Abstract

    Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.

    View details for DOI 10.1038/ng.2344

    View details for PubMedID 22772370

  • Pediatric Versus Adult Drug Trials for Conditions With High Pediatric Disease Burden PEDIATRICS Bourgeois, F. T., Murthy, S., Pinto, C., Olson, K. L., Ioannidis, J. P., Mandl, K. D. 2012; 130 (2): 285-292

    Abstract

    Optimal treatment decisions in children require sufficient evidence on the safety and efficacy of pharmaceuticals in pediatric patients. However, there is concern that not enough trials are conducted in children and that pediatric trials differ from those performed in adults. Our objective was to measure the prevalence of pediatric studies among clinical drug trials and compare trial characteristics and quality indicators between pediatric and adult drug trials.For conditions representing a high burden of pediatric disease, we identified all drug trials registered in ClinicalTrials.gov with start dates between 2006 and 2011 and tracked the resulting publications. We measured the proportion of pediatric trials and subjects for each condition and compared pediatric and adult trial characteristics and quality indicators.For the conditions selected, 59.9% of the disease burden was attributable to children, but only 12.0% (292/2440) of trials were pediatric (P < .001). Among pediatric trials, 58.6% were conducted without industry funding compared with 35.0% of adult trials (P < .001). Fewer pediatric compared with adult randomized trials examined safety outcomes (10.1% vs 16.9%, P = .008). Pediatric randomized trials were slightly more likely to be appropriately registered before study start (46.9% vs 39.3%, P = .04) and had a modestly higher probability of publication in the examined time frame (32.8% vs 23.2%, P = .04).There is substantial discrepancy between pediatric burden of disease and the amount of clinical trial research devoted to pediatric populations. This may be related in part to trial funding, with pediatric trials relying primarily on government and nonprofit organizations.

    View details for DOI 10.1542/peds.2012-0139

    View details for Web of Science ID 000307123000049

    View details for PubMedID 22826574

    View details for PubMedCentralID PMC3408692

  • Estimating the contribution of genetic variants to difference in incidence of disease between population groups EUROPEAN JOURNAL OF HUMAN GENETICS Moonesinghe, R., Ioannidis, J. P., Flanders, W. D., Yang, Q., Truman, B. I., Khoury, M. J. 2012; 20 (8): 831-836

    Abstract

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

    View details for DOI 10.1038/ejhg.2012.15

    View details for Web of Science ID 000306556600007

    View details for PubMedID 22333905

    View details for PubMedCentralID PMC3400729

  • Concordance of Sleep and Pain Outcomes of Diverse Interventions: An Umbrella Review PLOS ONE Doufas, A. G., Panagiotou, O. A., Ioannidis, J. P. 2012; 7 (7)

    Abstract

    Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep.We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes.151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P = 0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r = 0.17, P = 0.092).Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain.

    View details for DOI 10.1371/journal.pone.0040891

    View details for Web of Science ID 000306507000039

    View details for PubMedID 22815856

    View details for PubMedCentralID PMC3398909

  • Usefulness of Medical Conferences Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2012; 308 (1): 32–33

    View details for DOI 10.1001/jama.2012.6378

    View details for Web of Science ID 000306183000016

  • Time to compare impact and feasibility of prediction models in real life reply BRITISH MEDICAL JOURNAL Siontis, G. C., Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2012; 344

    View details for DOI 10.1136/bmj.e4360

    View details for Web of Science ID 000306274800015

  • Consistency of genome-wide associations across major ancestral groups HUMAN GENETICS Ntzani, E. E., Liberopoulos, G., Manolio, T. A., Ioannidis, J. P. 2012; 131 (7): 1057-1071

    Abstract

    It is not well known whether genetic markers identified through genome-wide association studies (GWAS) confer similar or different risks across people of different ancestry. We screened a regularly updated catalog of all published GWAS curated at the NHGRI website for GWAS-identified associations that had reached genome-wide significance (p ≤ 5 × 10(-8)) in at least one major ancestry group (European, Asian, African) and for which replication data were available for comparison in at least two different major ancestry groups. These groups were compared for the correlation between and differences in risk allele frequencies and genetic effects' estimates. Data on 108 eligible GWAS-identified associations with a total of 900 datasets (European, n = 624; Asian, n = 217; African, n = 60) were analyzed. Risk-allele frequencies were modestly correlated between ancestry groups, with >10% absolute differences in 75-89% of the three pairwise comparisons of ancestry groups. Genetic effect (odds ratio) point estimates between ancestry groups correlated modestly (pairwise comparisons' correlation coefficients: 0.20-0.33) and point estimates of risks were opposite in direction or differed more than twofold in 57%, 79%, and 89% of the European versus Asian, European versus African, and Asian versus African comparisons, respectively. The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups.

    View details for DOI 10.1007/s00439-011-1124-4

    View details for Web of Science ID 000305195400004

    View details for PubMedID 22183176

  • Effectiveness and harms of seasonal and pandemic influenza vaccines in children, adults and elderly A critical review and re-analysis of 15 meta-analyses HUMAN VACCINES & IMMUNOTHERAPEUTICS Manzoli, L., Ioannidis, J. P., Flacco, M. E., De Vito, C., Villari, P. 2012; 8 (7): 851-862

    Abstract

    Fifteen meta-analyses have been published between 1995 and 2011 to evaluate the efficacy/effectiveness and harms of diverse influenza vaccines--seasonal, H5N1 and 2009 (H1N1)--in various age-classes (healthy children, adults or elderly). These meta-analyses have often adopted different analyses and study selection criteria. Because it is difficult to have a clear picture of vaccine benefits and harms examining single systematic reviews, we compiled the main findings and evaluated which could be the most reasonable explanations for some differences in findings (or their interpretation) across previously published meta-analyses. For each age group, we performed analyses that included all trials that had been included in at least one relevant meta-analysis, also exploring whether effect sizes changed over time. Although we identified several discrepancies among the meta-analyses on seasonal vaccines for children and elderly, overall most seasonal influenza vaccines showed statistically significant efficacy/effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases. The available evidence on parenteral inactivated vaccines for children aged < 2 y remains scarce. Pre-pandemic "avian" H5N1 and pandemic 2009 (H1N1) vaccines can achieve satisfactory immunogenicity, but no meta-analysis has addressed H1N1 vaccination impact on clinical outcomes. Data on harms are overall reassuring, but their value is diminished by inconsistent reporting.

    View details for DOI 10.4161/hv.19917

    View details for Web of Science ID 000307107600010

    View details for PubMedID 22777099

    View details for PubMedCentralID PMC3495721

  • Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists JOURNAL OF CLINICAL EPIDEMIOLOGY Panagiotou, O. A., Ioannidis, J. P. 2012; 65 (7): 740-747

    Abstract

    To assess the interpretation of a highly heterogeneous meta-analysis by authors of primary studies and by methodologists.We surveyed the authors of studies on the association between insulin-like growth factor 1 (IGF-1) and prostate cancer, and 20 meta-analysis methodologists. Authors and methodologists presented with the respective meta-analysis results were queried about the effect size and potential causality of the association. We evaluated whether author responses correlated with the number of IGF-related articles they had published and their study results included in the meta-analysis. We also compared authors' and methodologists' responses.Authors who had published more IGF-related papers offered more generous effect size estimates for the association (ρ(s)=0.61, P=0.01) and higher likelihood that the odds ratio (OR) was greater than 1.20 (ρ(s)=0.63, P=0.01). Authors who had published themselves studies with statistically significant effects for a positive association were more likely to believe that the true OR is greater than 1.20 compared with methodologists (median likelihood 50% versus 2.5%, P=0.01).Researchers are influenced by their own investment in the field, when interpreting a meta-analysis that includes their own study. Authors who published significant results are more likely to believe that a strong association exists compared with methodologists.

    View details for DOI 10.1016/j.jclinepi.2012.01.008

    View details for Web of Science ID 000305357300006

    View details for PubMedID 22537426

  • Systematic evaluation of environmental factors: persistent pollutants and nutrients correlated with serum lipid levels INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patel, C. J., Cullen, M. R., Ioannidis, J. P., Butte, A. J. 2012; 41 (3): 828-843

    Abstract

    Both genetic and environmental factors contribute to triglyceride, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) levels. Although genome-wide association studies are currently testing the genetic factors systematically, testing and reporting one or a few factors at a time can lead to fragmented literature for environmental chemical factors. We screened for correlation between environmental factors and lipid levels, utilizing four independent surveys with information on 188 environmental factors from the Centers of Disease Control, National Health and Nutrition Examination Survey, collected between 1999 and 2006.We used linear regression to correlate each environmental chemical factor to triglycerides, LDL-C and HDL-C adjusting for age, age(2), sex, ethnicity, socio-economic status and body mass index. Final estimates were adjusted for waist circumference, diabetes status, blood pressure and survey. Multiple comparisons were controlled for by estimating the false discovery rate and significant findings were tentatively validated in an independent survey.We identified and validated 29, 9 and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Findings include hydrocarbons and nicotine associated with lower HDL-C and vitamin E (γ-tocopherol) associated with unfavourable lipid levels. Higher triglycerides and lower HDL-C were correlated with higher levels of fat-soluble contaminants (e.g. polychlorinated biphenyls and dibenzofurans). Nutrients and vitamin markers (e.g. vitamins B, D and carotenes), were associated with favourable triglyceride and HDL-C levels.Our systematic association study has enabled us to postulate about broad environmental correlation to lipid levels. Although subject to confounding and reverse causality bias, these findings merit evaluation in additional cohorts.

    View details for DOI 10.1093/ije/dys003

    View details for Web of Science ID 000306417300030

    View details for PubMedID 22421054

    View details for PubMedCentralID PMC3396318

  • Systematic Identification of Interaction Effects Between Validated Genome- and Environment-Wide Associations on Type 2 Diabetes Mellitus Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. AMER DIABETES ASSOC. 2012: A394

    View details for Web of Science ID 000209842903180

  • Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS Knowles, J. W., Assimes, T. L., Kiernan, M., Pavlovic, A., Goldstein, B. A., Yank, V., McConnell, M. V., Absher, D., Bustamante, C., Ashley, E. A., Ioannidis, J. P. 2012; 5 (3): 368-376

    View details for DOI 10.1161/CIRCGENETICS.112.962746

    View details for Web of Science ID 000309884900017

    View details for PubMedID 22715281

    View details for PubMedCentralID PMC3394683

  • Standard 6: Age Groups for Pediatric Trials PEDIATRICS Williams, K., Thomson, D., Seto, I., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Hartling, L., Klassen, T. 2012; 129: S153-S160

    View details for DOI 10.1542/peds.2012-0055I

    View details for Web of Science ID 000307396800008

    View details for PubMedID 22661762

  • Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Boffetta, P., Winn, D. M., Ioannidis, J. P., Thomas, D. C., Little, J., Smith, G. D., Cogliano, V. J., Hecht, S. S., Seminara, D., Vineis, P., Khoury, M. J. 2012; 41 (3): 686-704

    Abstract

    We propose guidelines to evaluate the cumulative evidence of gene-environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.

    View details for DOI 10.1093/ije/dys010

    View details for Web of Science ID 000306417300018

    View details for PubMedID 22596931

    View details for PubMedCentralID PMC3481885

  • Empirical Evaluation of Age Groups and Age-Subgroup Analyses in Pediatric Randomized Trials and Pediatric Meta-analyses PEDIATRICS Contopoulos-Ioannidis, D. G., Seto, I., Hamm, M. P., Thomson, D., Hartling, L., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Klassen, T., Williams, K. 2012; 129: S161-S184

    Abstract

    An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed.We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported.The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8-10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance.We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.

    View details for DOI 10.1542/peds.2012-0055J

    View details for Web of Science ID 000307396800009

    View details for PubMedID 22661763

  • Comparisons of established risk prediction models for cardiovascular disease: systematic review BRITISH MEDICAL JOURNAL Siontis, G. C., Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2012; 344

    Abstract

    To evaluate the evidence on comparisons of established cardiovascular risk prediction models and to collect comparative information on their relative prognostic performance.Systematic review of comparative predictive model studies.Medline and screening of citations and references.Studies examining the relative prognostic performance of at least two major risk models for cardiovascular disease in general populations.Information on study design, assessed risk models, and outcomes. We examined the relative performance of the models (discrimination, calibration, and reclassification) and the potential for outcome selection and optimism biases favouring newly introduced models and models developed by the authors.20 articles including 56 pairwise comparisons of eight models (two variants of the Framingham risk score, the assessing cardiovascular risk to Scottish Intercollegiate Guidelines Network to assign preventative treatment (ASSIGN) score, systematic coronary risk evaluation (SCORE) score, Prospective Cardiovascular Münster (PROCAM) score, QRESEARCH cardiovascular risk (QRISK1 and QRISK2) algorithms, Reynolds risk score) were eligible. Only 10 of 56 comparisons exceeded a 5% relative difference based on the area under the receiver operating characteristic curve. Use of other discrimination, calibration, and reclassification statistics was less consistent. In 32 comparisons, an outcome was used that had been used in the original development of only one of the compared models, and in 25 of these comparisons (78%) the outcome-congruent model had a better area under the receiver operating characteristic curve. Moreover, authors always reported better area under the receiver operating characteristic curves for models that they themselves developed (in five articles on newly introduced models and in three articles on subsequent evaluations).Several risk prediction models for cardiovascular disease are available and their head to head comparisons would benefit from standardised reporting and formal, consistent statistical comparisons. Outcome selection and optimism biases apparently affect this literature.

    View details for DOI 10.1136/bmj.e3318

    View details for Web of Science ID 000304591600005

    View details for PubMedID 22628003

  • Invited commentary-Genetic prediction for common diseases. Archives of internal medicine Ioannidis, J. P. 2012; 172 (9): 744-746

    View details for DOI 10.1001/archinternmed.2012.931

    View details for PubMedID 22782208

  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture NATURE GENETICS Estrada, K., Styrkarsdottir, U., Evangelou, E., Hsu, Y., Duncan, E. L., Ntzani, E. E., Oei, L., Albagha, O. M., Amin, N., Kemp, J. P., Koller, D. L., Li, G., Liu, C., Minster, R. L., Moayyeri, A., Vandenput, L., Willner, D., Xiao, S., Yerges-Armstrong, L. M., Zheng, H., Alonso, N., Eriksson, J., Kammerer, C. M., Kaptoge, S. K., Leo, P. J., Thorleifsson, G., Wilson, S. G., Wilson, J. F., Aalto, V., Alen, M., Aragaki, A. K., Aspelund, T., Center, J. R., Dailiana, Z., Duggan, D. J., Garcia, M., Garcia-Giralt, N., Giroux, S., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Khusainova, R., Kim, G. S., Kooperberg, C., Koromila, T., Kruk, M., Laaksonen, M., LaCroix, A. Z., Lee, S. H., Leung, P. C., Lewis, J. R., Masi, L., Mencej-Bedrac, S., Nguyen, T. V., Nogues, X., Patel, M. S., Prezelj, J., Rose, L. M., Scollen, S., Siggeirsdottir, K., Smith, A. V., Svensson, O., Trompet, S., Trummer, O., van Schoor, N. M., Woo, J., Zhu, K., Balcells, S., Brandi, M. L., Buckley, B. M., Cheng, S., Christiansen, C., Cooper, C., Dedoussis, G., Ford, I., Frost, M., Goltzman, D., Gonzalez-Macias, J., Kahonen, M., Karlsson, M., Khusnutdinova, E., Koh, J., Kollia, P., Langdahl, B. L., Leslie, W. D., Lips, P., Ljunggren, O., Lorenc, R. S., Marc, J., Mellstrom, D., Obermayer-Pietsch, B., Olmos, J. M., Pettersson-Kymmer, U., Reid, D. M., Riancho, J. A., Ridker, P. M., Rousseau, F., Slagboom, P. E., Tang, N. L., Urreizti, R., Van Hul, W., Viikari, J., Zarrabeitia, M. T., Aulchenko, Y. S., Castano-Betancourt, M., Grundberg, E., Herrera, L., Ingvarsson, T., Johannsdottir, H., Kwan, T., Li, R., Luben, R., Medina-Gomez, C., Palsson, S. T., Reppe, S., Rotter, J. I., Sigurdsson, G., van Meurs, J. B., Verlaan, D., Williams, F. M., Wood, A. R., Zhou, Y., Gautvik, K. M., Pastinen, T., Raychaudhuri, S., Cauley, J. A., Chasman, D. I., Clark, G. R., Cummings, S. R., Danoy, P., Dennison, E. M., Eastell, R., Eisman, J. A., Gudnason, V., Hofman, A., Jackson, R. D., Jones, G., Jukema, J. W., Khaw, K., Lehtimaki, T., Liu, Y., Lorentzon, M., McCloskey, E., Mitchell, B. D., Nandakumar, K., Nicholson, G. C., Oostra, B. A., Peacock, M., Pols, H. A., Prince, R. L., Raitakari, O., Reid, I. R., Robbins, J., Sambrook, P. N., Sham, P. C., Shuldiner, A. R., Tylavsky, F. A., van Duijn, C. M., Wareham, N. J., Cupples, L. A., Econs, M. J., Evans, D. M., Harris, T. B., Kung, A. W., Psaty, B. M., Reeve, J., Spector, T. D., Streeten, E. A., Zillikens, M. C., Thorsteinsdottir, U., Ohlsson, C., Karasik, D., Richards, J. B., Brown, M. A., Stefansson, K., Uitterlinden, A. G., Ralston, S. H., Ioannidis, J. P., Kiel, D. P., Rivadeneira, F. 2012; 44 (5): 491-?

    Abstract

    Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

    View details for DOI 10.1038/ng.2249

    View details for Web of Science ID 000303416300007

    View details for PubMedID 22504420

    View details for PubMedCentralID PMC3338864

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement (vol 53, pg 377, 2011) PREVENTIVE MEDICINE Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. A., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 54 (5): 367

    View details for DOI 10.1016/j.ypmed.2012.02.019

    View details for Web of Science ID 000304497800018

  • Methodological Standards and Patient-Centeredness in Comparative Effectiveness Research The PCORI Perspective JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Basch, E., Aronson, N., Berg, A., Flum, D., Gabriel, S., Goodman, S. N., Helfand, M., Ioannidis, J. P., Lauer, M., Meltzer, D., Mittman, B., Newhouse, R., Normand, S., Schneeweiss, S., Slutsky, J., Tinetti, M., Yancy, C. 2012; 307 (15): 1636-1640

    Abstract

    Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.

    View details for Web of Science ID 000302896100026

  • A Multidimensional Prognostic Index in Common Conditions Leading to Death in Older Patients reply ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2012; 172 (7): 594-595

    View details for Web of Science ID 000302555300016

  • Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Nair, V. S., Maeda, L. S., Ioannidis, J. P. 2012; 104 (7): 528-540

    Abstract

    MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -

    View details for DOI 10.1093/jnci/djs027

    View details for Web of Science ID 000302293200008

    View details for PubMedID 22395642

    View details for PubMedCentralID PMC3317879

  • Research needs grants, funding and money - missing something? EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P. 2012; 42 (4): 349-351

    View details for DOI 10.1111/j.1365-2362.2011.02617.x

    View details for Web of Science ID 000301491800001

    View details for PubMedID 22050119

  • Are Medical Conferences Useful? And for Whom? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2012; 307 (12): 1257-1258

    View details for Web of Science ID 000301978400018

    View details for PubMedID 22453564

  • Re-rethinking the article by Thombs and colleagues Response CANADIAN MEDICAL ASSOCIATION JOURNAL Thombs, B. D., Coyne, J. C., Cuijpers, P., de Jonge, P., Gilbody, S., Ioannidis, J. P., Johnson, B. T., Patten, S. B., Turner, E. H., Ziegelstein, R. C. 2012; 184 (4): 438-439

    View details for DOI 10.1503/cmaj.112-2024

    View details for Web of Science ID 000301465400020

  • Rethinking recommendations for screening for depression in primary care CANADIAN MEDICAL ASSOCIATION JOURNAL Thombs, B. D., Coyne, J. C., Cuijpers, P., de Jonge, P., Gilbody, S., Ioannidis, J. P., Johnson, B. T., Patten, S. B., Turner, E. H., Ziegelstein, R. C. 2012; 184 (4): 413-418

    View details for DOI 10.1503/cmaj.111035

    View details for Web of Science ID 000301465400009

    View details for PubMedID 21930744

    View details for PubMedCentralID PMC3291670

  • Minimal and Null Predictive Effects for the Most Popular Blood Biomarkers of Cardiovascular Disease CIRCULATION RESEARCH Ioannidis, J. P., Tzoulaki, I. 2012; 110 (5): 658-662

    View details for DOI 10.1161/RES.0b013e31824da8ad

    View details for Web of Science ID 000301045500006

    View details for PubMedID 22383708

  • The effectiveness of long-term psychoanalytic psychotherapy-A meta-analysis of randomized controlled trials CLINICAL PSYCHOLOGY REVIEW Smit, Y., Huibers, M. J., Ioannidis, J. P., Van Dyck, R., van Tilburg, W., Arntz, A. 2012; 32 (2): 81-92

    Abstract

    The effectiveness of psychoanalysis and long-term psychoanalytic psychotherapy (LTPP) is debated. We evaluated the effectiveness of LTPP, compared to other treatments or no treatment, in patients with clearly defined metal disorders. We selected randomised or quasi-randomised controlled trials on LTPP. Two authors independently identified trials for inclusion. Eleven trials were eligible. The risk difference for recovery (primary outcome) at the longest available follow-up was 0.00 (95% CI: -0.17 to 0.17; p=0.96; I-squared: 58%). The combined Hedges' g, at the longest follow-up for each study, were: for target problems: -0.05 (95% CI -0.55 to 0.46; p=0.86; I-squared=88%); general psychiatric symptoms: 0.69 (95% CI -0.19 to 1.57; p=0.13; I-squared=96%); personality pathology: 0.17 (95% CI: -0.25 to 0.59; p=0.42; I-squared=41%); social functioning: 0.20 (95% CI -0.10 to 0.50; p=0.19; I-squared=53%); overall effectiveness: 0.33 (95% CI -0.31 to 0.96; p=0.32; I-squared=94%); and quality of life: -0.37 (95% CI: -0.78 to 0.04; p=0.08; I-squared=55%). A subgroup analysis of the domain target problem showed that LTPP did significantly better when compared to control treatments without a specialized psychotherapy component, but not when compared to various specialized psychotherapy control treatments. An exploratory meta-regression indicated that there might be a relation between the difference in treatment intensity between the intervention and control group (session ratio) and effect size. We came to conclude that the recovery rate of various mental disorders was equal after LTPP or various control treatments, including treatment as usual. The effect sizes of the individual trials varied substantially in direction and magnitude. In contrast to previous reviews, we found the evidence for the effectiveness of LTPP to be limited and at best conflicting.

    View details for DOI 10.1016/j.cpr.2011.11.003

    View details for Web of Science ID 000300033800001

    View details for PubMedID 22227111

  • First-Trimester Ductus Venosus Screening for Cardiac Defects: A Meta-Analysis EDITORIAL COMMENT OBSTETRICAL & GYNECOLOGICAL SURVEY Papatheodorou, S. I., Evangelou, E., Makrydimas, G., Ioannidis, J. A. 2012; 67 (3): 148–49

    View details for DOI 10.1097/OGX.0b013e31824b6fd3

    View details for Web of Science ID 000302177800007

  • Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database PLOS GENETICS Lill, C. M., Roehr, J. T., McQueen, M. B., Kavvoura, F. K., Bagade, S., Schjeide, B. M., Schjeide, L. M., Meissner, E., Zauft, U., Allen, N. C., Liu, T., Schilling, M., Anderson, K. J., Beecham, G., Berg, D., Biernacka, J. M., Brice, A., DeStefano, A. L., Do, C. B., Eriksson, N., Factor, S. A., Farrer, M. J., Foroud, T., Gasser, T., Hamza, T., Hardy, J. A., Heutink, P., Hill-Burns, E. M., Klein, C., Latourelle, J. C., Maraganore, D. M., Martin, E. R., Martinez, M., Myers, R. H., Nalls, M. A., Pankratz, N., Payami, H., Satake, W., Scott, W. K., Sharma, M., Singleton, A. B., Stefansson, K., Toda, T., Tung, J. Y., Vance, J., Wood, N. W., Zabetian, C. P., Young, P., Tanzi, R. E., Khoury, M. J., Zipp, F., Lehrach, H., Ioannidis, J. P., Bertram, L. 2012; 8 (3)

    Abstract

    More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P  =  1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.

    View details for DOI 10.1371/journal.pgen.1002548

    View details for Web of Science ID 000302254800024

    View details for PubMedID 22438815

    View details for PubMedCentralID PMC3305333

  • Claims for improved survival from systemic corticosteroids in diverse conditions: an umbrella review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2012; 42 (3): 233-244

    Abstract

    Systemic corticosteroids have been proposed for numerous indications and there are many claims that corticosteroids can reduce mortality in diverse conditions.We performed an umbrella, agenda-wide review of the evidence on systemic corticosteroids and mortality, focusing primarily on large trials (defined as those with > 100 deaths) and meta-analyses. Searches were performed in PubMed and Cochrane Central Register of Controlled Trials (last update February 2011). We also examined whether spurious subset analyses may be responsible for claims of survival benefits in indications where only small trials had been available.Among 257 identified randomized trials with mortality data in their abstract, we found 14 large trials pertaining to 10 different indications. Although 10 of these 14 trials have reported statistically significant survival differences in subset analyses, none shows a nominally statistically significant (P < 0·05) decrease in death risk for any of the tested conditions when all deaths on all randomized patients are analysed. Meta-analyses for these conditions show statistically significant reductions in mortality only with antenatal corticosteroids for preterm labour (relative risk 0·77, 95% CI, 0·67-0·89) and in tuberculous meningitis (relative risk 0·78, 95% CI, 0·67-0·91). For conditions without any large trials, statistically significant reductions in mortality in meta-analyses were noted for Pneumocystis pneumonia (relative risk 0·54, 95% CI, 0·38-0·79) and alcoholic hepatitis (relative risk 0·63, 95% CI, 0·50-0·80). Many small trials that claim significant benefits, even those for classic indications such as typhoid fever and tetanus, have shown these benefits only in subset analyses.Corticosteroids have been documented to decrease mortality in some indications, in particular, antenatal use for preterm labour, tuberculous meningitis, Pneumocystis pneumonia, and alcoholic hepatitis. Many postulated benefits of corticosteroids on mortality may reflect 'vibration of treatment effects' leading to false-positive claims from spurious subset analyses and even for standard indications, such biases may have inflated the treatment effect estimates. More large trials are needed for serious, common conditions where use of corticosteroids is proposed.

    View details for DOI 10.1111/j.1365-2362.2011.02584.x

    View details for Web of Science ID 000299832800002

    View details for PubMedID 21880039

  • What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Panagiotou, O. A., Ioannidis, J. P. 2012; 41 (1): 273-286

    Abstract

    Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ≤ 5 × 10(-8) are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance.We defined as 'borderline' associations those with P > 5 × 10(-8) and P ≤ 1 × 10(-7). The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ≤ 5 × 10(-8) with inclusion of additional data from subsequent GWA studies.Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ≤ 5 × 10(-8) for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P < 10(-8). If the seven associations that did not reach P ≤ 5 × 10(-8) when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 10(-6) [corresponding false-discovery rate 19% (95% CI 7-39%)].A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold.

    View details for DOI 10.1093/ije/dyr178

    View details for Web of Science ID 000302026800032

    View details for PubMedID 22253303

  • STrengthening the reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): an extension of the STROBE statement (vol 26, pg 797, 2011) EUROPEAN JOURNAL OF EPIDEMIOLOGY Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. A., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Bernadette Schoket, Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 27 (2): 151

    View details for DOI 10.1007/s10654-012-9662-1

    View details for Web of Science ID 000301839200010

  • The Clinical Utility of Prognostic Indices: The Proof of the Pudding Is in the Eating reply ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2012; 172 (2): 195-195

    View details for Web of Science ID 000299392500028

  • Reversals of Established Medical Practices Evidence to Abandon Ship JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Prasad, V., Cifu, A., Ioannidis, J. P. 2012; 307 (1): 37-38

    View details for DOI 10.1001/jama.2011.1960

    View details for Web of Science ID 000298792300016

    View details for PubMedID 22215160

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 42 (1): 1-16

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1111/j.1365-2362.2011.02561.x

    View details for Web of Science ID 000297738500001

    View details for PubMedID 22023344

  • Scientific Communication Is Down at the Moment, Please Check Again Later PSYCHOLOGICAL INQUIRY Ioannidis, J. A. 2012; 23 (3): 267–70

    View details for DOI 10.1080/1047840X.2012.699427

    View details for Web of Science ID 000308983900010

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement MUTAGENESIS Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 27 (1): 17-29

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and / or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1093/mutage/ger039

    View details for Web of Science ID 000298385400002

    View details for PubMedID 22027842

  • Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination PLOS ONE Ioannidis, J. P., Manzoli, L., De Vito, C., D'Addario, M., Villari, P. 2011; 6 (12)

    Abstract

    Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics with new emerging infectious agents. We carried out an observational survey to evaluate how many randomized controlled trials testing 2009 H1N1 vaccines were published among those registered, and what was the time lag from their start to publication and from their completion to publication.PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving influenza vaccines in any setting.73 eligible trials were identified that had been registered in 2009-2010. By June 30, 2011 only 21 (29%) of these trials had been published, representing 38% of the randomized sample size (19905 of 52765). Trials starting later were published less rapidly (hazard ratio 0.42 per month; 95% Confidence Interval: 0.27 to 0.64; p<0.001). Similarly, trials completed later were published less rapidly (hazard ratio 0.43 per month; 95% CI: 0.27 to 0.67; p<0.001). Randomized controlled trials were completed promptly (median, 5 months from start to completion), but only a minority were subsequently published.Most registered randomized trials on vaccines for the H1N1 pandemic are not published in the peer-reviewed literature.

    View details for DOI 10.1371/journal.pone.0028346

    View details for Web of Science ID 000298171400075

    View details for PubMedID 22164274

    View details for PubMedCentralID PMC3229554

  • Improving Validation Practices in "Omics" Research SCIENCE Ioannidis, J. P., Khoury, M. J. 2011; 334 (6060): 1230-1232

    Abstract

    "Omics" research poses acute challenges regarding how to enhance validation practices and eventually the utility of this rich information. Several strategies may be useful, including routine replication, public data and protocol availability, funding incentives, reproducibility rewards or penalties, and targeted repeatability checks.

    View details for DOI 10.1126/science.1211811

    View details for Web of Science ID 000297553600037

    View details for PubMedID 22144616

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology STROBE-ME: an extension of the STROBE statement JOURNAL OF CLINICAL EPIDEMIOLOGY Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 64 (12): 1350-1363

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change susceptibility and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1016/j.jclinepi.2011.07.010

    View details for Web of Science ID 000296995000014

    View details for PubMedID 22030070

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement PREVENTIVE MEDICINE Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Loannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 53 (6): 377-387

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrenghtening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1016/j.ypmed.2011.08.007

    View details for Web of Science ID 000298073500005

    View details for PubMedID 22029945

  • Prognostic effect size of cardiovascular biomarkers in datasets from observational studies versus randomised trials: meta-epidemiology study BRITISH MEDICAL JOURNAL Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2011; 343

    Abstract

    To compare the reported effect sizes of cardiovascular biomarkers in datasets from observational studies with those in datasets from randomised controlled trials.Review of meta-analyses.Meta-analyses of emerging cardiovascular biomarkers (not part of the Framingham risk score) that included datasets from at least one observational study and at least one randomised controlled trial were identified through Medline (last update, January 2011).Study-specific risk ratios were extracted from all identified meta-analyses and synthesised with random effects for (a) all studies, and (b) separately for observational and for randomised controlled trial populations for comparison.31 eligible meta-analyses were identified. For seven major biomarkers (C reactive protein, non-HDL cholesterol, lipoprotein(a), post-load glucose, fibrinogen, B-type natriuretic peptide, and troponins), the prognostic effect was significantly stronger in datasets from observational studies than in datasets from randomised controlled trials. For five of the biomarkers the effect was less than half as strong in the randomised controlled trial datasets. Across all 31 meta-analyses, on average datasets from observational studies suggested larger prognostic effects than those from randomised controlled trials; from a random effects meta-analysis, the estimated average difference in the effect size was 24% (95% CI 7% to 40%) of the overall biomarker effect.Cardiovascular biomarkers often have less promising results in the evidence derived from randomised controlled trials than from observational studies.

    View details for DOI 10.1136/bmj.d6829

    View details for Web of Science ID 000297057800012

    View details for PubMedID 22065657

    View details for PubMedCentralID PMC3209745

  • First-trimester ductus venosus screening for cardiac defects: a meta-analysis BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY Papatheodorou, S. I., Evangelou, E., Makrydimas, G., Ioannidis, J. P. 2011; 118 (12): 1438-1445

    Abstract

    Heart defects are the most common congenital abnormalities.We aimed to evaluate in a meta-analysis the screening performance of abnormal ductus venosus (DV) Doppler waveform for detection of congenital heart disease (CHD) in chromosomally normal fetuses.Studies were retrieved from a search of MEDLINE, ISI, SCOPUS and EMBASE (from 1999 to March 2011) using the keywords 'ductus venosus', 'DV', 'chromosomal abnormalities', 'congenital heart disease' and 'nuchal translucency'.We considered all studies that examined the diagnostic performance of DV in the first trimester for CHD in chromosomally normal fetuses. We included studies that were limited to fetuses with increased nuchal translucency (NT), normal NT, and studies that examined fetuses regardless of NT status.Seven studies (n = 50,354) regardless of the NT status, nine studies (n = 2908) with increased NT and seven studies (n = 47,610) with normal NT were included in the meta-analysis. We drew hierarchical summary receiver operating characteristic (HSROC) curves using the parameters of the fitted models.In populations including participants regardless of NT status, the summary sensitivity and specificity of DV for detecting CHD were 50 and 93%, respectively. In participants with increased NT, the summary sensitivity and specificity were 83 and 80%, and in those with normal NT, they were 19 and 96%, respectively.The estimated performance of DV assessment for detection of CHD in chromosomally normal fetuses can be considered in evaluating the potential use and limitations of this screening test.

    View details for DOI 10.1111/j.1471-0528.2011.03029.x

    View details for Web of Science ID 000296203900004

    View details for PubMedID 21668765

  • Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease NEUROBIOLOGY OF AGING Sharma, M., Maraganore, D. M., Ioannidis, J. P., Riess, O., Aasly, J. O., Annesi, G., Abahuni, N., Bentivoglio, A. R., Brice, A., Van Broeckhoven, C., Chartier-Harlin, M., Destee, A., Djarmati, A., Elbaz, A., Farrer, M., Ferrarese, C., Gibson, J. M., Gispert, S., Hattori, N., Jasinska-Myga, B., Klein, C., Lesage, S., Lynch, T., Lichtner, P., Lambert, J., Lang, A. E., Mellick, G. D., de Nigris, F., Opala, G., Quattrone, A., Riva, C., Rogaeva, E., Ross, O. A., Satake, W., Silburn, P. A., Theuns, J., Toda, T., Tomiyama, H., Uitti, R. J., Wirdefeldt, K., Wszolek, Z., Gasser, T., Krueger, R. 2011; 32 (11)

    Abstract

    Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies.

    View details for DOI 10.1016/j.neurobiolaging.2011.05.024

    View details for Web of Science ID 000295220700025

    View details for PubMedID 21782285

  • Predicting Death An Empirical Evaluation of Predictive Tools for Mortality ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2011; 171 (19): 1721-1726

    Abstract

    The ability to predict death is crucial in medicine, and many relevant prognostic tools have been developed for application in diverse settings. We aimed to evaluate the discriminating performance of predictive tools for death and the variability in this performance across different clinical conditions and studies.We used Medline to identify studies published in 2009 that assessed the accuracy (based on the area under the receiver operating characteristic curve [AUC]) of validated tools for predicting all-cause mortality. For tools where accuracy was reported in 4 or more assessments, we calculated summary accuracy measures. Characteristics of studies of the predictive tools were evaluated to determine if they were associated with the reported accuracy of the tool.A total of 94 eligible studies provided data on 240 assessments of 118 predictive tools. The AUC ranged from 0.43 to 0.98 (median [interquartile range], 0.77 [0.71-0.83]), with only 23 of the assessments reporting excellent discrimination (10%) (AUC, >0.90). For 10 tools, accuracy was reported in 4 or more assessments; only 1 tool had a summary AUC exceeding 0.80. Established tools showed large heterogeneity in their performance across different cohorts (I(2) range, 68%-95%). Reported AUC was higher for tools published in journals with lower impact factor (P = .01), with larger sample size (P = .01), and for those that aimed to predict mortality among the highest-risk patients (P = .002) and among children (P < .001).Most tools designed to predict mortality have only modest accuracy, and there is large variability across various diseases and populations. Most proposed tools do not have documented clinical utility.

    View details for DOI 10.1001/archinternmed.2011.334

    View details for Web of Science ID 000296198200006

    View details for PubMedID 21788535

  • Magnitude of effects in clinical trials published in high-impact general medical journals INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Siontis, K. C., Evangelou, E., Ioannidis, J. P. 2011; 40 (5): 1280-1291

    Abstract

    Prestigious journals select for publication studies that are considered most important and informative. We aimed to examine whether high-impact general (HIG) medical journals systematically demonstrate more favourable results for experimental interventions compared with the rest of the literature.We scrutinized systematic reviews of the Cochrane Database (Issue 4, 2009) and meta-analyses published in four general journals (2008-09). Eligible articles included ≥1 binary outcome meta-analysis(es) pertaining to effectiveness with ≥1 clinical trial(s) published in NEJM, JAMA or Lancet. Effect sizes in trials from NEJM, JAMA or Lancet were compared with those from other trials in the same meta-analyses by deriving summary relative odds ratios (sRORs). Additional analyses examined separately early- and late-published trials in HIG journals and journal-specific effects.A total of 79 meta-analyses including 1043 clinical trials were analysed. Trials in HIG journals had similar effects to trials in other journals, when there was large-scale evidence, but showed more favourable results for experimental interventions when they were small. When HIG trials had less than 40 events, the sROR was 1.64 [95% confidence interval (95% CI): 1.23-2.18). The difference was most prominent when small early trials published in HIG journals were compared with subsequent trials [sROR 2.68 (95% CI: 1.33-5.38)]. Late-published HIG trials showed no consistent inflation of effects. The patterns did not differ beyond chance between NEJM, JAMA or Lancet.Small trials published in the most prestigious journals show more favourable effects for experimental interventions, and this is most prominent for early-published trials in such journals. No effect inflation is seen for large trials.

    View details for DOI 10.1093/ije/dyr095

    View details for Web of Science ID 000296634900020

    View details for PubMedID 22039194

  • Risk factors and interventions with statistically significant tiny effects INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Siontis, G. C., Ioannidis, J. P. 2011; 40 (5): 1292-1307

    Abstract

    Large studies may identify postulated risk factors and interventions with very small effect sizes. We aimed to assess empirically a large number of statistically significant relative risks (RRs) of tiny magnitude and their interpretation by investigators.RRs in the range between 0.95 and 1.05 were identified in abstracts of articles of cohort studies; articles published in NEJM, JAMA or Lancet; and Cochrane reviews. For each eligible tiny effect and the respective study, we recorded information on study design, participants, risk factor/intervention, outcome, effect estimates, P-values and interpretation by study investigators. We also calculated the probability that each effect lies outside specific intervals around the null (RR interval 0.97-1.03, 0.95-1.05, 0.90-1.10).We evaluated 51 eligible tiny effects (median sample size 112 786 for risk factors and 36 021 for interventions). Most (37/51) appeared in articles published in 2006-10. The effects pertained to nutrition (n = 19), genetic and other biomarkers (n = 8), correlates of health care (n = 8) and diverse other topics (n = 16) of clinical or public health importance and mostly referred to major clinical outcomes. A total of 15 of the 51 effects were >80% likely to lie outside the RR interval 0.97-1.03, but only 8 were >40% likely to lie outside the RR interval 0.95-1.05 and none was >1.7% likely to lie outside the RR interval 0.90-1.10. The authors discussed at least one concern for 23 effects (small magnitude n = 19, residual confounding n = 11, selection bias n = 1). No concerns were expressed for 28 effects.Statistically significant tiny effects for risk factors and interventions of clinical or public health importance become more common in the literature. Cautious interpretation is warranted, since most of these effects could be eliminated with even minimal biases and their importance is uncertain.

    View details for DOI 10.1093/ije/dyr099

    View details for Web of Science ID 000296634900021

    View details for PubMedID 21737403

  • Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects JOURNAL OF CLINICAL EPIDEMIOLOGY Pereira, T. V., Ioannidis, J. P. 2011; 64 (10): 1060-1069

    Abstract

    To assess whether nominally statistically significant effects in meta-analyses of clinical trials are true and whether their magnitude is inflated.Data from the Cochrane Database of Systematic Reviews 2005 (issue 4) and 2010 (issue 1) were used. We considered meta-analyses with binary outcomes and four or more trials in 2005 with P<0.05 for the random-effects odds ratio (OR). We examined whether any of these meta-analyses had updated counterparts in 2010. We estimated the credibility (true-positive probability) under different prior assumptions and inflation in OR estimates in 2005.Four hundred sixty-one meta-analyses in 2005 were eligible, and 80 had additional trials included by 2010. The effect sizes (ORs) were smaller in the updating data (2005-2010) than in the respective meta-analyses in 2005 (median 0.85-fold, interquartile range [IQR]: 0.66-1.06), even more prominently for meta-analyses with less than 300 events in 2005 (median 0.67-fold, IQR: 0.54-0.96). Mean credibility of the 461 meta-analyses in 2005 was 63-84% depending on the assumptions made. Credibility estimates changed >20% in 19-31 (24-39%) of the 80 updated meta-analyses.Most meta-analyses with nominally significant results pertain to truly nonnull effects, but exceptions are not uncommon. The magnitude of observed effects, especially in meta-analyses with limited evidence, is often inflated.

    View details for DOI 10.1016/j.jclinepi.2010.12.012

    View details for Web of Science ID 000294526700003

    View details for PubMedID 21454050

  • Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study LANCET NEUROLOGY Ross, O. A., Soto-Ortolaza, A. I., Heckman, M. G., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Van Broeckhoven, C., Carr, J., Chartier-Harlin, M., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., Ferraris, A., Fiske, B., Gibson, J. M., Gibson, R., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lesage, S., Lin, C., Lynch, T., Maraganore, D. M., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Park, S. S., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Theuns, J., Tomiyama, H., Uitti, R. J., Valente, E. M., van de Loo, S., Vassilatis, D. K., Vilarino-Gueell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Farrer, M. J. 2011; 10 (10): 898-908

    Abstract

    Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012).The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.Michael J Fox Foundation and National Institutes of Health.

    View details for DOI 10.1016/S1474-4422(11)70175-2

    View details for Web of Science ID 000295814600011

    View details for PubMedID 21885347

    View details for PubMedCentralID PMC3208320

  • STrengthening the reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): an extension of the STROBE statement EUROPEAN JOURNAL OF EPIDEMIOLOGY Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 26 (10): 797-810

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility, and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as STrengthening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1007/s10654-011-9622-1

    View details for Web of Science ID 000297474500006

    View details for PubMedID 22037796

  • STrengthening the Reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): An Extension of the STROBE Statement PLOS MEDICINE Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2011; 8 (10)

    View details for DOI 10.1371/journal.pmed.1001117

    View details for Web of Science ID 000296552400015

    View details for PubMedID 22039356

    View details for PubMedCentralID PMC3201942

  • More time for research: fund people not projects. Nature Ioannidis, J. P. 2011; 477 (7366): 529-531

    View details for DOI 10.1038/477529a

    View details for PubMedID 21956312

  • Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration HUMAN MOLECULAR GENETICS Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H., Reynolds, R., Raychaudhuri, S., Chin, K. A., Sobrin, L., Evangelou, E., Lee, P. H., Lee, A. Y., Leveziel, N., Zack, D. J., Campochiaro, B., Campochiaro, P., Smith, R. T., Barile, G. R., Guymer, R. H., Hogg, R., Chakravarthy, U., Robman, L. D., Gustafsson, O., Sigurdsson, H., Ortmann, W., Behrens, T. W., Stefansson, K., Uitterlinden, A. G., van Duijn, C. M., Vingerling, J. R., Klaver, C. C., Allikmets, R., Brantley, M. A., Baird, P. N., Katsanis, N., Thorsteinsdottir, U., Ioannidis, J. P., Daly, M. J., Graham, R. R., Seddon, J. M. 2011; 20 (18): 3699-3709

    Abstract

    Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

    View details for DOI 10.1093/hmg/ddr270

    View details for Web of Science ID 000294442200016

    View details for PubMedID 21665990

    View details for PubMedCentralID PMC3159552

  • Public Availability of Published Research Data in High-Impact Journals PLOS ONE Alsheikh-Ali, A. A., Qureshi, W., Al-Mallah, M. H., Ioannidis, J. P. 2011; 6 (9)

    Abstract

    There is increasing interest to make primary data from published research publicly available. We aimed to assess the current status of making research data available in highly-cited journals across the scientific literature.We reviewed the first 10 original research papers of 2009 published in the 50 original research journals with the highest impact factor. For each journal we documented the policies related to public availability and sharing of data. Of the 50 journals, 44 (88%) had a statement in their instructions to authors related to public availability and sharing of data. However, there was wide variation in journal requirements, ranging from requiring the sharing of all primary data related to the research to just including a statement in the published manuscript that data can be available on request. Of the 500 assessed papers, 149 (30%) were not subject to any data availability policy. Of the remaining 351 papers that were covered by some data availability policy, 208 papers (59%) did not fully adhere to the data availability instructions of the journals they were published in, most commonly (73%) by not publicly depositing microarray data. The other 143 papers that adhered to the data availability instructions did so by publicly depositing only the specific data type as required, making a statement of willingness to share, or actually sharing all the primary data. Overall, only 47 papers (9%) deposited full primary raw data online. None of the 149 papers not subject to data availability policies made their full primary data publicly available.A substantial proportion of original research papers published in high-impact journals are either not subject to any data availability policies, or do not adhere to the data availability instructions in their respective journals. This empiric evaluation highlights opportunities for improvement.

    View details for DOI 10.1371/journal.pone.0024357

    View details for Web of Science ID 000294802500039

    View details for PubMedID 21915316

    View details for PubMedCentralID PMC3168487

  • Meta-Analysis of the Immunogenicity and Tolerability of Pandemic Influenza A 2009 (H1N1) Vaccines PLOS ONE Manzoli, L., De Vito, C., Salanti, G., D'Addario, M., Villari, P., Ioannidis, J. P. 2011; 6 (9)

    Abstract

    Although the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation.We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis.Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 µg (even with as little as 1.875 µg of hemagglutinin antigen) was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects). However, mild to moderate adverse reactions were more (and very) frequent for oil-in-water adjuvanted vaccines.Several one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is used. Given that 15 RCTs were sponsored by vaccine manufacturers, future trials sponsored by non-industry agencies and comparing vaccines using different types of adjuvants are needed.

    View details for DOI 10.1371/journal.pone.0024384

    View details for Web of Science ID 000294689200040

    View details for PubMedID 21915319

    View details for PubMedCentralID PMC3167852

  • Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 41 (9): 1010-1035

    Abstract

    • The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. • Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency, quality and completeness of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1111/j.1365-2362.2011.02493.x

    View details for Web of Science ID 000293509200013

    View details for PubMedID 21434890

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 41 (9): 1004-1009

    Abstract

    • The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting vary. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. • A detailed Explanation and Elaboration document is published as an accompanying article [1].

    View details for DOI 10.1111/j.1365-2362.2011.02494.x

    View details for Web of Science ID 000293509200012

    View details for PubMedID 21434891

  • Strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS): explanation and elaboration. Journal of clinical epidemiology Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 64 (8): e1-e22

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1016/j.jclinepi.2011.02.003

    View details for PubMedID 21414753

  • Homophily and co-occurrence patterns shape randomized trials agendas: illustration in antifungal agents JOURNAL OF CLINICAL EPIDEMIOLOGY Rizos, E. C., Salanti, G., Kontoyiannis, D. P., Ioannidis, J. P. 2011; 64 (8): 830-842

    Abstract

    To assess whether there are preferences and avoidances for specific comparisons in a clinical trials agenda.We tested for homophily (preference to compare agents against others in the same class) and co-occurrence (preference or avoidance of specific head-to-head comparisons) in the randomized trials agenda of antifungal agents. We searched MEDLINE and Cochrane Library databases for English language randomized trials evaluating systemic antifungals against Candida or Aspergillus in adults. We extracted data on compared regimens, sample size, publication year, indication (treatment/prophylaxis), and underlying disease.One hundred forty-four trials (74 treatments, 70 prophylaxes) were found (n=27,497 patients). Among polyene and azole groups, agents were compared within the same class more often than across classes (homophily test P<0.001). Lipid amphotericin was compared almost entirely against conventional amphotericin (18 trials), with only three comparisons against azoles. Head-to-head comparisons of newer agents were avoided. Only one of 14 trials for echinocandins compared head-to-head two different echinocandins (P<0.001 for co-occurrence). Of 11 trials on newer azoles, only one compared a newer azole with an echinocandin (P<0.001 for co-occurrence).Trial networks for antifungals show that specific comparisons are preferred and others avoided, generating a potentially biased clinical research agenda.

    View details for DOI 10.1016/j.jclinepi.2010.11.017

    View details for Web of Science ID 000292413400004

    View details for PubMedID 21411286

  • Excess Significance Bias in the Literature on Brain Volume Abnormalities ARCHIVES OF GENERAL PSYCHIATRY Ioannidis, J. P. 2011; 68 (8): 773-780

    Abstract

    Many studies report volume abnormalities in diverse brain structures in patients with various mental health conditions.To evaluate whether there is evidence for an excess number of statistically significant results in studies of brain volume abnormalities that suggest the presence of bias in the literature.PubMed (articles published from January 2006 to December 2009).Recent meta-analyses of brain volume abnormalities in participants with various mental health conditions vs control participants with 6 or more data sets included, excluding voxel-based morphometry.Standardized effect sizes were extracted in each data set, and it was noted whether the results were "positive" (P < .05) or not. For each data set in each meta-analysis, I estimated the power to detect at α = .05 an effect equal to the summary effect of the respective meta-analysis. The sum of the power estimates gives the number of expected positive data sets. The expected number of positive data sets can then be compared against the observed number.From 8 articles, 41 meta-analyses with 461 data sets were evaluated (median, 10 data sets per meta-analysis) pertaining to 7 conditions. Twenty-one of the 41 meta-analyses had found statistically significant associations, and 142 of 461 (31%) data sets had positive results. Even if the summary effect sizes of the meta-analyses were unbiased, the expected number of positive results would have been only 78.5 compared with the observed number of 142 (P < .001).There are too many studies with statistically significant results in the literature on brain volume abnormalities. This pattern suggests strong biases in the literature, with selective outcome reporting and selective analyses reporting being possible explanations.

    View details for DOI 10.1001/archgenpsychiatry.2011.28

    View details for Web of Science ID 000293359800002

    View details for PubMedID 21464342

  • Comprehensive Field Synopsis and Systematic Meta-analyses of Genetic Association Studies in Cutaneous Melanoma JOURNAL OF THE NATIONAL CANCER INSTITUTE Chatzinasiou, F., Lill, C. M., Kypreou, K., Stefanaki, I., Nicolaou, V., Spyrou, G., Evangelou, E., Roehr, J. T., Kodela, E., Katsambas, A., Tsao, H., Ioannidis, J. P., Bertram, L., Stratigos, A. J. 2011; 103 (16): 1227-1235

    Abstract

    Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported.We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided.Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 × 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility.To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM.

    View details for DOI 10.1093/jnci/djr219

    View details for Web of Science ID 000294074500008

    View details for PubMedID 21693730

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement EUROPEAN JOURNAL OF HUMAN GENETICS Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 19 (8): 833-836

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies, building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published on the EJHG website.

    View details for DOI 10.1038/ejhg.2011.25

    View details for Web of Science ID 000292957600006

    View details for PubMedID 21407265

  • Use of reclassification for assessment of improved prediction: an empirical evaluation INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Tzoulaki, I., Liberopoulos, G., Ioannidis, J. P. 2011; 40 (4): 1094-1105

    Abstract

    An increasing number of studies evaluate the ability of predictors to change risk stratification and alter medical decisions, i.e. reclassification performance. We examined the reported design and analysis of recent studies of reclassification and the robustness of their claims for improved reclassification.Two independent investigators searched PubMed and citations to the article that introduced the currently most popular reclassification metric (net reclassification index, NRI) to identify studies performing reclassification analysis (January 2006-January 2010). We focused on articles that included any analyses comparing the performance of a baseline predictive model vs the baseline model plus some additional predictor for a prospectively assessed outcome. We recorded information on the baseline model used, outcomes assessed, choice of risk thresholds and features of reclassification analyses.Of 58 baseline models used in 51 eligible papers, only 14 (24%) were previously described, used as described and had same outcomes as originally intended. Calibration was examined in 53% of the studies. Sixteen studies (31%) provided a reference for the choice of risk thresholds and only six used the previously proposed categories or justified the use of alternative thresholds. Only 14 studies (27%) stated that the chosen risk thresholds had different therapeutic intervention implications. NRI was calculated in 38 studies and was smaller in studies with adequately referenced or justified risk thresholds vs others (P < 0.0001).Reclassification studies would benefit from more rigorous methodological standards; otherwise claims for improved reclassification may remain spurious.

    View details for DOI 10.1093/ije/dyr013

    View details for Web of Science ID 000294108700040

    View details for PubMedID 21325392

  • Strengthening the reporting of Genetic RIsk Prediction Studies: the GRIPS Statement JOURNAL OF CLINICAL EPIDEMIOLOGY Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 64 (8): 843-847

    View details for DOI 10.1016/j.jclinepi.2011.02.004

    View details for Web of Science ID 000292413400005

    View details for PubMedID 21414754

  • Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials BRITISH MEDICAL JOURNAL Sterne, J. A., Sutton, A. J., Ioannidis, J. P., Terrin, N., Jones, D. R., Lau, J., Carpenter, J., Ruecker, G., Harbord, R. M., Schmid, C. H., Tetzlaff, J., Deeks, J. J., Peters, J., Macaskill, P., Schwarzer, G., Duval, S., Altman, D. G., Moher, D., Higgins, J. P. 2011; 343

    View details for DOI 10.1136/bmj.d4002

    View details for Web of Science ID 000293169000008

    View details for PubMedID 21784880

  • The False-positive to False-negative Ratio in Epidemiologic Studies EPIDEMIOLOGY Ioannidis, J. P., Tarone, R., McLaughlin, J. K. 2011; 22 (4): 450-456

    Abstract

    The ratio of false-positive to false-negative findings (FP:FN ratio) is an informative metric that warrants further evaluation. The FP:FN ratio varies greatly across different epidemiologic areas. In genetic epidemiology, it has varied from very high values (possibly even >100:1) for associations reported in candidate-gene studies to very low values (1:100 or lower) for associations with genome-wide significance. The substantial reduction over time in the FP:FN ratio in human genome epidemiology has corresponded to the routine adoption of stringent inferential criteria and comprehensive, agnostic reporting of all analyses. Most traditional fields of epidemiologic research more closely follow the practices of past candidate gene epidemiology, and thus have high FP:FN ratios. Further, FP and FN results do not necessarily entail the same consequences, and their relative importance may vary in different settings. This ultimately has implications for what is the acceptable FP:FN ratio and for how the results of published epidemiologic studies should be presented and interpreted.

    View details for DOI 10.1097/EDE.0b013e31821b506e

    View details for Web of Science ID 000291252100001

    View details for PubMedID 21490505

  • X-WAS, Traditional Epidemiology, and Policy Action EPIDEMIOLOGY Ioannidis, J. A., Tarone, R., McLaughlin, J. K. 2011; 22 (4): 467–68

    View details for DOI 10.1097/EDE.0b013e31821e28f3

    View details for Web of Science ID 000291252100005

  • Replication of genome-wide discovered breast cancer risk loci in the Cypriot population BREAST CANCER RESEARCH AND TREATMENT Loizidou, M. A., Hadjisavvas, A., Ioannidis, J. P., Kyriacou, K. 2011; 128 (1): 267-272

    Abstract

    Genome-wide association studies (GWAS) have identified associations with robust statistical support for influencing breast cancer susceptibility. Most GWAS and replications have been conducted in Northern European populations and to a lesser extent in Asians, and Ashkenazi Jews. It is important to evaluate whether these variants confer risk across different populations and also to assess the magnitude of risk conferred. The aim of this study was to evaluate previously GWAS-identified breast cancer risk variants in the Cypriot population. Eleven GWAS-discovered single nucleotide polymorphisms (SNPs) were analyzed for association with breast cancer in 1,109 Cypriot female breast cancer patients and 1,177 healthy female controls. Four of the 11 SNPs evaluated were found to be nominally significantly associated (P < 0.05) with breast cancer risk in the Cypriot population. Based on estimated power, five associations would be expected to be nominally significant. The correlation coefficient of effect sizes (per-allele odds ratio) between the Cypriot population and the original GWAS populations where these SNPs had been discovered was 0.58 (P = 0.064), while allele frequencies were very similar (r = 0.88, P < 0.001). Overall, we show modest concordance for breast cancer GWAS-discovered alleles and their effect sizes in the Cypriot population. The effects sizes of GWAS-discovered SNPs need to be verified separately in different populations.

    View details for DOI 10.1007/s10549-010-1319-8

    View details for Web of Science ID 000291656200031

    View details for PubMedID 21210208

  • Individualized Cost-Effectiveness Analysis PLOS MEDICINE Ioannidis, J. P., Garber, A. M. 2011; 8 (7)

    View details for DOI 10.1371/journal.pmed.1001058

    View details for Web of Science ID 000293169700008

    View details for PubMedID 21765810

    View details for PubMedCentralID PMC3134464

  • Understanding and Harnessing the Health Effects of Rapid Urbanization in China ENVIRONMENTAL SCIENCE & TECHNOLOGY Zhu, Y., Ioannidis, J. P., Li, H., Jones, K. C., Martin, F. L. 2011; 45 (12): 5099-5104

    Abstract

    China is undergoing a rapid transition from a rural to an urban society. This societal change is a consequence of a national drive toward economic prosperity. Rapid urbanization impacts on infrastructure, environmental health and human wellbeing. Unlike many cases of urban expansion, Chinese urbanization has led to containment, rather than to increase, in the spread of infectious diseases. Conversely, the incidence of chronic conditions such as cardiovascular and metabolic diseases has risen, with higher rates occurring in urban regions. This rural-urban gradient in disease incidence seems not to be a reflection simply of more aggressive diagnosis or healthcare access. Other diseases exhibit little rural versus urban differences (e.g., liver cancer or respiratory disease), or even occur at a higher rate in the rural population (e.g., esophageal cancer). This article examines the impact of this changing demographic on environmental health and human wellbeing in China. Lessons learned from epidemiological studies mostly carried out in Europe and the U.S. may not be directly transferable to China. We advocate that there is now a need to establish robust systems of accurate data collection, a Chinese biobank network to facilitate the profiling of human health effects, and relevant randomized controlled trials to identify effective interventions in the Chinese urbanized setting. Such studies could allow for the future implementation of disease-preventive strategies.

    View details for DOI 10.1021/es2004254

    View details for Web of Science ID 000291422200008

    View details for PubMedID 21542627

  • Different Black Box Warning Labeling for Same-Class Drugs JOURNAL OF GENERAL INTERNAL MEDICINE Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Papanikolaou, P. N., Ntzani, E. E., Ioannidis, J. P. 2011; 26 (6): 603-610

    Abstract

    Black box warnings (BBWs) are the strongest medication-related safety warnings in a drug's labeling information and highlight major risks. Absence of a BBW or asynchronous addition of a BBW among same-class drugs could have major implications.We identified the 20 top-selling drugs in 2008 (10 with BBWs and 10 without BBWs on their label) that belonged to different drug classes. We collected labeling information on all drugs belonging in these 20 classes, and recorded differences in the presence and timing of acquisition of BBWs for same-class drugs.Across the 20 evaluated drug classes, we identified 176 different agents, of which 7 had been withdrawn for safety reasons. The reasons for the withdrawals became BBWs in other same-class agents only in two of the seven cases. Differences were identified in 9 of the 20 classes corresponding to 15 BBWs that were not present in all drugs of the same class. The information for 10 of the 15 different BBWs were included in the labels of same-class drugs as simple warnings or text, while it was absent entirely in 5 BBWs. The median interval from the time the BBW had appeared in another drug of the same class was 66 months.Differences in BBW labeling in same-class drugs are common and shape impressions about the safety of similar agents. BBW labeling needs to become more systematic.

    View details for DOI 10.1007/s11606-011-1633-9

    View details for Web of Science ID 000290576600010

    View details for PubMedID 21286838

    View details for PubMedCentralID PMC3101972

  • A roadmap for successful applications of clinical proteomics PROTEOMICS CLINICAL APPLICATIONS Ioannidis, J. P. 2011; 5 (5-6): 241-247

    Abstract

    Despite over 30,000 publications on proteomics in the last decade, and the accumulation of extensive interesting information on the human proteome in diverse observations, the clinical translation of proteomics to-date has had major setbacks. I review here a roadmap for improving the success rate of clinical proteomics. The roadmap includes steps for improvements that need to be made in analytical tools, discovery, validation, clinical application, and post-clinical application appraisal. It is likely that most if not all of the components that are necessary for clinical success are either readily available, or should be possible to put in place with more rigorous research standards and concerted efforts of the research community, clinicians, and health agencies. Enthusiasm for the clinical impact of proteomics may need to be tempered currently until robust evidence can be obtained, but some clinical successes should eventually be feasible.

    View details for DOI 10.1002/prca.201000096

    View details for Web of Science ID 000291087800005

    View details for PubMedID 21523915

  • Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-analyses JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Panagiotou, O. A. 2011; 305 (21): 2200-2210

    Abstract

    Many biomarkers are proposed in highly cited studies as determinants of disease risk, prognosis, or response to treatment, but few eventually transform clinical practice.To examine whether the magnitude of the effect sizes of biomarkers proposed in highly cited studies is accurate or overestimated.We searched ISI Web of Science and MEDLINE until December 2010.We included biomarker studies that had a relative risk presented in their abstract. Eligible articles were those that had received more than 400 citations in the ISI Web of Science and that had been published in any of 24 highly cited biomedical journals. We also searched MEDLINE for subsequent meta-analyses on the same associations (same biomarker and same outcome).In the highly cited studies, data extraction was focused on the disease/outcome, biomarker under study, and first reported relative risk in the abstract. From each meta-analysis, we extracted the overall relative risk and the relative risk in the largest study. Data extraction was performed independently by 2 investigators.We evaluated 35 highly cited associations. For 30 of the 35 (86%), the highly cited studies had a stronger effect estimate than the largest study; for 3 the largest study was also the highly cited study; and only twice was the effect size estimate stronger in the largest than in the highly cited study. For 29 of the 35 (83%) highly cited studies, the corresponding meta-analysis found a smaller effect estimate. Only 15 of the associations were nominally statistically significant based on the largest studies, and of those only 7 had a relative risk point estimate greater than 1.37.Highly cited biomarker studies often report larger effect estimates for postulated associations than are reported in subsequent meta-analyses evaluating the same associations.

    View details for Web of Science ID 000291106300023

    View details for PubMedID 21632484

  • An Epidemic of False Claims SCIENTIFIC AMERICAN Ioannidis, J. P. 2011; 304 (6): 16-16

    View details for Web of Science ID 000290707400014

    View details for PubMedID 21608392

  • Impact of Phenotype Definition on Genome-Wide Association Signals: Empirical Evaluation in Human Immunodeficiency Virus Type 1 Infection AMERICAN JOURNAL OF EPIDEMIOLOGY Evangelou, E., Fellay, J., Colombo, S., Martinez-Picado, J., Obel, N., Goldstein, D. B., Telenti, A., Ioannidis, J. P. 2011; 173 (11): 1336-1342

    Abstract

    Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

    View details for DOI 10.1093/aje/kwr024

    View details for Web of Science ID 000291058400015

    View details for PubMedID 21490045

  • Commentary: Adjusting for bias: a user's guide to performing plastic surgery on meta-analyses of observational studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2011; 40 (3): 777-779

    View details for DOI 10.1093/ije/dyq265

    View details for Web of Science ID 000293618300029

    View details for PubMedID 21233141

  • Guidelines on Chemotherapy in Advanced Stage Gynecological Malignancies: An Evaluation of 224 Professional Societies and Organizations PLOS ONE Polyzos, N. P., Mauri, D., Ioannidis, J. P. 2011; 6 (5)

    Abstract

    Clinical practice guidelines are important for guiding practice, but it is unclear if they are commensurate with the available evidence.We examined guidelines produced by cancer and gynecological societies and organizations and evaluated their coverage of and stance towards chemotherapy for advanced stage disease among 4 gynecological malignancies (breast, ovarian, cervical, endometrial cancer) where the evidence for the use of chemotherapy is very different (substantial and conclusive for breast and ovarian cancer, limited and suggesting no major benefit for cervical and endometrial cancer). Eligible societies and organizations were identified through systematic internet searches (last update June 2009). Pertinent websites were scrutinized for presence of clinical practice guidelines, and relative guidelines were analyzed.Among 224 identified eligible societies and organizations, 69 (31%) provided any sort of guidelines, while recommendations for chemotherapy on advanced stage gynecological malignancies were available in 20 of them. Only 14 had developed their own guideline, and only 5 had developed guidelines for all 4 malignancies. Use of levels of evidence and grades of recommendations, and aspects of the production, implementation, and timeliness of the guidelines did not differ significantly across malignancies. Guidelines on breast and ovarian cancer utilized significantly more randomized trials and meta-analyses. Guidelines differed across malignancies on their coverage of disease-free survival (p = 0.033), response rates (p = 0.024), symptoms relief (p = 0.005), quality of life (p = 0.001) and toxicity (p = 0.039), with breast and ovarian cancer guidelines typically covering more frequently these outcomes. All guidelines explicitly or implicitly endorsed the use of chemotherapy.Clinical practice guidelines are provided by the minority of professional societies and organizations. Available guidelines tend to recommend chemotherapy even for diseases where the effect of chemotherapy is controversial and recommendations are based on scant evidence.

    View details for DOI 10.1371/journal.pone.0020106

    View details for Web of Science ID 000290657500042

    View details for PubMedID 21611154

    View details for PubMedCentralID PMC3096663

  • Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration EUROPEAN JOURNAL OF HUMAN GENETICS Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 19 (5)

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1038/ejhg.2011.27

    View details for Web of Science ID 000289789500001

    View details for PubMedID 21407270

    View details for PubMedCentralID PMC3083630

  • Strengthening the reporting of Genetic Risk Prediction Studies: The GRIPS statement GENETICS IN MEDICINE Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 13 (5): 453-456

    View details for DOI 10.1097/GIM.0b013e318212fa82

    View details for Web of Science ID 000290435700013

    View details for PubMedID 21502867

  • New Prognostic Markers for Outcome of Acute Pancreatitis Overview of Reporting in 184 Studies PANCREAS Sigounas, D. E., Tatsioni, A., Christodoulou, D. K., Tsianos, E. V., Ioannidis, J. P. 2011; 40 (4): 522-532

    Abstract

    The objective of this study was to assess the reporting of studies on new prognostic markers of outcome in acute pancreatitis.We used MEDLINE searches complemented with perusal of review articles' references to identify eligible English-language studies. We included studies evaluating nonroutine markers for acute pancreatitis. Eligible outcomes included Atlanta criteria, Japanese criteria for severity, multiple/single organ failure, complications, interventional treatment, hospitalization length, and death. We generated a 47-item checklist on Acute Pancreatitis Prognosis by adapting a previously constructed reporting guidance instrument for prognostic tumor markers (REMARK [Reporting Recommendations for Tumor Marker Prognostic Studies]). The checklist addresses the reporting of essential information in prognostic studies.The 184 identified eligible studies reported on 196 different prognostic markers. One hundred forty-four studies (78.3%) found at least 1 prognostic marker to be nominally statistically significant. Significant improvements over time were seen in the reporting for 17 items, but major deficiencies were noted even in 2004-2009 studies. Particularly, 12 items were reported in less than 10% of studies overall and even within the most recent studies.Despite some improvements over time, the reporting of important aspects of prognostic studies in acute pancreatitis remains suboptimal. The proposed REMARK-based checklist may help improve the quality and reporting of research in this field.

    View details for DOI 10.1097/MPA.0b013e31820bf8ac

    View details for Web of Science ID 000289404900005

    View details for PubMedID 21343832

  • Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study ANNALS OF THE RHEUMATIC DISEASES Panoutsopoulou, K., Southam, L., Elliott, K. S., Wrayner, N., Zhai, G., Beazley, C., Thorleifsson, G., Arden, N. K., Carr, A., Chapman, K., Deloukas, P., Doherty, M., McCaskie, A., Ollier, W. E., Ralston, S. H., Spector, T. D., Valdes, A. M., Wallis, G. A., Wilkinson, J. M., ARDEN, E., Battley, K., Blackburn, H., Blanco, F. J., Bumpstead, S., Cupples, L. A., Day-Williams, A. G., Dixon, K., Doherty, S. A., Esko, T., Evangelou, E., Felson, D., Gomez-Reino, J. J., Gonzalez, A., Gordon, A., Gwilliam, R., Halldorsson, B. V., Hauksson, V. B., Hofman, A., Hunt, S. E., Ioannidis, J. P., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Keen, R., Kerkhof, H. J., Kloppenburg, M. G., KOLLER, N., Lakenberg, N., Lane, N. E., Lee, A. T., Metspalu, A., Meulenbelt, I., Nevitt, M. C., O'Neill, F., Parimi, N., Potter, S. C., Rego-Perez, I., Riancho, J. A., Sherburn, K., Slagboom, P. E., Stefansson, K., Styrkarsdottir, U., Sumillera, M., Swift, D., Thorsteinsdottir, U., Tsezou, A., Uitterlinden, A. G., van Meurs, J. B., Watkins, B., Wheeler, M., Mitchell, S., Zhu, Y., Zmuda, J. M., Zeggini, E., Loughlin, J. 2011; 70 (5): 864-867

    Abstract

    The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

    View details for DOI 10.1136/ard.2010.141473

    View details for Web of Science ID 000289070500026

    View details for PubMedID 21177295

    View details for PubMedCentralID PMC3070286

  • An empirical assessment of validation practices for molecular classifiers BRIEFINGS IN BIOINFORMATICS Castaldi, P. J., Dahabreh, I. J., Ioannidis, J. P. 2011; 12 (3): 189-202

    Abstract

    Proposed molecular classifiers may be overfit to idiosyncrasies of noisy genomic and proteomic data. Cross-validation methods are often used to obtain estimates of classification accuracy, but both simulations and case studies suggest that, when inappropriate methods are used, bias may ensue. Bias can be bypassed and generalizability can be tested by external (independent) validation. We evaluated 35 studies that have reported on external validation of a molecular classifier. We extracted information on study design and methodological features, and compared the performance of molecular classifiers in internal cross-validation versus external validation for 28 studies where both had been performed. We demonstrate that the majority of studies pursued cross-validation practices that are likely to overestimate classifier performance. Most studies were markedly underpowered to detect a 20% decrease in sensitivity or specificity between internal cross-validation and external validation [median power was 36% (IQR, 21-61%) and 29% (IQR, 15-65%), respectively]. The median reported classification performance for sensitivity and specificity was 94% and 98%, respectively, in cross-validation and 88% and 81% for independent validation. The relative diagnostic odds ratio was 3.26 (95% CI 2.04-5.21) for cross-validation versus independent validation. Finally, we reviewed all studies (n = 758) which cited those in our study sample, and identified only one instance of additional subsequent independent validation of these classifiers. In conclusion, these results document that many cross-validation practices employed in the literature are potentially biased and genuine progress in this field will require adoption of routine external validation of molecular classifiers, preferably in much larger studies than in current practice.

    View details for DOI 10.1093/bib/bbq073

    View details for Web of Science ID 000290324500002

    View details for PubMedID 21300697

    View details for PubMedCentralID PMC3088312

  • The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance ANNALS OF THE RHEUMATIC DISEASES Valdes, A. M., Evangelou, E., Kerkhof, H. J., Tamm, A., Doherty, S. A., Kisand, K., Tamm, A., Kerna, I., Uitterlinden, A., Hofman, A., Rivadeneira, F., Cooper, C., Dennison, E. M., Zhang, W., Muir, K. R., Ioannidis, J. P., wheeler, M., Maciewicz, R. A., van Meurs, J. B., Arden, N. K., Spector, T. D., Doherty, M. 2011; 70 (5): 873-U308

    View details for DOI 10.1136/ard.2010.134155

    View details for Web of Science ID 000289070500029

    View details for PubMedID 20870806

  • Independent and Joint Effects of the MAPT and SNCA Genes in Parkinson Disease ANNALS OF NEUROLOGY Elbaz, A., Ross, O. A., Ioannidis, J. P., Soto-Ortolaza, A. I., Moisan, F., Aasly, J., Annesi, G., Bozi, M., Brighina, L., Chartier-Harlin, M., Destee, A., Ferrarese, C., Ferraris, A., Gibson, J. M., Gispert, S., Hadjigeorgiou, G. M., Jasinska-Myga, B., Klein, C., Krueger, R., Lambert, J., Lohmann, K., van de Loo, S., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Stefanis, L., Uitti, R. J., Valente, E. M., Vilarino-Gueell, C., Wirdefeldt, K., Wszolek, Z. K., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J. 2011; 69 (5): 778-792

    Abstract

    We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium.Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach.Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale.This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.

    View details for DOI 10.1002/ana.22321

    View details for Web of Science ID 000290156300005

    View details for PubMedID 21391235

  • Industry involvement and baseline assumptions of cost-effectiveness analyses: diagnostic accuracy of the Papanicolaou test CANADIAN MEDICAL ASSOCIATION JOURNAL Polyzos, N. P., Valachis, A., Mauri, D., Ioannidis, J. P. 2011; 183 (6): E337-E343

    Abstract

    Industry involvement has been associated with more favourable cost-effectiveness ratios in cost-effectiveness analyses, but the mechanisms for this association are unclear. We evaluated whether the assumed accuracy of the Papanicolaou (Pap) test was correlated with the features of cost-effectiveness analysis studies.We searched PubMed (last updated April 2010) for cost-effectiveness analysis studies in which at least one strategy involved the Pap test for cervical cancer. We assessed the baseline assumed diagnostic sensitivity and specificity of the Pap test in each study and the association of these values with three levels of manufacturer involvement in the study.Among 88 analyzed cost-effectiveness analysis studies, the assumed sensitivity of the Pap test was lower in studies with manufacturer-affiliated authors, manufacturer funding or manufacturer-related competing interests versus studies without (mean sensitivity 60% v. 70%, p < 0.001). The assumed specificity of the Pap test was lower in cost-effectiveness analyses involving new screening tests (mean 93% v. 96%, p = 0.016). The assumed specificity did not differ between trials with manufacturer involvement versus those without (mean 95% v. 95%, p = 0.755).The results of cost-effectiveness analyses may be affected by a downgrading of the assumed diagnostic accuracy of the standard Pap test against which newer tests or interventions are compared. New technology then seems to have more favourable results against a straw-man comparator.

    View details for DOI 10.1503/cmaj.101506

    View details for Web of Science ID 000288872600014

    View details for PubMedID 21402681

    View details for PubMedCentralID PMC3071415

  • Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration EUROPEAN JOURNAL OF EPIDEMIOLOGY Janssens, A. C., Ioannidis, J. P., Bedrosian, S., Boffetta, P., Dolan, S. M., Dowling, N., Fortier, I., Freedman, A. N., Grimshaw, J. M., Gulcher, J., Gwinn, M., Hlatky, M. A., Janes, H., Kraft, P., Melillo, S., O'Donnell, C. J., Pencina, M. J., Ransohoff, D., Schully, S. D., Seminara, D., Winn, D. M., Wright, C. F., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 26 (4): 313-337

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

    View details for DOI 10.1007/s10654-011-9551-z

    View details for Web of Science ID 000290333700009

    View details for PubMedID 21424820

    View details for PubMedCentralID PMC3088812

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement CIRCULATION-CARDIOVASCULAR GENETICS Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 4 (2): 206-209

    View details for DOI 10.1161/CIRCGENETICS.111.959668

    View details for Web of Science ID 000289712700017

    View details for PubMedID 21406688

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement EUROPEAN JOURNAL OF EPIDEMIOLOGY Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 26 (4): 255-259

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published.

    View details for DOI 10.1007/s10654-011-9552-y

    View details for Web of Science ID 000290333700002

    View details for PubMedID 21431409

    View details for PubMedCentralID PMC3088799

  • Vaccination in adult patients with auto-immune inflammatory rheumatic diseases: A systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases AUTOIMMUNITY REVIEWS van Assen, S., Elkayam, O., Agmon-Levin, N., Cervera, R., Doran, M. F., Dougados, M., Emery, P., Geborek, P., Ioannidis, J. P., Jayne, D. R., Kallenberg, C. G., Mueller-Ladner, U., Shoenfeld, Y., Stojanovich, L., Valesini, G., Wulffraat, N. M., Bijl, M. 2011; 10 (6): 341-352

    Abstract

    To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD).AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ≤ 5 participants. Articles in English and regarding patients ≥ 16 years of age, were eligible.Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive.Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.

    View details for DOI 10.1016/j.autrev.2010.12.003

    View details for Web of Science ID 000290059400009

    View details for PubMedID 21182987

  • Quantifying Selective Reporting and the Proteus Phenomenon for Multiple Datasets with Similar Bias PLOS ONE Pfeiffer, T., Bertram, L., Ioannidis, J. P. 2011; 6 (3)

    Abstract

    Meta-analyses play an important role in synthesizing evidence from diverse studies and datasets that address similar questions. A major obstacle for meta-analyses arises from biases in reporting. In particular, it is speculated that findings which do not achieve formal statistical significance are less likely reported than statistically significant findings. Moreover, the patterns of bias can be complex and may also depend on the timing of the research results and their relationship with previously published work. In this paper, we present an approach that is specifically designed to analyze large-scale datasets on published results. Such datasets are currently emerging in diverse research fields, particularly in molecular medicine. We use our approach to investigate a dataset on Alzheimer's disease (AD) that covers 1167 results from case-control studies on 102 genetic markers. We observe that initial studies on a genetic marker tend to be substantially more biased than subsequent replications. The chances for initial, statistically non-significant results to be published are estimated to be about 44% (95% CI, 32% to 63%) relative to statistically significant results, while statistically non-significant replications have almost the same chance to be published as statistically significant replications (84%; 95% CI, 66% to 107%). Early replications tend to be biased against initial findings, an observation previously termed Proteus phenomenon: The chances for non-significant studies going in the same direction as the initial result are estimated to be lower than the chances for non-significant studies opposing the initial result (73%; 95% CI, 55% to 96%). Such dynamic patterns in bias are difficult to capture by conventional methods, where typically simple publication bias is assumed to operate. Our approach captures and corrects for complex dynamic patterns of bias, and thereby helps generating conclusions from published results that are more robust against the presence of different coexisting types of selective reporting.

    View details for DOI 10.1371/journal.pone.0018362

    View details for Web of Science ID 000289054600050

    View details for PubMedID 21479240

    View details for PubMedCentralID PMC3066227

  • Research Methods & Reporting Strengthening the reporting of genetic risk prediction studies: the GRIPS statement BMJ-BRITISH MEDICAL JOURNAL Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 342

    View details for DOI 10.1136/bmj.d631

    View details for Web of Science ID 000209546100001

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement ANNALS OF INTERNAL MEDICINE Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 154 (6): 421-W141

    View details for DOI 10.1059/0003-4819-154-6-201103150-00008

    View details for Web of Science ID 000288370000006

    View details for PubMedID 21403077

  • RE: "THE EMERGENCE OF TRANSLATIONAL EPIDEMIOLOGY: FROM SCIENTIFIC DISCOVERY TO POPULATION HEALTH IMPACT" REPLY AMERICAN JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Gwinn, M., Ioannidis, J. P. 2011; 173 (6): 718-U131

    View details for DOI 10.1093/aje/kwq450

    View details for Web of Science ID 000288274800018

  • EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases ANNALS OF THE RHEUMATIC DISEASES van Assen, S., Agmon-Levin, N., Elkayam, O., Cervera, R., Doran, M. F., Dougados, M., Emery, P., Geborek, P., Ioannidis, J. P., Jayne, D. R., Kallenberg, C. G., Mueller-Ladner, U., Shoenfeld, Y., Stojanovich, L., Valesini, G., Wulffraat, N. M., Bijl, M. 2011; 70 (3): 414-422

    Abstract

    To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD).A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force.Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed.Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

    View details for DOI 10.1136/ard.2010.137216

    View details for Web of Science ID 000286927800003

    View details for PubMedID 21131643

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement PLOS MEDICINE Janssens, A. W., Ioannidis, J. A., van Duijn, C. M., Little, J., Khoury, M. J., GRIPS Grp 2011; 8 (3): e1000420

    View details for DOI 10.1371/journal.pmed.1000420

    View details for Web of Science ID 000288945200001

    View details for PubMedID 21423587

    View details for PubMedCentralID PMC3058100

  • Polymorphisms in the 5 ' flank of COL1A1 gene and osteoporosis: meta-analysis of published studies OSTEOPOROSIS INTERNATIONAL Jin, H., Evangelou, E., Ioannidis, J. P., Ralston, S. H. 2011; 22 (3): 911-921

    Abstract

    A meta-analysis of studies was conducted involving 24,511 participants with 7,864 fractures in which polymorphisms in the 5' flank of COL1A1 (rs1107946, rs2412298, and rs1800012) were related to osteoporosis phenotypes. Polymorphisms of all three sites were associated with BMD, and rs1800012 was associated with fracture but effect sizes were modest.Polymorphisms in the 5' flank of COL1A1 gene have been implicated as genetic markers for susceptibility to osteoporosis, but previous studies have yielded conflicting results.We conducted a meta-analysis of 32 studies including 24,511 participants and 7,864 fractures in which alleles at the -1997G/T (rs1107946), -1663in/delT (rs2412298), and Sp1 binding site polymorphisms (rs1800012) of COL1A1 had been related to bone mineral density (BMD) or fracture.For the Sp1 polymorphism, BMD values in TT homozygotes were 0.13 units [95% CI, 0.03 to 0.24] lower at the spine (p = 0.01) and 0.16 units [0.10 to 0.23] lower at the hip (p = 1 x 10⁻⁶) than GG homozygotes. Clinical fractures were 1.31-fold [1.04-1.65] increased in TT homozygotes (p = 0.02) and vertebral fractures were 1.34-fold [1.01-1.77] increased (p = 0.04). We also observed associations between spine BMD and allelic variants at the -1997G/T (p = 0.05) and the -1663indelT (p = 0.009) sites. We found no association between alleles at the -1997G/T or -1663indelT sites and fracture but power was limited.The COL1A1 Sp1 polymorphism is associated with a modest reduction in BMD and an increased risk of fracture, although we cannot fully exclude the possibility that the results may have been influenced by publication bias. Further studies are required to fully evaluate the contribution of the -1997G/T and -1663in/delT sites to these phenotypes and to determine if they interact with the Sp1 polymorphism to regulate susceptibility to osteoporosis.

    View details for DOI 10.1007/s00198-010-1364-5

    View details for Web of Science ID 000287101600018

    View details for PubMedID 20798928

  • A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease NEUROBIOLOGY OF AGING Krueger, R., Sharma, M., Riess, O., Gasser, T., Van Broeckhoven, C., Theuns, J., Aasly, J., Annesi, G., Bentivoglio, A. R., Brice, A., Djarmati, A., Elbaz, A., Farrer, M., Ferrarese, C., Gibson, J. M., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Klein, C., Lambert, J., Lesage, S., Lin, J., Lynch, T., Mellick, G. D., de Nigris, F., Opala, G., Prigione, A., Quattrone, A., Ross, O. A., Satake, W., Silburn, P. A., Tan, E. K., Toda, T., Tomiyama, H., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Maraganore, D. M. 2011; 32 (3)

    Abstract

    High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.

    View details for DOI 10.1016/j.neurobiolaging.2009.11.021

    View details for Web of Science ID 000289944800028

    View details for PubMedID 20036034

  • Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P., Siontis, G. C. 2011; 103 (3)

    View details for DOI 10.1093/jnci/djq503

    View details for Web of Science ID 000287027000014

    View details for PubMedID 21163904

  • Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial JOURNAL OF CLINICAL EPIDEMIOLOGY Salanti, G., Ades, A. E., Ioannidis, J. P. 2011; 64 (2): 163-171

    Abstract

    To present some simple graphical and quantitative ways to assist interpretation and improve presentation of results from multiple-treatment meta-analysis (MTM).We reanalyze a published network of trials comparing various antiplatelet interventions regarding the incidence of serious vascular events using Bayesian approaches for random effects MTM, and we explore the advantages and drawbacks of various traditional and new forms of quantitative displays and graphical presentations of results.We present the results under various forms, conventionally based on the mean of the distribution of the effect sizes; based on predictions; based on ranking probabilities; and finally, based on probabilities to be within an acceptable range from a reference. We show how to obtain and present results on ranking of all treatments and how to appraise the overall ranks.Bayesian methodology offers a multitude of ways to present results from MTM models, as it enables a natural and easy estimation of all measures based on probabilities, ranks, or predictions.

    View details for DOI 10.1016/j.jclinepi.2010.03.016

    View details for Web of Science ID 000287281300007

    View details for PubMedID 20688472

  • Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 ANNALS OF THE RHEUMATIC DISEASES Evangelou, E., Valdes, A. M., Kerkhof, H. J., Styrkarsdottir, U., Zhu, Y., Meulenbelt, I., Lories, R. J., Karassa, F. B., Tylzanowski, P., Bos, S. D., Akune, T., Arden, N. K., Carr, A., Chapman, K., Cupples, L. A., Dai, J., Deloukas, P., Doherty, M., Doherty, S., Engstrom, G., Gonzalez, A., Halldorsson, B. V., Hammond, C. L., Hart, D. J., Helgadottir, H., Hofman, A., Ikegawa, S., Ingvarsson, T., Jiang, Q., Jonsson, H., Kaprio, J., Kawaguchi, H., Kisand, K., Kloppenburg, M., Kujala, U. M., Lohmander, L. S., Loughlin, J., Luyten, F. P., Mabuchi, A., McCaskie, A., Nakajima, M., Nilsson, P. M., Nishida, N., Ollier, W. E., Panoutsopoulou, K., Van de Putte, T., Ralston, S. H., Rivadeneira, F., Saarela, J., Schulte-Merker, S., Shi, D., Slagboom, P. E., Sudo, A., Tamm, A., Tamm, A., Thorleifsson, G., Thorsteinsdottir, U., Tsezou, A., Wallis, G. A., Wilkinson, J. M., Yoshimura, N., Zeggini, E., Zhai, G., Zhang, F., Jonsdottir, I., Uitterlinden, A. G., Felson, D. T., van Meurs, J. B., Stefansson, K., Ioannidis, J. P., Spector, T. D. 2011; 70 (2): 349-355

    Abstract

    Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component.A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets.With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10⁻⁹), thereby confirming its role as a susceptibility locus for OA.The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

    View details for DOI 10.1136/ard.2010.132787

    View details for Web of Science ID 000286179000022

    View details for PubMedID 21068099

  • Optimal timing of coronary angiography and potential intervention in non-ST-elevation acute coronary syndromes EUROPEAN HEART JOURNAL Katritsis, D. G., Siontis, G. C., Kastrati, A., van't Hof, A. W., Neumann, F., Siontis, K. C., Ioannidis, J. P. 2011; 32 (1): 32-40

    Abstract

    An invasive approach is superior to medical management for the treatment of patients with acute coronary syndromes without ST-segment elevation (NSTE-ACS), but the optimal timing of coronary angiography and subsequent intervention, if indicated, has not been settled.We conducted a meta-analysis of randomized trials addressing the optimal timing (early vs. delayed) of coronary angiography in NSTE-ACS. Four trials with 4013 patients were eligible (ABOARD, ELISA, ISAR-COOL, TIMACS), and data for longer follow-up periods than those published became available for this meta-analysis by the ELISA and ISAR-COOL investigators. The median time from admission or randomization to coronary angiography ranged from 1.16 to 14 h in the early and 20.8-86 h in the delayed strategy group. No statistically significant difference of risk of death [random effects risk ratio (RR) 0.85, 95% confidence interval (CI) 0.64-1.11] or myocardial infarction (MI) (RR 0.94, 95% CI 0.61-1.45) was detected between the two strategies. Early intervention significantly reduced the risk for recurrent ischaemia (RR 0.59, 95% CI 0.38-0.92, P = 0.02) and the duration of hospital stay (by 28%, 95% CI 22-35%, P < 0.001). Furthermore, decreased major bleeding events (RR 0.78, 95% CI 0.57-1.07, P = 0.13), and less major events (death, MI, or stroke) (RR 0.91, 95% CI 0.82-1.01, P = 0.09) were observed with the early strategy but these differences were not nominally significant.Early coronary angiography and potential intervention reduces the risk of recurrent ischaemia, and shortens hospital stay in patients with NSTE-ACS.

    View details for DOI 10.1093/eurheartj/ehq276

    View details for Web of Science ID 000286006200012

    View details for PubMedID 20709722

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement. BMJ (Clinical research ed.) Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 342

    View details for DOI 10.1136/bmj.d631

    View details for PubMedID 21411493

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement. Genome medicine Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 3 (3): 16-?

    Abstract

    The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of genetic risk prediction studies (the GRIPS statement), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published at http://www.plosmedicine.org.

    View details for DOI 10.1186/gm230

    View details for PubMedID 21410995

  • Strengthening the reporting of genetic risk prediction studies: the GRIPS statement GENOME MEDICINE Janssens, A. C., Ioannidis, J. P., van Duijn, C. M., Little, J., Khoury, M. J. 2011; 3

    View details for DOI 10.1186/gm230

    View details for Web of Science ID 000208627400016

    View details for PubMedCentralID PMC3058100

  • Allergens responsible for allergic contact dermatitis among children: a systematic review and meta-analysis CONTACT DERMATITIS Bonitsis, N. G., Tatsioni, A., Bassioukas, K., Ioannidis, J. P. 2011; 64 (5): 245-257

    Abstract

    Multiple studies have evaluated diverse allergens in paediatric populations. Consensus is still lacking on which allergens are most commonly implicated in allergic contact dermatitis.To evaluate the proportion of positive reactions for allergens tested in children and to identify allergens with positive reactions in at least 1% of them.This was a systematic review of studies in PubMed (1966-2010) investigating allergens in at least 100 enrolled children. Proportions of positive reactions for each allergen were combined with random effects models across studies.We included 49 studies with available data on 170 allergens. Each study tested a median of two allergens. Among the 94 allergens evaluated by at least two studies, 58 had estimates of positive reactions of at least 1% by random effects calculations, and for 21 of them the 95% confidence interval ensured that the proportion of positive reactions was at least 1%. The top five allergens tested by at least two studies included nickel sulfate, ammonium persulfate, gold sodium thiosulfate, thimerosal, and toluene-2,5-diamine (p-toluenediamine). For most allergens, the proportion of positive reactions was higher in studies published after 1995 than in earlier studies (p = 0.0065).This meta-analysis offers guidance on which allergens are most prevalent in the paediatric population and should have priority for inclusion in standardized allergen series.

    View details for DOI 10.1111/j.1600-0536.2010.01860.x

    View details for Web of Science ID 000289474000001

    View details for PubMedID 21480911

  • Combining molecular and genetic data from different sources. IARC scientific publications Ntzani, E. E., Khoury, M. J., Ioannidis, J. P. 2011: 323-336

    Abstract

    The rapidly growing number of molecular epidemiology studies is providing an enormous, often multidimensional, body of evidence on the association of various disease outcomes and biomarkers. The testing and validation of statistical hypotheses in genetic and molecular epidemiology presents a major challenge requiring methodological rigor and analytical power. The non-replication of many genetic and other biomarker association studies suggests that there may be an abundance of spurious findings in the field. This chapter will discuss ways of combining evidence from different sources using meta-analysis methods. Research synthesis not only aims at producing a summary effect estimate for a specific biomarker, but also offers a unique opportunity for a meticulous attempt to critically appraise a research field, identify substantial differences between or within studies, and detect sources of bias. Systematic reviews and meta-analyses in human genome epidemiology are specifically discussed, as they comprise the bulk of the available evidence in molecular epidemiology where these methods have been applied to date. Considered here are issues regarding validity and interpretation in genetic association studies, as well as strategies for developing and integrating evidence through international consortia. Finally, there is a brief look at how combining data through meta-analysis may be applied in other areas of molecular epidemiology.

    View details for PubMedID 22997870

  • EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Ioannidis, J. P., Aringer, M., Bollen, E., Bombardieri, S., Bruce, I. N., Cervera, R., Dalakas, M., DORIA, A., Hanly, J. G., Huizinga, T. W., Isenberg, D., Kallenberg, C., Piette, J. C., Schneider, M., Scolding, N., Smolen, J., Stara, A., Tassiulas, I., Tektonidou, M., Tincani, A., van Buchem, M. A., van Vollenhoven, R., Ward, M., Gordon, C., Boumpas, D. T. 2010; 69 (12): 2074-2082

    Abstract

    To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations.The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design.Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence > 5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1-5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD.Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

    View details for DOI 10.1136/ard.2010.130476

    View details for Web of Science ID 000284407300004

    View details for PubMedID 20724309

  • Is there a glass ceiling for highly cited scientists at the top of research universities? FASEB JOURNAL Ioannidis, J. P. 2010; 24 (12): 4635-4638

    Abstract

    University leaders aim to protect, shape, and promote the missions of their institutions. I evaluated whether top highly cited scientists are likely to occupy these positions. Of the current leaders of 96 U.S. high research activity universities, only 6 presidents or chancellors were found among the 4009 U.S. scientists listed in the ISIHighlyCited.com database. Of the current leaders of 77 UK universities, only 2 vice-chancellors were found among the 483 UK scientists listed in the same database. In a sample of 100 top-cited clinical medicine scientists and 100 top-cited biology and biochemistry scientists, only 1 and 1, respectively, had served at any time as president of a university. Among the leaders of 25 U.S. universities with the highest citation volumes, only 12 had doctoral degrees in life, natural, physical or computer sciences, and 5 of these 12 had a Hirsch citation index m < 1.0. The participation of highly cited scientists in the top leadership of universities is limited. This could have consequences for the research and overall mission of universities.

    View details for DOI 10.1096/fj.10-162974

    View details for Web of Science ID 000284824400004

    View details for PubMedID 20686108

  • Laboratory Mouse Models for the Human Genome-Wide Associations PLOS ONE Kitsios, G. D., Tangri, N., Castaldi, P. J., Ioannidis, J. P. 2010; 5 (11)

    Abstract

    The agnostic screening performed by genome-wide association studies (GWAS) has uncovered associations for previously unsuspected genes. Knowledge about the functional role of these genes is crucial and laboratory mouse models can provide such information. Here, we describe a systematic juxtaposition of human GWAS-discovered loci versus mouse models in order to appreciate the availability of mouse models data, to gain biological insights for the role of these genes and to explore the extent of concordance between these two lines of evidence. We perused publicly available data (NHGRI database for human associations and Mouse Genome Informatics database for mouse models) and employed two alternative approaches for cross-species comparisons, phenotype- and gene-centric. A total of 293 single gene-phenotype human associations (262 unique genes and 69 unique phenotypes) were evaluated. In the phenotype-centric approach, we identified all mouse models and related ortholog genes for the 51 human phenotypes with a comparable phenotype in mice. A total of 27 ortholog genes were found to be associated with the same phenotype in humans and mice, a concordance that was significantly larger than expected by chance (p<0.001). In the gene-centric approach, we were able to locate at least 1 knockout model for 60% of the 262 genes. The knockouts for 35% of these orthologs displayed pre- or post-natal lethality. For the remaining non-lethal orthologs, the same organ system was involved in mice and humans in 71% of the cases (p<0.001). Our project highlights the wealth of available information from mouse models for human GWAS, catalogues extensive information on plausible physiologic implications for many genes, provides hypothesis-generating findings for additional GWAS analyses and documents that the concordance between human and mouse genetic association is larger than expected by chance and can be informative.

    View details for DOI 10.1371/journal.pone.0013782

    View details for Web of Science ID 000283645700007

    View details for PubMedID 21072174

    View details for PubMedCentralID PMC2967475

  • Science mapping analysis characterizes 235 biases in biomedical research JOURNAL OF CLINICAL EPIDEMIOLOGY Chavalarias, D., Ioannidis, J. P. 2010; 63 (11): 1205-1215

    Abstract

    Many different types of bias have been described. Some biases may tend to coexist or be associated with specific research settings, fields, and types of studies. We aimed to map systematically the terminology of bias across biomedical research.We used advanced text-mining and clustering techniques to evaluate 17,265,924 items from PubMed (1958-2008). We considered 235 bias terms and 103 other terms that appear commonly in articles dealing with bias.Forty bias terms were used in the title or abstract of more than 100 articles each. Pseudo-inclusion clustering identified 252 clusters of terms. The clusters were organized into macroscopic maps that cover a continuum of research fields. The resulting maps highlight which types of biases tend to co-occur and may need to be considered together and what biases are commonly encountered and discussed in specific fields. Most of the common bias terms have had continuous use over time since their introduction, and some (in particular confounding, selection bias, response bias, and publication bias) show increased usage through time.This systematic mapping offers a dynamic classification of biases in biomedical investigation and related fields and can offer insights for the multifaceted aspects of bias.

    View details for DOI 10.1016/j.jclinepi.2009.12.011

    View details for Web of Science ID 000282861600006

    View details for PubMedID 20400265

  • Genome-wide Significant Associations for Variants With Minor Allele Frequency of 5% or Less - An Overview: A HuGE Review AMERICAN JOURNAL OF EPIDEMIOLOGY Panagiotou, O. A., Evangelou, E., Ioannidis, J. P. 2010; 172 (8): 869-889

    Abstract

    The authors survey uncommon variants (minor allele frequency, ≤5%) that have reached genome-wide significance (P ≤ 10⁻⁷) in genome-wide association study(ies) (GWAS). They examine the typical effect sizes of these associations; whether they have arisen in multiple GWAS on the same phenotype; and whether they pertain to genetic loci that have other variants discovered through GWAS, perceived biologic plausibility from the candidate gene era, or known mutations associated with related phenotypes. Forty-three associations with minor allele frequency of 5% or less and P ≤ 10⁻⁷ were studied, 12 of which involved nonsynonymous variants. Per-allele odds ratios ranged from 1.03 to 22.11. Thirty-two associations had P ≤ 10⁻⁸. Eight uncommon variants were identified in multiple GWAS. For 14 associations, also other common polymorphisms with genome-wide significance were identified in the same loci. Thirteen associations pertained to genetic loci considered to have biologic plausibility for association in the candidate gene era, and mutations with related phenotypic effects were identified for 11 associations. Twenty-five uncommon variants are common in at least 1 of the 4 different ancestry samples of the International HapMap Project. Although the number of uncommon variants with genome-wide significance is still limited, these data suggest a possible confluence of rare/uncommon and common genetic variation on the same genetic loci.

    View details for DOI 10.1093/aje/kwq234

    View details for Web of Science ID 000283089700001

    View details for PubMedID 20876667

  • Evaluating novel agent effects in multiple-treatments meta-regression STATISTICS IN MEDICINE Salanti, G., Dias, S., Welton, N. J., Ades, A. E., Golfinopoulos, V., Kyrgiou, M., Mauri, D., Ioannidis, J. P. 2010; 29 (23): 2369-2383

    Abstract

    Multiple-treatments meta-analyses are increasingly used to evaluate the relative effectiveness of several competing regimens. In some fields which evolve with the continuous introduction of new agents over time, it is possible that in trials comparing older with newer regimens the effectiveness of the latter is exaggerated. Optimism bias, conflicts of interest and other forces may be responsible for this exaggeration, but its magnitude and impact, if any, needs to be formally assessed in each case. Whereas such novelty bias is not identifiable in a pair-wise meta-analysis, it is possible to explore it in a network of trials involving several treatments. To evaluate the hypothesis of novel agent effects and adjust for them, we developed a multiple-treatments meta-regression model fitted within a Bayesian framework. When there are several multiple-treatments meta-analyses for diverse conditions within the same field/specialty with similar agents involved, one may consider either different novel agent effects in each meta-analysis or may consider the effects to be exchangeable across the different conditions and outcomes. As an application, we evaluate the impact of modelling and adjusting for novel agent effects for chemotherapy and other non-hormonal systemic treatments for three malignancies. We present the results and the impact of different model assumptions to the relative ranking of the various regimens in each network. We established that multiple-treatments meta-regression is a good method for examining whether novel agent effects are present and estimation of their magnitude in the three worked examples suggests an exaggeration of the hazard ratio by 6 per cent (2-11 per cent).

    View details for DOI 10.1002/sim.4001

    View details for Web of Science ID 000282622200001

    View details for PubMedID 20687172

  • Assessment of cumulative evidence for the association between glutathione S-transferase polymorphisms and lung cancer: application of the Venice interim guidelines PHARMACOGENETICS AND GENOMICS Langevin, S. M., Ioannidis, J. P., Vineis, P., Taioli, E. 2010; 20 (10): 586-597

    Abstract

    There is an overwhelming abundance of genetic association studies available in the literature, which can often be collectively difficult to interpret. To address this issue, the Venice interim guidelines were established for determining the credibility of the cumulative evidence. The objective of this report is to evaluate the literature on the association of common glutathione S-transferase (GST) variants (GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphism) and lung cancer, and to assess the credibility of the associations using the newly proposed cumulative evidence guidelines.Information from the literature was enriched with an updated meta-analysis and a pooled analysis using data from the Genetic Susceptibility to Environmental Carcinogens database.There was a significant association between GSTM1 null and lung cancer for the meta-analysis (meta odds ratio=1.17, 95% confidence interval: 1.10-1.25) and pooled analysis (adjusted odds ratio=1.10, 95% confidence interval: 1.04-1.16), although substantial heterogeneity was present. No overall association between lung cancer and GSTT1 null or GSTP1 Ile105Val was found. When the Venice criteria was applied, cumulative evidence for all associations were considered 'weak', with the exception of East Asian carriers of the G allele of GSTP1 Ile105Val, which was graded as 'moderate' evidence.Despite the large amounts of studies, and several statistically significant summary estimates produced by meta-analyses, the application of the Venice criteria suggests extensive heterogeneity and susceptibility to bias for the studies on association of common genetic polymorphisms, such as with GST variants and lung cancer.

    View details for DOI 10.1097/FPC.0b013e32833c3892

    View details for Web of Science ID 000281830900002

    View details for PubMedID 20729793

  • The need to consider the wider agenda in systematic reviews and meta-analyses: breadth, timing, and depth of the evidence BRITISH MEDICAL JOURNAL Ioannidis, J. P., Karassa, F. B. 2010; 341

    View details for DOI 10.1136/bmj.c4875

    View details for Web of Science ID 000282089500010

    View details for PubMedID 20837576

  • The Emergence of Translational Epidemiology: From Scientific Discovery to Population Health Impact AMERICAN JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Gwinn, M., Ioannidis, J. P. 2010; 172 (5): 517-524

    Abstract

    Recent emphasis on translational research (TR) is highlighting the role of epidemiology in translating scientific discoveries into population health impact. The authors present applications of epidemiology in TR through 4 phases designated T1-T4, illustrated by examples from human genomics. In T1, epidemiology explores the role of a basic scientific discovery (e.g., a disease risk factor or biomarker) in developing a "candidate application" for use in practice (e.g., a test used to guide interventions). In T2, epidemiology can help to evaluate the efficacy of a candidate application by using observational studies and randomized controlled trials. In T3, epidemiology can help to assess facilitators and barriers for uptake and implementation of candidate applications in practice. In T4, epidemiology can help to assess the impact of using candidate applications on population health outcomes. Epidemiology also has a leading role in knowledge synthesis, especially using quantitative methods (e.g., meta-analysis). To explore the emergence of TR in epidemiology, the authors compared articles published in selected issues of the Journal in 1999 and 2009. The proportion of articles identified as translational doubled from 16% (11/69) in 1999 to 33% (22/66) in 2009 (P = 0.02). Epidemiology is increasingly recognized as an important component of TR. By quantifying and integrating knowledge across disciplines, epidemiology provides crucial methods and tools for TR.

    View details for DOI 10.1093/aje/kwq211

    View details for Web of Science ID 000281324100003

    View details for PubMedID 20688899

  • Expectations, validity, and reality in omics JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P. 2010; 63 (9): 945-949

    Abstract

    Diverse methods of large-scale measurements of biological processes have emerged in the last 15 years and their list is growing rapidly. Almost invariably, these advances in omics have been associated with major expectations of transforming not only biological knowledge but also medicine and health. However, practical applications of omics in biomedicine have often suffered from poor attention to issues of validity. As a consequence, major promises of personalized medicine have not yet materialized in improving patient or population outcomes. Several omics fields increasingly realize the need to safeguard the validity of their efforts, make reporting more transparent, and improve the translational potential of their studies. Many discoveries point indeed toward a highly individualized profile of health and disease, where each case is different, but this is currently difficult to translate into more effective personalized treatment or prevention. Given the exponential growth of collected data, understanding is often drowning in the sea of measurements.

    View details for DOI 10.1016/j.jclinepi.2010.04.002

    View details for Web of Science ID 000280746000002

    View details for PubMedID 20573481

  • Published articles should not be dead and buried: introducing research updates EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P., Tatsioni, A., Karassa, F. B. 2010; 40 (9): 767-769

    View details for DOI 10.1111/j.1365-2362.2010.02350.x

    View details for Web of Science ID 000280669100001

    View details for PubMedID 20698877

  • Fifty-Year Fate and Impact of General Medical Journals PLOS ONE Ioannidis, J. P., Belbasis, L., Evangelou, E. 2010; 5 (9)

    Abstract

    Influential medical journals shape medical science and practice and their prestige is usually appraised by citation impact metrics, such as the journal impact factor. However, how permanent are medical journals and how stable is their impact over time?We evaluated what happened to general medical journals that were publishing papers half a century ago, in 1959. Data were retrieved from ISI Web of Science for citations and PubMed (Journals function) for journal history. Of 27 eligible journals publishing in 1959, 4 have stopped circulation (including two of the most prestigious journals in 1959) and another 7 changed name between 1959 and 2009. Only 6 of these 27 journals have been published continuously with their initial name since they started circulation. The citation impact of papers published in 1959 gives a very different picture from the current journal impact factor; the correlation between the two is non-significant and very close to zero. Only 13 of the 5,223 papers published in 1959 received at least 5 citations in 2009.Journals are more permanent entities than single papers, but they are also subject to major change and their relative prominence can change markedly over time.

    View details for DOI 10.1371/journal.pone.0012531

    View details for Web of Science ID 000281456100023

    View details for PubMedID 20824146

  • Partisan Perspectives in the Medical Literature: A Study of High Frequency Editorialists Favoring Hormone Replacement Therapy JOURNAL OF GENERAL INTERNAL MEDICINE Tatsioni, A., Siontis, G. C., Ioannidis, J. P. 2010; 25 (9): 914-919

    Abstract

    Unfavorable results of major studies have led to a large shrinkage of the market for hormone replacement therapy (HRT) in the last 6 years. Some scientists continue to strongly support the use of HRT.We analyzed a sample of partisan editorializing articles on HRT to examine their arguments, the reporting of competing interests, the journal venues and their sponsoring societies.Through Thomson ISI database, we selected articles without primary data written by the five most prolific editorialists that addressed clinical topics pertaining to HRT and that were published in regular journal issues in 2002-2008.We recorded the number of articles with a partisan stance and their arguments, the number of partisan articles that reported conflicting interests, and the journal venues and their sponsoring societies publishing the partisan editorials.We analyzed 114 eligible articles (58 editorials, 16 guidelines, 37 reviews, 3 letters), of which 110 (96%) had a partisan stance favoring HRT. Typical arguments were benefits for menopausal and related symptoms (64.9%), criticism of unfavorable studies (78.9%), preclinical data that showed favorable effects of HRT (50%), and benefits for major outcomes such as osteoporosis and fractures (49.1%), cardiovascular disease (31.6%), dementia (24.6%) or colorectal cancer (20.2%), but also even breast cancer (4.4%). All 5 prolific editorialists had financial relationships with hormone manufacturers, but these were reported in only 6 of the 110 partisan articles. Four journals published 15-37 partisan articles each. The medical societies of these journals reported on their websites that several pharmaceutical companies sponsored them or their conferences.There is a considerable body of editorializing articles favoring HRT use and very few of these articles report conflicts of interest. Full disclosure of conflicts of interest is needed, especially for articles without primary data.

    View details for DOI 10.1007/s11606-010-1360-7

    View details for Web of Science ID 000280728300011

    View details for PubMedID 20425148

  • Recommendations for Biomarker Identification and Qualification in Clinical Proteomics SCIENCE TRANSLATIONAL MEDICINE Mischak, H., Allmaier, G., Apweiler, R., Attwood, T., Baumann, M., Benigni, A., Bennett, S. E., Bischoff, R., Bongcam-Rudloff, E., Capasso, G., Coon, J. J., D'Haese, P., Dominiczak, A. F., Dakna, M., Dihazi, H., Ehrich, J. H., Fernandez-Llama, P., Fliser, D., Frokiaer, J., Garin, J., Girolami, M., Hancock, W. S., Haubitz, M., Hochstrasser, D., Holman, R. R., Ioannidis, J. P., Jankowski, J., Julian, B. A., Klein, J. B., Kolch, W., Luider, T., Massy, Z., Mattes, W. B., Molina, F., Monsarrat, B., Novak, J., Peter, K., Rossing, P., Sanchez-Carbayo, M., Schanstra, J. P., Semmes, O. J., Spasovski, G., Theodorescu, D., Thongboonkerd, V., Vanholder, R., Veenstra, T. D., Weissinger, E., Yamamoto, T., Vlahou, A. 2010; 2 (46)

    Abstract

    Clinical proteomics has yielded some early positive results-the identification of potential disease biomarkers-indicating the promise for this analytical approach to improve the current state of the art in clinical practice. However, the inability to verify some candidate molecules in subsequent studies has led to skepticism among many clinicians and regulatory bodies, and it has become evident that commonly encountered shortcomings in fundamental aspects of experimental design mainly during biomarker discovery must be addressed in order to provide robust data. In this Perspective, we assert that successful studies generally use suitable statistical approaches for biomarker definition and confirm results in independent test sets; in addition, we describe a brief set of practical and feasible recommendations that we have developed for investigators to properly identify and qualify proteomic biomarkers, which could also be used as reporting requirements. Such recommendations should help put proteomic biomarker discovery on the solid ground needed for turning the old promise into a new reality.

    View details for DOI 10.1126/scitranslmed.3001249

    View details for Web of Science ID 000288435800002

    View details for PubMedID 20739680

  • Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal TRIALS Kent, D. M., Rothwell, P. M., Ioannidis, J. P., Altman, D. G., Hayward, R. A. 2010; 11

    Abstract

    Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability.

    View details for DOI 10.1186/1745-6215-11-85

    View details for Web of Science ID 000282599100001

    View details for PubMedID 20704705

  • Comparative Effectiveness of Medical Interventions in Adults Versus Children JOURNAL OF PEDIATRICS Contopoulos-Ioannidis, D. G., Baltogianni, M. S., Ioannidis, J. P. 2010; 157 (2): 322-330

    Abstract

    To estimate the comparative effectiveness of medical interventions in adults versus children.We identified from the Cochrane Database of Systematic Reviews (Issue 1, 2007) meta-analyses with data on at least 1 adult and 1 pediatric randomized trial with binary primary efficacy outcome. For each meta-analysis, we calculated the summary odds ratio of the adult trials and the pediatric trials, respectively; the relative odds ratio (ROR) of the adult versus pediatric odds ratios per meta-analysis; and the summary ROR across all meta-analyses. ROR <1 means that the experimental intervention is more unfavorable in children than adults.Across 128 eligible meta-analyses (1051 adult and 343 pediatric trials), the summary ROR did not show a statistically significant difference between adults and children (0.96; 95% confidence intervals, 0.86 to 1.08). However, in all meta-analyses except for 1, the individual ROR's 95% confidence intervals could not exclude a relative difference in efficacy over 20%. In two-thirds, the relative difference in observed point estimates exceeded 50%. Nine statistically significant discrepancies were identified; 4 of them were also clinically important.Treatment effects are on average similar in adults and children, but available evidence leaves large uncertainty about their relative efficacy. Clinically important discrepancies may occur.

    View details for DOI 10.1016/j.jpeds.2010.02.011

    View details for Web of Science ID 000279871700031

    View details for PubMedID 20434730

  • Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies EUROPEAN JOURNAL OF HUMAN GENETICS Siontis, K. C., Patsopoulos, N. A., Ioannidis, J. P. 2010; 18 (7): 832-837

    Abstract

    Genome-wide association studies (GWASs) have created a paradigm shift in discovering genetic associations for common diseases and phenotypes, but it is unclear whether the thousands of candidate genetic association studies performed in the pre-GWAS era had found any reliable associations for common diseases and phenotypes. We aimed to systematically evaluate whether loci proposed to harbor candidate associations before the advent of GWASs are replicated in GWASs. The GWAS data published through August, 2008 and included in the NHGRI catalog were screened and variants in candidate loci were selected on the basis of statistical significance (P<0.05) to create a list of independent, non-redundant associations. Altogether, 159 articles on GWASs were evaluated, 100 of which addressed past proposed candidate loci. A total of 291 independent, nominally significant (P<0.05) candidate gene associations were assembled after keeping only the SNP with lowest P-value for each locus and each phenotype; 108 of those had P<10(-3) for association and 41 had P<10(-7). A total of 22 of these 41 candidate gene associations pertained to binary phenotypes with a median odds ratio=2.91 (IQR: 1.82-4.6) and median minor allele frequency=0.17 (IQR: 0.12-0.29) in Caucasians; for comparison, 60 new associations of binary outcomes with P<10(-7) discovered in the same GWASs had much smaller effects (median odds ratio 1.30, IQR: 1.18-1.58) and modestly larger minor allele frequencies (median 0.27, IQR: 0.15-0.43). Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.

    View details for DOI 10.1038/ejhg.2010.26

    View details for Web of Science ID 000278838800016

    View details for PubMedID 20234392

  • Meta-research: The art of getting it wrong RESEARCH SYNTHESIS METHODS Ioannidisa, J. A. 2010; 1 (3-4): 169–84

    Abstract

    Meta-analysis has major strengths, but sometimes it can often lead to wrong and misleading answers. In this SRSM presidential address, I discuss some case studies that exemplify these problems, including examples from meta-analyses of both clinical trials and observational associations. I also discuss issues of effect size estimation, bias (in particular significance-chasing biases), and credibility in meta-research. I examine the factors that affect the credibility of meta-analyses, including magnitude of effects, multiplicity of analyses, scale of data, flexibility of analyses, reporting, and conflicts of interest. Under the current circumstances, a survey of expert meta-analysts attending the SRSM meeting showed that most of them believe that the true effect is practically equally likely to lie within the 95% confidence interval of a meta-analysis or outside of it. Finally, I address the placement of meta-analysis in the wider current research agenda and make a plea for adoption of more prospective meta-designs. In many/most/all fields, all primary original research may be designed, executed, and interpreted as a prospective meta-analysis. Copyright © 2011 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/jrsm.19

    View details for Web of Science ID 000209380500001

    View details for PubMedID 26061464

  • Development of a combined database for meta-epidemiological research RESEARCH SYNTHESIS METHODS Savovic, J., Harris, R. J., Wood, L., Beynon, R., Altman, D., Als-Nielsen, B., Balk, E. M., Deeks, J., Gluud, L. L., Gluud, C., Ioannidis, J. P., Juni, P., Moher, D., Pildal, J., Schulz, K. F., Sterne, J. A. 2010; 1 (3-4): 212-225

    Abstract

    Collections of meta-analyses assembled in meta-epidemiological studies are used to study associations of trial characteristics with intervention effect estimates. However, methods and findings are not consistent across studies. To combine data from 10 meta-epidemiological studies into a single database, and derive a harmonized dataset without overlap between meta-analyses. The database design allowed trials to be contained in different meta-analyses, multiple meta-analyses in systematic reviews, overlapping meta-analyses between systematic reviews, and multiple references to the same trial or review. Unique identifiers were assigned to each reference and used to identify duplicate trials. Sets of meta-analyses with overlapping trials were identified and duplicates removed. Overlapping trials were used to examine agreement between assessments of trial characteristics. The combined database contained 427 reviews, 454 meta-analyses and 4874 trial results. Of these, 258 meta-analyses were unique, while for 196 at least one trial overlapped with another meta-analysis. Median kappa statistics for reliability of assessments were 0.60 for sequence generation, 0.58 for allocation concealment and 0.87 for blinding. Based on inspection of sets of overlapping meta-analyses, 91 meta-analyses containing 1344 trial results were removed. Additionally, 24 duplicated trial results were removed from 16 meta-analyses, to derive a final database containing 363 meta-analyses and 3477 unique trial results. The final database will be used to examine the combined evidence on sources of bias in randomized controlled trials. The strategy used to remove overlap between meta-analyses may be of use for future empirical research. Copyright © 2010 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/jrsm.18

    View details for Web of Science ID 000209380500004

    View details for PubMedID 26061467

  • A Compendium of Genome-Wide Associations for Cancer: Critical Synopsis and Reappraisal JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P., Castaldi, P., Evangelou, E. 2010; 102 (12): 846-858

    Abstract

    Since 2007, genome-wide association (GWA) studies have identified numerous well-supported, novel genetic risk loci for common cancers; however, there are concerns that this technology is reaching its limits. We provide an overview of GWA-identified genetic associations with solid tumors. We simulated the distribution of population risk alleles for colorectal, prostate, testicular, and thyroid cancers based on genetic variants identified in GWA studies. We also evaluated whether statistical power to detect typical genetic effects could be improved with studies performing GWA analyses of all available samples rather than multistage designs. Fifty-six eligible articles yielded 92 eligible associations between cancer phenotypes and genetic variants with a median per-allele odds ratio (OR) of 1.22 (interquartile range = 1.15-1.36). Half of the associations pertained to prostate, colorectal, or breast cancer. Individuals at the upper quartile of simulated risk had only 2.1- to 4.2-fold higher relative risk than those in the lower quartile. Comprehensive evaluation of currently available samples with GWA platforms would yield few additional variants with per-allele OR = 1.4, but many more variants with OR = 1.2 could be detected; statistical power to detect weak associations (OR = 1.07) would still be negligible. The GWA approach is effective in identifying common genetic variants with moderate effect; however, identifying loci with very small effects and rare variants will require major new efforts. At present, the utility of GWA-identified risk loci in risk stratification for cancer is limited.

    View details for DOI 10.1093/jnci/djq173

    View details for Web of Science ID 000279925200006

    View details for PubMedID 20505153

  • Authors Response INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patsopoulos, N. A., Ioannidis, J. P. 2010; 39 (3): 933-933

    View details for DOI 10.1093/ije/dyp158

    View details for Web of Science ID 000278438500035

  • Home Blood Pressure as a Cardiovascular Outcome Predictor It's Time to Take This Method Seriously HYPERTENSION Stergiou, G. S., Siontis, K. C., Ioannidis, J. P. 2010; 55 (6): 1301-1303

    View details for DOI 10.1161/HYPERTENSIONAHA.110.150771

    View details for Web of Science ID 000277848100004

    View details for PubMedID 20385967

  • Evaluation of Association of HNF1B Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies PLOS ONE Elliott, K. S., Zeggini, E., McCarthy, M. I., Gudmundsson, J., Sulem, P., Stacey, S. N., Thorlacius, S., Amundadottir, L., Groenberg, H., Xu, J., Gaborieau, V., Eeles, R. A., Neal, D. E., Donovan, J. L., Hamdy, F. C., Muir, K., Hwang, S., Spitz, M. R., Zanke, B., Carvajal-Carmona, L., Brown, K. M., Hayward, N. K., Macgregor, S., Tomlinson, I. P., Lemire, M., Amos, C. I., Murabito, J. M., Isaacs, W. B., Easton, D. F., Brennan, P., Barkardottir, R. B., Gudbjartsson, D. F., Rafnar, T., Hunter, D. J., Chanock, S. J., Stefansson, K., Ioannidis, J. P. 2010; 5 (5)

    Abstract

    Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10(-15) for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10(-15) for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association.The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.

    View details for DOI 10.1371/journal.pone.0010858

    View details for Web of Science ID 000278222100002

    View details for PubMedID 20526366

  • Selection and Presentation of Imaging Figures in the Medical Literature PLOS ONE Siontis, G. C., Patsopoulos, N. A., Vlahos, A. P., Ioannidis, J. P. 2010; 5 (5)

    Abstract

    Images are important for conveying information, but there is no empirical evidence on whether imaging figures are properly selected and presented in the published medical literature. We therefore evaluated the selection and presentation of radiological imaging figures in major medical journals.We analyzed articles published in 2005 in 12 major general and specialty medical journals that had radiological imaging figures. For each figure, we recorded information on selection, study population, provision of quantitative measurements, color scales and contrast use. Overall, 417 images from 212 articles were analyzed. Any comment/hint on image selection was made in 44 (11%) images (range 0-50% across the 12 journals) and another 37 (9%) (range 0-60%) showed both a normal and abnormal appearance. In 108 images (26%) (range 0-43%) it was unclear whether the image came from the presented study population. Eighty-three images (20%) (range 0-60%) had any quantitative or ordered categorical value on a measure of interest. Information on the distribution of the measure of interest in the study population was given in 59 cases. For 43 images (range 0-40%), a quantitative measurement was provided for the depicted case and the distribution of values in the study population was also available; in those 43 cases there was no over-representation of extreme than average cases (p = 0.37).The selection and presentation of images in the medical literature is often insufficiently documented; quantitative data are sparse and difficult to place in context.

    View details for DOI 10.1371/journal.pone.0010888

    View details for Web of Science ID 000278222100017

    View details for PubMedID 20526360

  • RE: "UNDERLYING GENETIC MODELS OF INHERITANCE IN ESTABLISHED TYPE 2 DIABETES ASSOCIATIONS" - THREE AUTHORS REPLY AMERICAN JOURNAL OF EPIDEMIOLOGY Salanti, G., Zeggini, E., Ioannidis, J. P. 2010; 171 (10): 1155-1156

    View details for DOI 10.1093/aje/kwq059

    View details for Web of Science ID 000277728400013

  • Genome-wide meta-analyses identify multiple loci associated with smoking behavior NATURE GENETICS Furberg, H., Kim, Y., Dackor, J., Boerwinkle, E., Franceschini, N., Ardissino, D., Bernardinelli, L., Mannucci, P. M., Mauri, F., Merlini, P. A., Absher, D., Assimes, T. L., Fortmann, S. P., Iribarren, C., Knowles, J. W., Quertermous, T., Ferrucci, L., Tanaka, T., Bis, J. C., Furberg, C. D., Haritunians, T., McKnight, B., Psaty, B. M., Taylor, K. D., Thacker, E. L., Almgren, P., Groop, L., Ladenvall, C., Boehnke, M., Jackson, A. U., Mohlke, K. L., Stringham, H. M., Tuomilehto, J., Benjamin, E. J., Hwang, S., Levy, D., Preis, S. R., Vasan, R. S., Duan, J., Gejman, P. V., Levinson, D. F., Sanders, A. R., Shi, J., Lips, E. H., McKay, J. D., Agudo, A., Barzan, L., Bencko, V., Benhamou, S., Castellsague, X., Canova, C., Conway, D. I., Fabianova, E., Foretova, L., Janout, V., Healy, C. M., Holcatova, I., Kjaerheim, K., Lagiou, P., Lissowska, J., Lowry, R., Macfarlane, T. V., Mates, D., Richiardi, L., Rudnai, P., Szeszenia-Dabrowska, N., Zaridze, D., Znaor, A., Lathrop, M., Brennan, P., Bandinelli, S., Frayling, T. M., Guralnik, J. M., Milaneschi, Y., Perry, J. R., Altshuler, D., Elosua, R., Kathiresan, S., Lucas, G., Melander, O., O'Donnell, C. J., Salomaa, V., Schwartz, S. M., Voight, B. F., Penninx, B. W., Smit, J. H., Vogelzangs, N., Boomsma, D. I., de Geus, E. J., Vink, J. M., Willemsen, G., Chanock, S. J., Gu, F., Hankinson, S. E., Hunter, D. J., Hofman, A., Tiemeier, H., Uitterlinden, A. G., van Duijn, C. M., Walter, S., Chasman, D. I., Everett, B. M., Pare, G., Ridker, P. M., Li, M. D., Maes, H. H., Audrain-McGovern, J., Posthuma, D., Thornton, L. M., Lerman, C., Kaprio, J., Rose, J. E., Ioannidis, J. P., Kraft, P., Lin, D., Sullivan, P. F. 2010; 42 (5): 441-U134

    Abstract

    Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

    View details for DOI 10.1038/ng.571

    View details for Web of Science ID 000277179500017

    View details for PubMedID 20418890

    View details for PubMedCentralID PMC2914600

  • Sources of funding for Nobel Prize-winning work: public or private? FASEB JOURNAL Tatsioni, A., Vavva, E., Ioannidis, J. P. 2010; 24 (5): 1335-1339

    Abstract

    Funding is important for scientists' work and may contribute to exceptional research outcomes. We analyzed the funding sources reported in the landmark scientific papers of Nobel Prize winners. Between 2000 and 2008, 70 Nobel laureates won recognition in medicine, physics, and chemistry. Sixty five (70%) of the 93 selected papers related to the Nobel-awarded work reported some funding source including U.S. government sources in 53 (82%), non-U.S. government sources in 19 (29%), and nongovernment sources in 33 (51%). A substantial portion of this exceptional work was unfunded. We contacted Nobel laureates whose landmark papers reported no funding. Thirteen Nobel laureates responded and offered their insights about the funding process and difficulties inherent in funding. Overall, very diverse sources amounting to a total of 64 different listed sponsors supported Nobel-related work. A few public institutions, in particular the U.S. National Institutes of Health (with n=26 funded papers) and the National Science Foundation (with n=17 papers), stood out for their successful record for funding exceptional research. However, Nobel-level work arose even from completely unfunded research, especially when institutions offered a protected environment for dedicated scientists.

    View details for DOI 10.1096/fj.09-148239

    View details for Web of Science ID 000277158900006

    View details for PubMedID 20056712

  • What Makes a Good Predictor? The Evidence Applied to Coronary Artery Calcium Score JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Tzoulaki, I. 2010; 303 (16): 1646-1647

    View details for Web of Science ID 000277085200030

    View details for PubMedID 20424257

  • Assessing Predictive Performance Beyond the Framingham Risk Score Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tzoulaki, I., Liberopoulos, G., Ioannidis, J. P. 2010; 303 (14): 1369-1369

    View details for Web of Science ID 000276597300017

  • Who is afraid of reviewers' comments? Or, why anything can be published and anything can be cited EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P., Tatsioni, A., Karassa, F. B. 2010; 40 (4): 285-287

    View details for DOI 10.1111/j.1365-2362.2010.02272.x

    View details for Web of Science ID 000275728900001

    View details for PubMedID 20486989

  • Critical interpretation of Cochran's Q test depends on power and prior assumptions about heterogeneity RESEARCH SYNTHESIS METHODS Pereira, T. V., Patsopoulos, N. A., Salanti, G., Ioannidis, J. P. 2010; 1 (2): 149-161

    Abstract

    We describe how an appropriate interpretation of the Q-test depends on its power to detect a given typical amount of between-study variance (τ(2)) as well as prior beliefs on heterogeneity. We illustrate these concepts in an evaluation of 1011 meta-analyses of clinical trials with ⩾4 studies and binary outcomes. These concepts can be seen as an application of the Bayes theorem. Across the 1011 meta-analyses, power to detect typical heterogeneity was low in most situations. Thus, usually a non-significant Q test did not change perceptibly prior convictions on heterogeneity. Conversely, significant results for the Q test typically augmented considerably the probability of heterogeneity. The posterior probability of heterogeneity depends on what τ(2) we want to detect. With the same approach, one may also estimate the posterior probability for the presence of heterogeneity that is large enough to annul statistically significant summary effects; that is half the average within-study variance of the combined studies; and that is able to change the summary effect estimate of the meta-analysis by 20%. The discussed analyses are exploratory, and may depend heavily on prior assumptions when power for the Q-test is low. Statistical heterogeneity in meta-analyses should be cautiously interpreted considering the power to detect a specific τ(2) and prior assumptions about the presence of heterogeneity. Copyright © 2010 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/jrsm.13

    View details for Web of Science ID 000209380400005

    View details for PubMedID 26061380

  • Correspondence to Sand et Al. "Critical reappraisal of a catechol-o-methyltransferase transversion variant in schizophrenia". Biological psychiatry Lill, C. M., Schjeide, B. M., Roehr, J. T., Zauft, U., Allen, N. C., Zipp, F., McQueen, M. B., Kavvoura, F. K., Ioannidis, J. P., Khoury, M. J., Tanzi, R. E., Bertram, L. 2010; 67 (7): e45-8

    View details for DOI 10.1016/j.biopsych.2010.02.003

    View details for PubMedID 20303423

  • Validation of the Greek translation of the Dundee Ready Education Environment Measure (DREEM). Education for health (Abingdon, England) Dimoliatis, I. D., Vasilaki, E., ANASTASSOPOULOS, P., Ioannidis, J. P., Roff, S. 2010; 23 (1): 348-?

    Abstract

    The educational environment makes an important contribution to student learning. The DREEM questionnaire is a validated tool assessing the environment.To translate and validate the DREEM into Greek.Forward translations from English were produced by three independent Greek translators and then back translations by five independent bilingual translators. The Greek DREEM.v0 that was produced was administered to 831 undergraduate students from six Greek medical schools. Cronbach's alpha and test-retest correlation were used to evaluate reliability and factor analysis was used to assess validity. Questions that increased alpha if deleted and/or sorted unexpectedly in factor analysis were further checked through two focus groups.Questionnaires were returned by 487 respondents (59%), who were representative of all surveyed students by gender but not by year of study or medical school. The instrument's overall alpha was 0.90, and for the learning, teachers, academic, atmosphere and social subscales the alphas were 0.79 (expected 0.69), 0.78 (0.67), 0.69 (0.60), 0.68 (0.69), 0.48 (0.57), respectively. In a subset of the whole sample, test and retest alphas were both 0.90, and mean item scores highly correlated (p<0.001). Factor analysis produced meaningful subscales but not always matching the original ones. Focus group evaluation revealed possible misunderstanding for questions 17, 25, 29 and 38, which were revised in the DREEM.Gr.v1. The group mean overall scale score was 107.7 (SD 20.2), with significant differences across medical schools (p<0.001).Alphas and test-retest correlation suggest the Greek translated and validated DREEM scale is a reliable tool for assessing the medical education environment and for informing policy. Factor analysis and focus group input suggest it is a valid tool. Reasonable school differences suggest the instrument's sensitivity.

    View details for PubMedID 20589604

  • Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and 6q23 loci: a meta-analysis ANNALS OF THE RHEUMATIC DISEASES Patsopoulos, N. A., Ioannidis, J. P. 2010; 69 (3): 561-566

    Abstract

    Genome-wide association studies have proposed susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus and 6q23 region. Furthermore, additional independent studies have investigated the same or highly linked polymorphisms in the same regions.To carry out a meta-analysis of the available evidence for the association of polymorphisms in the TRAF1-C5 locus and 6q23 region with rheumatoid arthritis.Data were synthesised for four polymorphisms: rs3761847 (n=13 datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23 region. Meta-analyses for subgroups defined by anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status were also performed.The polymorphism rs6920220 reached genome-wide statistical significance with p=7.9 x 10(-17) and an allelic odds ratio of 1.24 (95% CI 1.18 to 1.30) and no between-study heterogeneity (I(2)=0%). The risk was significantly stronger in patients with anti-CCP antibodies and in patients with RF. The other three variants showed large between-study heterogeneity across datasets (I(2) range 74-82%); rs10499194 was nominally statistically significant after exclusion of the discovery data. Two variants had genome-wide statistical significance in subgroups defined by the presence of RF (rs3761847 and rs6920220) or anti-CCP (rs6920220).Genetic markers in the 6q23 region and TRAF1-C5 are associated with rheumatoid arthritis, in particular with positive anti-CCP and RF profile. With the exception of rs6920220, which shows highly consistent results, other proposed markers have high between-study heterogeneity that may reflect unrecognised phenotypic or genetic variability (eg, gene environment interactions) within rheumatoid arthritis. Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones.

    View details for DOI 10.1136/ard.2009.109447

    View details for Web of Science ID 000275458700016

    View details for PubMedID 19401279

  • Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer TRENDS IN GENETICS Galvan, A., Ioannidis, J. P., Dragani, T. A. 2010; 26 (3): 132-141

    Abstract

    Genome-wide association studies (GWAS) using population-based designs have identified many genetic loci associated with risk of a range of complex diseases including cancer; however, each locus exerts a very small effect and most heritability remains unexplained. Family-based pedigree studies have also suggested tentative loci linked to increased cancer risk, often characterized by pedigree-specificity. However, comparison between the results of population- and family-based studies shows little concordance. Explanations for this unidentified genetic 'dark matter' of cancer include phenotype ascertainment issues, limited power, gene-gene and gene-environment interactions, population heterogeneity, parent-of-origin-specific effects, and rare and unexplored variants. Many of these reasons converge towards the concept of genetic heterogeneity that might implicate hundreds of genetic variants in regulating cancer risk. Dissecting the dark matter is a challenging task. Further insights can be gained from both population association and pedigree studies.

    View details for DOI 10.1016/j.tig.2009.12.008

    View details for Web of Science ID 000275272600007

    View details for PubMedID 20106545

  • Associations of polymorphisms of eight muscle- or metabolism-related genes with performance in Mount Olympus marathon runners JOURNAL OF APPLIED PHYSIOLOGY Tsianos, G. I., Evangelou, E., Boot, A., Zillikens, M. C., van Meurs, J. B., Uitterlinden, A. G., Ioannidis, J. P. 2010; 108 (3): 567-574

    Abstract

    Athletic endurance performance is probably partly under genetic control, but genetic association studies have yielded inconclusive results. The objective of the present study was to evaluate the association of polymorphisms in eight muscle- or metabolism-related genes with endurance performance in participants of the Olympus Marathon running race. We recruited 438 athletes who participated in the 2007 and 2008 annual running events of the Olympus Marathon: a 43.8-km race with an ascent from sea level to 2,690-m altitude and then a descent to 300 m. Phenotypes of interest were the competitive event time at the specific Olympus Marathon where the athlete was enrolled, the fastest reported timing ever achieved in an Olympus Marathon, and how many kilometers per week the athlete ran during the previous year. Eleven polymorphisms in alpha(3)-actinin (ACTN3), AMP deaminase-1 (AMPD1), bradykinin B(2) receptor (BDKRB2), beta(2)-adrenergic receptor (ADRB2), peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 alpha (PPARGC1A), PPAR-alpha (PPARA), PPAR-delta (PPARD), and apoliprotein E (APOE) were evaluated. Hardy-Weinberg equilibrium testing on the overall cohort of male athletes showed a significant deviation for BDKRB2 rs1799722 (P = 0.018; P = 0.006 when limited to 316 habitual male runners) with an excess of the TT genotype. Across all athletes, no associations showed nominal statistical significance for any of the three phenotypes, and the same was true when analyses were limited to men (n = 417). When limited to 316 male athletes who identified running as their preferred sport, ADRB2 rs1042713 had nominally significant associations with faster times for the minor (A) allele for the fastest time ever (P = 0.01). The direction of effect was identical as previously postulated only for BDKRB2 rs1799722 and ADRB2 rs1042713, indicating consistency. BDKRB2 rs1799722 and ADRB2 rs1042713 have some support for being implicated in endurance performance among habitual runners and require further investigation.

    View details for DOI 10.1152/japplphysiol.00780.2009

    View details for Web of Science ID 000275670400018

    View details for PubMedID 20044476

  • Industry sponsorship and selection of comparators in randomized clinical trials EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Lathyris, D. N., Patsopoulos, N. A., Salanti, G., Ioannidis, J. P. 2010; 40 (2): 172-182

    Abstract

    Most clinical trials on medical interventions are sponsored by the industry. The choice of comparators shapes the accumulated evidence. We aimed to assess how often major companies sponsor trials that involve only their own products.Studies were identified by searching ClinicalTrials.gov for trials registered in 2006. We focused on randomized trials involving the 15 companies that had sponsored the largest number of registered trials in ClinicalTrials.gov in that period.Overall, 577 randomized trials were eligible for analysis and 82% had a single industry sponsor [89% (166/187) of the placebo-control trials, 87% (91/105) of trials comparing different doses or ways of administration of the same intervention, and 78% (221/285) of other active control trials]. The compared intervention(s) belonged to a single company in 67% of the trials (89%, 81% and 47% in the three categories respectively). All 15 companies strongly preferred to run trials where they were the only industry sponsor or even the only owner of the assessed interventions. Co-sponsorship typically reflected co-ownership of the same intervention by both companies. Head-to-head comparison of different active interventions developed by different companies occurred in only 18 trials with two or more industry sponsors.Each company generates a clinical research agenda that is strongly focused on its own products, while comparisons involving different interventions from different companies are uncommon. This diminishes the ability to understand the relative merits of different interventions for the same condition.

    View details for DOI 10.1111/j.1365-2362.2009.02240.x

    View details for Web of Science ID 000273602200011

    View details for PubMedID 20050879

  • A Genome-Wide Association Study Identifies an Osteoarthritis Susceptibility Locus on Chromosome 7q22 ARTHRITIS AND RHEUMATISM Kerkhof, H. J., Lories, R. J., Meulenbelt, I., Jonsdottir, I., Valdes, A. M., Arp, P., Ingvarsson, T., Jhamai, M., Jonsson, H., Stolk, L., Thorleifsson, G., Zhai, G., Zhang, F., Zhu, Y., van der Breggen, R., Carr, A., Doherty, M., Doherty, S., Felson, D. T., Gonzalez, A., Halldorsson, B. V., Hart, D. J., Hauksson, V. B., Hofman, A., Ioannidis, J. P., Kloppenburg, M., Lane, N. E., Loughlin, J., Luyten, F. P., Nevitt, M. C., Parimi, N., Pols, H. A., Rivadeneira, F., Slagboom, E. P., Styrkarsdottir, U., Tsezou, A., Van de Putte, T., Zmuda, J., Spector, T. D., Stefansson, K., Uitterlinden, A. G., van Meurs, J. B. 2010; 62 (2): 499-510

    Abstract

    To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study.We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10(-7) considered genome-wide significant.The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10(-8)) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10(-12)). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA.Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.

    View details for DOI 10.1002/art.27184

    View details for Web of Science ID 000279432100028

    View details for PubMedID 20112360

  • A vision for the European Journal of Clinical Investigation: note from the new editors EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P., Tatsioni, A., Karassa, F. B. 2010; 40 (1): 1-3

    View details for DOI 10.1111/j.1365-2362.2009.02229.x

    View details for Web of Science ID 000272893100001

    View details for PubMedID 20055893

  • Primary open angle glaucoma due to T377M MYOC: Population mapping of a Greek founder mutation in Northwestern Greece. Clinical ophthalmology (Auckland, N.Z.) Kitsos, G., Petrou, Z., Grigoriadou, M., Samples, J. R., Hewitt, A. W., Kokotas, H., Giannoulia-Karantana, A., Mackey, D. A., Wirtz, M. K., Moschou, M., Ioannidis, J. P., Petersen, M. B. 2010; 4: 171-178

    Abstract

    Mutations in the MYOC gene have been shown to explain 5% of unrelated primary open angle glaucoma (POAG) in different populations. In particular, the T377M MYOC mutation has arisen at least three separate times in history, in Great Britain, India, and Greece. The purpose of this study is to investigate the distribution of the mutation among different population groups in the northwestern region of Greece.We explored the distribution of the "Greek" T377M founder mutation in the Epirus region in Northwestern Greece, which could be its origin. Genotyping was performed in POAG cases and controls by PCR amplification of the MYOC gene, followed by digestion with restriction enzyme. Statistical analyses were performed by an exact test, the Kaplan-Meier method and the t-test.In the isolated Chrysovitsa village in the Pindus Mountains, a large POAG family demonstrated the T377M mutation in 20 of 66 family members while no controls from the Epirus region (n = 124) carried this mutation (P < 0.001). Among other POAG cases from Epirus, 2 out of 14 familial cases and 1 out of 80 sporadic cases showed the mutation (P = 0.057). The probability of POAG diagnosis with advancing age among mutation carriers was 23% at age 40, and reached 100% at age 75. POAG patients with the T377M mutation were diagnosed at a mean age of 51 years (SD +/- 13.9), which is younger than the sporadic or familial POAG cases: 63.1 (SD +/- 11) and 66.8 (SD +/- 9.8) years, respectively.The T377M mutation was found in high proportion in members of the Chrysovitsa family (30.3%), in lower proportion in familial POAG cases (14.2%) and seems rare in sporadic POAG cases (1.2%), while no controls (0%) from the Epirus region carried the mutation. Historical and geographical data may explain the distribution of this mutation within Greece and worldwide.

    View details for PubMedID 20390039

  • Non-Replication of Association for Six Polymorphisms From Meta-Analysis of Genome-Wide Association Studies of Parkinson's Disease: Large-Scale Collaborative Study AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Evangelou, E., Maraganore, D. M., Annesi, G., Brijhina, L., Brice, A., Elbaz, A., Ferrarese, C., Hadjigeorgiou, G. M., Krueger, R., Lambert, J., Lesage, S., Markopoulou, K., Mellick, G. D., Meeus, B., Pedersen, N. L., Quattrone, A., Van Broeckhoven, C., Sharma, M., Silburn, P. A., Tan, E., Wirdefeldt, K., Ioannidis, J. P. 2010; 153B (1): 220-228

    Abstract

    Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques.

    View details for DOI 10.1002/ajmg.b.30980

    View details for Web of Science ID 000273440500025

    View details for PubMedID 19475631

  • Synopsis of Preterm Birth Genetic Association Studies: The Preterm Birth Genetics Knowledge Base (PTBGene) PUBLIC HEALTH GENOMICS Dolan, S. M., Hollegaard, M. V., Merialdi, M., Betran, A. P., Allen, T., Abelow, C., Nace, J., Lin, B. K., Khoury, M. J., Ioannidis, J. P., Bagade, S., Zheng, X., Dubin, R. A., Bertram, L., Edwards, D. R., Menon, R. 2010; 13 (7-8): 514-523

    Abstract

    Our goal wasto produce a field synopsis of genetic associations with preterm birth and to set up a publicly available online database summarizing the data.We performed a systematic review and meta-analyses to identify genetic associations with preterm birth. We have set up a publicly available online database of genetic association data on preterm birth called PTBGene (http://ric.einstein.yu.edu/ptbgene/index.html) and report on a structured synopsis thereof as of December 1, 2008.Data on 189 polymorphisms in 84 genes have been included and 36 meta-analyses have been performed. Five gene variants (4 in maternal DNA, one in newborn DNA) have shown nominally significant associations, but all have weak epidemiological credibility.After publishing this field synopsis, the PTBGene database will be regularly updated to keep track of the evolving evidence base of genetic factors in preterm birth with the goal of promoting knowledge sharing and multicenter collaboration among preterm birth research groups.

    View details for DOI 10.1159/000294202

    View details for Web of Science ID 000285011900015

    View details for PubMedID 20484876

  • Using Lifetime Risk Estimates in Personal Genomic Profiles: Estimation of Uncertainty AMERICAN JOURNAL OF HUMAN GENETICS Yang, Q., Flanders, W. D., Moonesinghe, R., Ioannidis, J. P., Guessous, I., Khoury, M. J. 2009; 85 (6): 786-800

    Abstract

    Personal genome tests are now offered direct-to-consumer (DTC) via genetic variants identified by genome-wide association studies (GWAS) for common diseases. Tests report risk estimates (age-specific and lifetime) for various diseases based on genotypes at multiple loci. However, uncertainty surrounding such risk estimates has not been systematically investigated. With breast cancer as an example, we examined the combined effect of uncertainties in population incidence rates, genotype frequency, effect sizes, and models of joint effects among genetic variants on lifetime risk estimates. We performed simulations to estimate lifetime breast cancer risk for carriers and noncarriers of genetic variants. We derived population-based cancer incidence rates from Surveillance, Epidemiology, and End Results (SEER) Program and comparative international data. We used data for non-Hispanic white women from 2003 to 2005. We derived genotype frequencies and effect sizes from published GWAS and meta-analyses. For a single genetic variant in FGFR2 gene (rs2981582), combination of uncertainty in these parameters produced risk estimates where upper and lower 95% simulation intervals differed by more than 3-fold. Difference in population incidence rates was the largest contributor to variation in risk estimates. For a panel of five genetic variants, estimated lifetime risk of developing breast cancer before age 80 for a woman that carried all risk variants ranged from 6.1% to 21%, depending on assumptions of additive or multiplicative joint effects and breast cancer incidence rates. Epidemiologic parameters involved in computation of disease risk have substantial uncertainty, and cumulative uncertainty should be properly recognized. Reliance on point estimates alone could be seriously misleading.

    View details for DOI 10.1016/j.ajhg.2009.10.017

    View details for Web of Science ID 000272797100003

    View details for PubMedID 19931039

  • Assessment of Claims of Improved Prediction Beyond the Framingham Risk Score JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tzoulaki, I., Liberopoulos, G., Ioannidis, J. P. 2009; 302 (21): 2345-2352

    Abstract

    With heightened interest in predictive medicine, many studies try to document information that can improve prediction of major clinical outcomes.To evaluate the reported design and analysis of studies that examined whether additional predictors improve predictive performance when added to the Framingham risk score (FRS), one of the most widely validated and cited clinical prediction scores.Two independent investigators searched 1908 articles citing the article that described the FRS in 1998 until September 2009 through the ISI Web of Knowledge database. Articles were eligible if they included any analyses comparing the predictive performance of the FRS vs the FRS plus some additional predictor for a prospectively assessed outcome. Data Analyses We recorded information on FRS calculation, modeling of additional predictors, outcomes assessed, population evaluated, subgroup analysis documentation, and flaws in the methods that may have affected the reported improvements in predictive ability. We also evaluated the correlation of reported design and analysis features with the predictive model discrimination and improvements with the additional predictors.We evaluated 79 eligible articles. Forty-nine studies (62%) did not calculate the FRS as it has been proposed, 15 (19%) modeled the additional predictor in more than 1 way and presented only the best-fit or area-under-the-curve (AUC) results for only 1 model, 41 (52%) did not examine the original outcome that the FRS was developed for, 33 (42%) studied a population different from what the FRS was intended for, and 25 (32%) claimed improved prediction in 1 subgroup but only 7 (9%) formally tested subgroup differences. Evaluation of independence in multivariable regressions, discrimination in AUC, calibration, and reclassification were reported in 77, 36, 7, and 7 studies, respectively, but these methods were adequately documented in only 60, 13, 4, and 2 studies, respectively. Overall, 63 studies (80%) claimed some improved prediction. Increase in AUC was larger when the predictive performance of the FRS was lower (rho = -0.57, P < .001). Increase in AUC was significantly larger when evaluation of independence in multivariable regression or discrimination in AUC analysis was not adequately documented and when the additional predictor had been modeled in more than 1 way and only 1 model was reported for AUC.The majority of examined studies claimed that they found factors that could offer additional predictive value beyond what the FRS could achieve; however, most had flaws in their design, analyses, and reporting that cast some doubt on the reliability of the claims for improved prediction.

    View details for Web of Science ID 000272239000023

    View details for PubMedID 19952321

  • Heterogeneous views on heterogeneity INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patsopoulos, N. A., Evangelou, E., Ioannidis, J. P. 2009; 38 (6): 1740-1742

    View details for DOI 10.1093/ije/dyn235

    View details for Web of Science ID 000272464700042

    View details for PubMedID 18940836

  • Researching Genetic Versus Nongenetic Determinants of Disease: A Comparison and Proposed Unification SCIENCE TRANSLATIONAL MEDICINE Ioannidis, J. P., Loy, E. Y., Poulton, R., Chia, K. S. 2009; 1 (7)

    Abstract

    Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limits. Studies are needed that massively measure genotypes, nongenetic exposures, and outcomes concurrently.

    View details for DOI 10.1126/scitranslmed.3000247

    View details for Web of Science ID 000277262200001

    View details for PubMedID 20368180

  • Discovery Properties of Genome-wide Association Signals From Cumulatively Combined Data Sets AMERICAN JOURNAL OF EPIDEMIOLOGY Pereira, T. V., Patsopoulos, N. A., Salanti, G., Ioannidis, J. P. 2009; 170 (10): 1197-1206

    Abstract

    Genetic effects for common variants affecting complex disease risk are subtle. Single genome-wide association (GWA) studies are typically underpowered to detect these effects, and combination of several GWA data sets is needed to enhance discovery. The authors investigated the properties of the discovery process in simulated cumulative meta-analyses of GWA study-derived signals allowing for potential genetic model misspecification and between-study heterogeneity. Variants with null effects on average (but also between-data set heterogeneity) could yield false-positive associations with seemingly homogeneous effects. Random effects had higher than appropriate false-positive rates when there were few data sets. The log-additive model had the lowest false-positive rate. Under heterogeneity, random-effects meta-analyses of 2-10 data sets averaging 1,000 cases/1,000 controls each did not increase power, or the meta-analysis was even less powerful than a single study (power desert). Upward bias in effect estimates and underestimation of between-study heterogeneity were common. Fixed-effects calculations avoided power deserts and maximized discovery of association signals at the expense of much higher false-positive rates. Therefore, random- and fixed-effects models are preferable for different purposes (fixed effects for initial screenings, random effects for generalizability applications). These results may have broader implications for the design and interpretation of large-scale multiteam collaborative studies discovering common gene variants.

    View details for DOI 10.1093/aje/kwp262

    View details for Web of Science ID 000271379800002

    View details for PubMedID 19808636

  • The elderly were under-represented in osteoarthritis clinical trials JOURNAL OF CLINICAL EPIDEMIOLOGY Liberopoulos, G., Trikalinos, N. A., Ioannidis, J. P. 2009; 62 (11): 1218-1223

    Abstract

    Osteoarthritis is the most common disease affecting joints in the elderly. We aimed to evaluate if elderly patients are properly represented in clinical trials of diverse osteoarthritis interventions.Clinical trials of osteoarthritis interventions were retrieved from Cochrane Library systematic reviews (2006, issue 2). We examined the age distribution of the trial participants and eligibility criteria.We analyzed data from 219 eligible trials from 18 systematic reviews. The average mean age of the participants was 63 years. Only 13 trials (6.4%) had a mean age between 71 and 80 years and only one trial had a mean age exceeding 80 years. Among trials where the age range of participants was available or could be approximately inferred, we estimated that 66 (38%) trials had not included any patients over 80 years old. Only 23 trials specifically excluded patients over 70 based on reported eligibility criteria, but 168 trials excluded patients with various comorbidities and 142 trials excluded patients receiving other specific treatments.Elderly patients are considerably under-represented in clinical trials of osteoarthritis. This causes an important deficit in the utility, relevance, and generalizability of trial results for this very common condition.

    View details for DOI 10.1016/j.jclinepi.2008.12.009

    View details for Web of Science ID 000270758900016

    View details for PubMedID 19356899

  • Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies NATURE GENETICS Rivadeneira, F., Styrkarsdottir, U., Estrada, K., Halldorsson, B. V., Hsu, Y., Richards, J. B., Zillikens, M. C., Kavvoura, F. K., Amin, N., Aulchenko, Y. S., Cupples, L. A., Deloukas, P., Demissie, S., Grundberg, E., Hofman, A., Kong, A., Karasik, D., van Meurs, J. B., Oostra, B., Pastinen, T., Pols, H. A., Sigurdsson, G., Soranzo, N., Thorleifsson, G., Thorsteinsdottir, U., Williams, F. M., Wilson, S. G., Zhou, Y., Ralston, S. H., van Duijn, C. M., Spector, T., Kiel, D. P., Stefansson, K., Ioannidis, J. P., Uitterlinden, A. G. 2009; 41 (11): 1199-U58

    Abstract

    Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.

    View details for DOI 10.1038/ng.446

    View details for Web of Science ID 000271247600012

    View details for PubMedID 19801982

  • STrengthening the REporting of Genetic Association Studies (STREGA)-An Extension of the STROBE Statement GENETIC EPIDEMIOLOGY Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A., Birkett, N. 2009; 33 (7): 581-598

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1002/gepi.20410

    View details for Web of Science ID 000271406100003

    View details for PubMedID 19278015

  • Replication in Genome-Wide Association Studies STATISTICAL SCIENCE Kraft, P., Zeggini, E., Ioannidis, J. P. 2009; 24 (4): 561-573

    Abstract

    Replication helps ensure that a genotype-phenotype association observed in a genome-wide association (GWA) study represents a credible association and is not a chance finding or an artifact due to uncontrolled biases. We discuss prerequisites for exact replication; issues of heterogeneity; advantages and disadvantages of different methods of data synthesis across multiple studies; frequentist vs. Bayesian inferences for replication; and challenges that arise from multi-team collaborations. While consistent replication can greatly improve the credibility of a genotype-phenotype association, it may not eliminate spurious associations due to biases shared by many studies. Conversely, lack of replication in well-powered follow-up studies usually invalidates the initially proposed association, although occasionally it may point to differences in linkage disequilibrium or effect modifiers across studies.

    View details for DOI 10.1214/09-STS290

    View details for Web of Science ID 000277257000013

  • Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis CANCER TREATMENT REVIEWS Golfinopoulos, V., Pentheroudakis, G., Salanti, G., Nearchou, A. D., Ioannidis, J. P., Pavlidis, N. 2009; 35 (7): 570-573

    Abstract

    To synthesize the evidence from randomized controlled trials concerning systemic treatment regimens for patients with cancer of unknown primary site (CUP).PubMed and the Cochrane Library Central Registry of Controlled Trials.We retrieved all randomized controlled trials comparing at least two arms of different systemic treatment regimens or a systemic regimen to no treatment in patients with CUP, excluding data on favorable subset CUP, whenever these could be separated. Treatments were categorized according to whether they involved platinum, taxane, both, or neither; non-platinum/non-taxane regimens were also categorized in monotherapy and combination regimens. We extracted or estimated the logarithm of the hazard ratio and its variance for death for each randomized comparison. Multiple-treatments meta-analysis with a hierarchical Bayesian model obtained summary hazard ratios with 95% credibility intervals.Ten articles were eligible for the meta-analysis. No trials compared systemic treatment to best supportive care and all arms referred to chemotherapy regimens. Overall 683 subjects were randomly assigned and eight randomized comparisons were used for the multiple-treatments meta-analysis of survival (543 patients). Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others, with wide credibility intervals. Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane).No type of chemotherapy has been solidly proven to prolong survival in patients with CUP. Regimens using either platinum or taxanes or both need further testing.

    View details for DOI 10.1016/j.ctrv.2009.05.005

    View details for Web of Science ID 000272098400006

    View details for PubMedID 19539430

  • Adverse Events in Randomized Trials Neglected, Restricted, Distorted, and Silenced ARCHIVES OF INTERNAL MEDICINE Ioannidis, J. P. 2009; 169 (19): 1737-1739

    View details for Web of Science ID 000271163800001

    View details for PubMedID 19858427

  • Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture ANNALS OF INTERNAL MEDICINE Richards, J. B., Kavvoura, F. K., Rivadeneira, F., Styrkarsdottir, U., Estrada, K., Halldorsson, B. V., Hsu, Y., Zillikens, M. C., Wilson, S. G., Mullin, B. H., Amin, N., Aulchenko, Y. S., Cupples, L. A., Deloukas, P., Demissie, S., Hofman, A., Kong, A., Karasik, D., van Meurs, J. B., Oostra, B. A., Pols, H. A., Sigurdsson, G., Thorsteinsdottir, U., Soranzo, N., Williams, F. M., Zhou, Y., Ralston, S. H., Thorleifsson, G., van Duijn, C. M., Kiel, D. P., Stefansson, K., Uitterlinden, A. G., Ioannidis, J. P., Spector, T. D. 2009; 151 (8): 528-U32

    Abstract

    Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.Large-scale meta-analysis of genome-wide association data.5 international, multicenter, population-based studies.Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

    View details for Web of Science ID 000271386200002

    View details for PubMedID 19841454

  • Integration of evidence from multiple meta-analyses: a primer on umbrella reviews, treatment networks and multiple treatments meta-analyses CANADIAN MEDICAL ASSOCIATION JOURNAL Ioannidis, J. P. 2009; 181 (8): 488-493

    View details for DOI 10.1503/cmaj.081086

    View details for Web of Science ID 000270712800009

    View details for PubMedID 19654195

  • Population-Wide Generalizability of Genome-Wide Discovered Associations JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P. 2009; 101 (19): 1297-1299

    View details for DOI 10.1093/jnci/djp298

    View details for Web of Science ID 000270709900004

    View details for PubMedID 19726754

  • Double Versus Single Stenting for Coronary Bifurcation Lesions A Meta-Analysis CIRCULATION-CARDIOVASCULAR INTERVENTIONS Katritsis, D. G., Siontis, G. C., Ioannidis, J. P. 2009; 2 (5): 409-U76

    Abstract

    Several trials have addressed whether bifurcation lesions require stenting of both the main vessel and side branch, but uncertainty remains on the benefits of such double versus single stenting of the main vessel only.We have conducted a meta-analysis of randomized trials including patients with coronary bifurcation lesions who were randomly selected to undergo percutaneous coronary intervention by either double or single stenting. Six studies (n=1642 patients) were eligible. There was increased risk of myocardial infarction with double stenting (risk ratio, 1.78; P=0.001 by fixed effects; risk ratio, 1.49 with Bayesian meta-analysis). The summary point estimate suggested also an increased risk of stent thrombosis with double stenting, but the difference was not nominally significant given the sparse data (risk ratio, 1.85; P=0.19). No obvious difference was seen for death (risk ratio, 0.81; P=0.66) and target lesion revascularization (risk ratio, 1.09; P=0.67).Stenting of both the main vessel and side branch in bifurcation lesions may increase myocardial infarction and stent thrombosis risk compared with stenting of the main vessel only.

    View details for DOI 10.1161/CIRCINTERVENTIONS.109.868091

    View details for Web of Science ID 000276068800007

    View details for PubMedID 20031750

  • The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 62 (10): e1-34

    Abstract

    Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement--a reporting guideline published in 1999--there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for DOI 10.1016/j.jclinepi.2009.06.006

    View details for PubMedID 19631507

  • Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations AMERICAN JOURNAL OF EPIDEMIOLOGY Salanti, G., Southam, L., Altshuler, D., Ardlie, K., Barroso, I., Boehnke, M., Cornelis, M. C., Frayling, T. M., Grallert, H., Grarup, N., Groop, L., Hansen, T., Hattersley, A. T., Hu, F. B., Hveem, K., Illig, T., Kuusisto, J., Laakso, M., Langenberg, C., Lyssenko, V., McCarthy, M. I., Morris, A., Morris, A. D., Palmer, C. N., Payne, F., Platou, C. G., Scott, L. J., Voight, B. F., Wareham, N. J., Zeggini, E., Ioannidis, J. P. 2009; 170 (5): 537-545

    Abstract

    For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.

    View details for DOI 10.1093/aje/kwp145

    View details for Web of Science ID 000269195000001

    View details for PubMedID 19602701

  • Prognostic factors and outcomes for osteosarcoma: An international collaboration EUROPEAN JOURNAL OF CANCER Pakos, E. E., Nearchou, A. D., Grimer, R. J., Koumoullis, H. D., Abudu, A., Bramer, J. A., Jeys, L. M., Franchi, A., Scoccianti, G., Campanacci, D., Capanna, R., Aparicio, J., Tabone, M., Holzer, G., Abdolvahab, F., Funovics, P., Dominkus, M., Ilhan, I., Berrak, S. G., Patino-Garcia, A., Sierrasesumaga, L., San-Julian, M., Garraus, M., Petrili, A. S., Garcia Filho, R. J., Pacheco Donato Macedo, C. R., de Seixas Alves, M. T., Seiwerth, S., Nagarajan, R., Cripe, T. P., Ioannidis, J. P. 2009; 45 (13): 2367-2375

    Abstract

    We aimed to evaluate the prognostic significance of traditional clinical predictors in osteosarcoma through an international collaboration of 10 teams of investigators (2680 patients) who participated. In multivariate models the mortality risk increased with older age, presence of metastatic disease at diagnosis, development of local recurrence when the patient was first seen, use of amputation instead of limb salvage/wide resection, employment of unusual treatments, use of chemotherapeutic regimens other than anthracycline and platinum and use of methotrexate. It was also influenced by the site of the tumour. The risk of metastasis increased when metastatic disease was present at the time the patient was first seen and also increased with use of amputation or unusual treatment combinations or chemotherapy regimens not including anthracycline and platinum. Local recurrence risk was higher in older patients, in those who had local recurrence when first seen and when no anthracycline and platinum were used in chemotherapy. Results were similar when limited to patients seen after 1990 and treated with surgery plus combination chemotherapy. This large-scale international collaboration identifies strong predictors of major clinical outcomes in osteosarcoma.

    View details for DOI 10.1016/j.ejca.2009.03.005

    View details for Web of Science ID 000270645700026

    View details for PubMedID 19349163

  • The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration ANNALS OF INTERNAL MEDICINE Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 151 (4): W65-W94

    Abstract

    Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement-a reporting guideline published in 1999-there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (www.prisma-statement.org) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for Web of Science ID 000269038900004

    View details for PubMedID 19622512

  • The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health-Centers for Disease Control and Prevention Multidisciplinary Workshop GENETICS IN MEDICINE Khoury, M. J., McBride, C. M., Schully, S. D., Ioannidis, J. P., Feero, W. G., Janssens, A. C., Gwinn, M., Simons-Morton, D. G., Bernhardt, J. M., Cargill, M., Chanock, S. J., Church, G. M., Coates, R. J., Collins, F. S., Croyle, R. T., Davis, B. R., Downing, G. J., DuRoss, A., Friedman, S., Gail, M. H., Ginsburg, G. S., Green, R. C., Greene, M. H., Greenland, P., Gulcher, J. R., Hsu, A., Hudson, K. L., Kardia, S. L., Kimmel, P. L., Lauer, M. S., Miller, A. M., Offit, K., Ransohoff, D. F., Roberts, J. S., Rasooly, R. S., Stefansson, K., Terry, S. F., Teutsch, S. M., Trepanier, A., Wanke, K. L., Witte, J. S., Xu, J. 2009; 11 (8): 559-567

    Abstract

    The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.

    View details for DOI 10.1097/GIM.0b013e3181b13a6c

    View details for Web of Science ID 000269273900001

    View details for PubMedID 19617843

  • Genome-Wide Association Studies, Field Synopses, and the Development of the Knowledge Base on Genetic Variation and Human Diseases AMERICAN JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Bertram, L., Boffetta, P., Butterworth, A. S., Chanock, S. J., Dolan, S. M., Fortier, I., Garcia-Closas, M., Gwinn, M., Higgins, J. P., Janssens, A. C., Ostell, J., Owen, R. P., Pagon, R. A., Rebbeck, T. R., Rothman, N., Bernstein, J. L., Burton, P. R., Campbell, H., Chockalingam, A., Furberg, H., Little, J., O'Brien, T. R., Seminara, D., Vineis, P., Winn, D. M., Yu, W., Ioannidis, J. P. 2009; 170 (3): 269-279

    Abstract

    Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues -- especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10(-7)). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.

    View details for DOI 10.1093/aje/kwp119

    View details for Web of Science ID 000268330300001

    View details for PubMedID 19498075

    View details for PubMedCentralID PMC2714948

  • Immunogenicity and adverse events of avian influenza A H5N1 vaccine in healthy adults: multiple-treatments meta-analysis LANCET INFECTIOUS DISEASES Manzoli, L., Salanti, G., De Vito, C., Boccia, A., Ioannidis, J. P., Villari, P. 2009; 9 (8): 482-492

    Abstract

    Influenza H5N1 is thought to be a likely causative agent for a future human influenza pandemic. Several types of H5N1 vaccine have been tested, including different doses and adjuvants, and a meta-analysis is needed to identify the best formulation. We searched Medline, Embase, the Cochrane Library, and other online databases to February, 2009, in any language for randomised trials comparing different H5N1 vaccines with or without placebo in healthy adults. Primary outcomes were seroconversion, seroresponse, or both according to haemagglutination-inhibition and microneutralisation. Secondary outcomes were adverse events. Because of the large number of compared formulations, multiple-treatments meta-analysis was used for primary outcomes. Direct-comparison meta-analyses were also done. We included 13 trials, which assessed 58 groups. With non-aluminium adjuvant, sufficiently high immunogenicity (greater than 70%) was achieved even at 12 microg or less (given as two doses of 6 microg or less), and higher doses did not provide major improvements. Immunogenicity for non-adjuvanted and aluminium-adjuvanted formulations increased with increasing dose, but was not sufficiently high. No serious vaccine-related adverse events were reported across 9600 participants. Currently, H5N1 influenza vaccines with non-aluminium adjuvants might represent the best available option in a pandemic. Large-scale studies are needed to verify the high immunogenicity of non-aluminium-adjuvanted vaccines that use very low doses of antigen.

    View details for Web of Science ID 000268625400016

    View details for PubMedID 19628173

  • The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration BRITISH MEDICAL JOURNAL Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 339

    Abstract

    Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (quality of reporting of meta-analysis) statement-a reporting guideline published in 1999-there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website (www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for DOI 10.1136/bmj.b2700

    View details for Web of Science ID 000268351400023

    View details for PubMedID 19622552

  • The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration PLOS MEDICINE Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., Moher, D. 2009; 6 (7)

    Abstract

    Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users.Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement--a reporting guideline published in 1999--there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions.The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

    View details for DOI 10.1371/journal.pmed.1000100

    View details for Web of Science ID 000268452400006

    View details for PubMedID 19621070

  • STrengthening the REporting of Genetic Association studies (STREGA)-an extension of the strengthening the reporting, of observational studies in epidemiology (STROBE) statement JOURNAL OF CLINICAL EPIDEMIOLOGY Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 62 (6): 597-608

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence, the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association (STREGA) studies initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1016/j.jclinepi.2008.12.004

    View details for Web of Science ID 000266291600009

    View details for PubMedID 19217256

  • Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand ARTHRITIS AND RHEUMATISM Evangelou, E., Chapman, K., Meulenbelt, I., Karassa, F. B., Loughlin, J., Carr, A., Doherty, M., Doherty, S., Gomez-Reino, J. J., Gonzalez, A., Halldorsson, B. V., Hauksson, V. B., Hofman, A., Hart, D. J., Ikegawa, S., Ingvarsson, T., Jiang, Q., Jonsdottir, I., Jonsson, H., Kerkhof, H. J., Kloppenburg, M., Lane, N. E., Li, J., Lories, R. J., van Meurs, J. B., Nakki, A., Nevitt, M. C., Rodriguez-Lopez, J., Shi, D., Slagboom, E., Stefansson, K., Tsezou, A., Wallis, G. A., Watson, C. M., Spector, T. D., Uitterlinden, A. G., Valdes, A. M., Ioannidis, J. P. 2009; 60 (6): 1710-1721

    Abstract

    GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09-1.22]) (P=9.4x10(-7)), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P=0.016]) or absent (for OA of the hand [P=0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P=0.019).Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.

    View details for DOI 10.1002/art.24524

    View details for Web of Science ID 000267116800021

    View details for PubMedID 19479880

  • Ranking antidepressants LANCET Ioannidis, J. P. 2009; 373 (9677): 1759-1760

    View details for Web of Science ID 000266337300019

    View details for PubMedID 19465221

  • GENOME-WIDE ASSOCIATION STUDIES Validating, augmenting and refining genome-wide association signals NATURE REVIEWS GENETICS Ioannidis, J. P., Thomas, G., Daly, M. J. 2009; 10 (5): 318-329

    Abstract

    Studies using genome-wide platforms have yielded an unprecedented number of promising signals of association between genomic variants and human traits. This Review addresses the steps required to validate, augment and refine such signals to identify underlying causal variants for well-defined phenotypes. These steps include: large-scale exact replication across both similar and diverse populations; fine mapping and resequencing; determination of the most informative markers and multiple independent informative loci; incorporation of functional information; and improved phenotype mapping of the implicated genetic effects. Even in cases for which replication proves that an effect exists, confident localization of the causal variant often remains elusive.

    View details for DOI 10.1038/nrg2544

    View details for Web of Science ID 000265264300014

  • STrengthening the REporting of Genetic Association studies (STREGA) - an extension of the STROBE statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 39 (4): 247-266

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis.

    View details for DOI 10.1111/j.1365-2362.2009.02125.x

    View details for Web of Science ID 000264021800001

    View details for PubMedID 19297801

  • EULAR points to consider for conducting clinical trials in systemic lupus erythematosus: literature based evidence for the selection of endpoints ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Ioannidis, J. P., Boletis, J., Bombardieri, S., Cervera, R., Dostal, C., Font, J., Gilboe, I. M., Houssiau, F., Huizinga, T., Isenberg, D., Kallenberg, C. G., Khamashta, M., Piette, J. C., Schneider, M., Smolen, J., Sturfelt, G., Tincani, A., van Vollenhoven, R., Boumpas, D. T., Gordon, C. 2009; 68 (4): 477-483

    Abstract

    To assess available evidence on the use of end-points (outcome measures) in clinical trials in systemic lupus erythematosus (SLE), as a part of the development of evidence-based recommendations for points to consider in clinical trials in SLE.The European League Against Rheumatism (EULAR) Task Force on SLE comprised 19 specialists, a clinical epidemiologist and a research fellow. Key questions addressing the evidence for clinical trial end-points in SLE were compiled using the Delphi technique. A systematic search of the PubMed and Cochrane Library databases was performed using McMaster/Hedges clinical query strategies and an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence and agreement on the statements was measured across the 19 specialists.Eight questions were generated regarding end-points for clinical trials. The evidence to support each proposition was evaluated. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not been formally validated in clinical trials, although some indirect validation has been undertaken.This systematic literature review forms the evidence base considered in the development of the EULAR recommendations for end-points in clinical trials in SLE.

    View details for DOI 10.1136/ard.2007.083030

    View details for Web of Science ID 000264196000005

    View details for PubMedID 18434449

  • EULAR points to consider for conducting clinical trials in systemic lupus erythematosus ANNALS OF THE RHEUMATIC DISEASES Gordon, C., Bertsias, G., Ioannidis, J. P., Boletis, J., Bombardieri, S., Cervera, R., Dostal, C., Font, J., Gilboe, I., Houssiau, F., Huizinga, T. W., Isenberg, D., Kallenberg, C. G., Khamashta, M. A., Piette, J., Schneider, M., Smolen, J. S., Sturfelt, G., Tincani, A., van Vollenhoven, R., Boumpas, D. T. 2009; 68 (4): 470-476

    Abstract

    Systemic lupus erythematosus (SLE) is a complex multi-organ disease, characterised by relapses and remissions.ng a high-quality randomised controlled trial poses many challenges. We have developed evidenced-based recommendations for points to consider in conducting clinical trials in patients with SLE.The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Initially, the evidence for clinical trial end-points in SLE was evaluated and this has been reported separately. A consensus approach was developed by the SLE Task Force in formulating recommendations for points to consider when conducting clinical trials in SLE.The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not actually been validated in clinical trials, although other forms of validation have been undertaken. The final recommendations for points to consider for conducting clinical trials in SLE address the following areas: study design, eligibility criteria, outcome measures including adverse events, concomitant therapies for SLE and its complications.Recommendations for points to consider when conducting clinical trials in SLE were developed using an evidence-based approach followed by expert consensus. The recommendations should be disseminated, implemented and then reviewed in detail and revised using an evidence-based approach in about 5 years, by which time there will be further evidence to consider from current clinical trials.

    View details for DOI 10.1136/ard.2007.083022

    View details for Web of Science ID 000264196000004

    View details for PubMedID 18388158

  • Overinterpretation of Clinical Applicability in Molecular Diagnostic Research CLINICAL CHEMISTRY Lumbreras, B., Parker, L. A., Porta, M., Pollan, M., Ioannidis, J. P., Hernandez-Aguado, I. 2009; 55 (4): 786-794

    Abstract

    We evaluated whether articles on molecular diagnostic tests interpret appropriately the clinical applicability of their results.We selected original-research articles published in 2006 that addressed the diagnostic value of a molecular test. We defined overinterpretation of clinical applicability by means of prespecified rules that evaluated study design, conclusions regarding applicability, presence of statements suggesting the need for further clinical evaluation of the test, and diagnostic accuracy. Two reviewers independently evaluated the articles; consensus was reached after discussion and arbitration by a third reviewer.Of 108 articles included in the study, 82 (76%) used a design that used healthy controls or alternative-diagnosis controls, only 15 (11%) addressed a clinically relevant population similar to that in which the test might be applied in practice, 104 articles (96%) made definitely favorable or promising statements regarding clinical applicability, and 61 (56%) of the articles apparently overinterpreted the clinical applicability of their findings. Articles published in journals with higher impact factors were more likely to overinterpret their results than those with lower impact factors (adjusted odds ratio, 1.71 per impact factor quartile; 95% CI, 1.09-2.69; P = 0.020). Overinterpretation was more common when authors were based in laboratories than in clinical settings (adjusted odds ratio, 18.7; 95% CI, 1.41-249; P = 0.036).Although expectations are high for new diagnostic tests based on molecular techniques, the majority of published research has involved preclinical phases of research. Overinterpretation of the clinical applicability of findings for new molecular diagnostic tests is common.

    View details for DOI 10.1373/clinchem.2008.121517

    View details for Web of Science ID 000264774200024

    View details for PubMedID 19233907

  • Persistent reservations against contradicted percutaneous coronary intervention indications: Citation content analysis AMERICAN HEART JOURNAL Siontis, G. C., Tatsioni, A., Katritsis, D. G., Ioannidis, J. P. 2009; 157 (4): 695-701

    Abstract

    Two large trials, Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Occluded Artery Trial (OAT), found no benefits of percutaneous coronary intervention (PCI) versus optimal medical therapy in chronic stable coronary artery disease and chronic total occlusion.We examined the stance of articles citing COURAGE and OAT to determine whether some authors continue to defend PCI despite this evidence, what persisting counterarguments are raised to express reservations, and whether specific characteristics of the citations are associated with reservations. We evaluated all citing articles entered in the Web of Science until February 1, 2008. Specific characteristics were recorded for each eligible citation, and a citation content analysis was performed. Counterarguments were categorized on participants, interventions, comparisons, and outcomes.Of 54 articles citing COURAGE and 33 articles citing OAT, 10 (19%) and 5 (15%), respectively, had an overall reserved stance. Alluded reservations included lack of power, eroded effects from crossover, selective inclusion and exclusion of specific types of patients, suboptimal clinical setting, use of bare-metal stents, suspiciously good results in the conservative treatment arm, and suboptimal outcome choices or definitions. Reserved articles were more likely than unreserved ones to have an interventional cardiologist as corresponding author (odds ratio 5.2, 95% confidence interval 1.6-17.1; P = .007) and to be commentaries focusing on one of these trials (odds ratio 3.3, 95% confidence interval 1.0-11.0; P = .05).Despite strong randomized evidence, a fraction of the literature, mostly corresponded by interventional cardiologists, continues to raise reservations about recently contradicted indications of PCI.

    View details for DOI 10.1016/j.ahj.2008.11.023

    View details for Web of Science ID 000265110100017

    View details for PubMedID 19332198

  • Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement HUMAN GENETICS Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 125 (2): 131-151

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1007/s00439-008-0592-7

    View details for Web of Science ID 000263496900003

    View details for PubMedID 19184668

  • An empirical comparison of meta-analyses of published gene-disease associations versus consortium analyses GENETICS IN MEDICINE Janssens, A. C., Ladd, A. M., Lopez-Leon, S., Ioannidis, J. P., Oostra, B. A., Khoury, M. J., van Duijn, C. M. 2009; 11 (3): 153-162

    Abstract

    Consortia of investigators currently compile sufficiently large sample sizes to investigate the effects of low-risk susceptibility genetic variants. It is not clear how the results obtained by consortia compare with those derived from meta-analyses of published studies.We performed meta-analyses of published data for 16 genetic polymorphisms investigated by the Breast Cancer Association Consortium, and compared sample sizes, heterogeneity, and effect sizes. PubMed, Web of Science, and Human Genome Epidemiology Network databases were searched for breast cancer case-control association studies.We found that meta-analyses of published data and consortium analyses were based on substantially different data. Published data by non-consortium teams amounted on average to 26.9% of all available data (range 3.0 -50.0%). Both approaches showed statistically significant decreased breast cancer risks for CASP8 D302H. The meta-analyses of published data demonstrated statistically significant results for five other genes and the consortium analyses for two other genes, but the strength of this evidence, evaluated on the basis of the Venice criteria, was not strong.Because both approaches identified the same gene out of 16 candidates, the methods can be complimentary. The expense and complexity of consortium-based studies should be considered vis-à-vis the potential methodological limitations of synthesis of published studies.

    View details for DOI 10.1097/GIM.0b013e3181929237

    View details for Web of Science ID 000264468300003

    View details for PubMedID 19367188

  • STrengthening the REporting of Genetic Association Studies (STREGA): An Extension of the STROBE Statement ANNALS OF INTERNAL MEDICINE Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 150 (3): 206-?

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information into the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and issues of data volume that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for Web of Science ID 000263029600008

    View details for PubMedID 19189911

  • Synthesis of observational studies should consider credibility ceilings JOURNAL OF CLINICAL EPIDEMIOLOGY Salanti, G., Ioannidis, J. P. 2009; 62 (2): 115-122

    Abstract

    Meta-analyses of observational studies often get spuriously precise results. We aimed to factor this skepticism in meta-analysis calculations.We developed a simple sensitivity analysis starting from the assumption that any single observational study cannot give us more than a maximum certainty c% (called credibility ceiling) that an effect is in a particular direction and not in the other. Each study included in meta-analysis is adjusted for different credibility ceilings c and the consistency of the conclusion examined. We applied the method in three meta-analyses of observational studies with nominally statistically significant summary effects (mortality with teaching versus nonteaching health care; risk of non-Hodgkin's lymphoma with hair dyes; mortality with omega-3 fatty acids).Between-study heterogeneity I(2) estimates dropped from 36%-72% without a ceiling effect to 0% with ceilings of 9%, 4%, and 4% in the three meta-analyses, respectively. Nominal statistical significance was lost with ceilings of 10%, 8%, and 11%, respectively. The likelihood ratios suggested that even with minimal ceiling effects, there was no strong support for the credibility of each of these three associations.Consideration of credibility ceilings allows conservative interpretation of observational evidence and can be applied routinely to meta-analyses of observational studies.

    View details for DOI 10.1016/j.jclinepi.2008.05.014

    View details for Web of Science ID 000262574100001

    View details for PubMedID 19131013

  • Repeatability of published microarray gene expression analyses NATURE GENETICS Ioannidis, J. P., Allison, D. B., Ball, C. A., Coulibaly, I., Cui, X., Culhane, A. C., Falchi, M., Furlanello, C., Game, L., Jurman, G., Mangion, J., Mehta, T., Nitzberg, M., Page, G. P., Petretto, E., van Noort, V. 2009; 41 (2): 149-155

    Abstract

    Given the complexity of microarray-based gene expression studies, guidelines encourage transparent design and public data availability. Several journals require public data deposition and several public databases exist. However, not all data are publicly available, and even when available, it is unknown whether the published results are reproducible by independent scientists. Here we evaluated the replication of data analyses in 18 articles on microarray-based gene expression profiling published in Nature Genetics in 2005-2006. One table or figure from each article was independently evaluated by two teams of analysts. We reproduced two analyses in principle and six partially or with some discrepancies; ten could not be reproduced. The main reason for failure to reproduce was data unavailability, and discrepancies were mostly due to incomplete data annotation or specification of data processing and analysis. Repeatability of published microarray studies is apparently limited. More strict publication rules enforcing public data availability and explicit description of data processing and analysis should be considered.

    View details for DOI 10.1038/ng.295

    View details for Web of Science ID 000263091300011

    View details for PubMedID 19174838

  • Prediction of Cardiovascular Disease Outcomes and Established Cardiovascular Risk Factors by Genome-Wide Association Markers CIRCULATION-CARDIOVASCULAR GENETICS Ioannidis, J. P. 2009; 2 (1): 7-15

    Abstract

    Genome-wide association (GWA) platforms have yielded a rapidly increasing number of new genetic markers. The ability of these markers to improve prediction of clinically important outcomes is debated.A systematic review was performed of GWA-derived markers associated with cardiovascular outcomes or other phenotypes that represent common established risk factors for cardiovascular outcomes. Sources of information included the National Human Genome Research Institute catalog of published GWA studies, and perusal of the eligible GWA articles, meta-analyses on the respective associations, and articles on the incremental predictive performance of common variants in the GWA era. A total of 95 eligible associations were retrieved from the National Human Genome Research Institute catalogue of published GWA studies as of September 2008. Of those 36 have statistical support of P<10(-7). In depth evaluation of the respective articles shows 28 independent associations with such statistical support, pertaining to coronary artery disease, myocardial infarction, atrial fibrillation/flutter, prolongation of QT interval, as well as type 2 diabetes, body mass index, high-density lipoprotein levels, low-density lipoprotein levels, and nicotine dependence. Between-study heterogeneity is not taken into account usually, but it seems common and it would pose a challenge to generalizability across different populations for these markers. Still limited data are available in non-white populations. Effect sizes are small and may be even smaller in subsequent replications and meta-analysis. Population attributable fractions are substantial, given the large frequency of the risk alleles. However, individualized risk measures are typically very small (proportion of variance explained <1% per marker). When used in conjunction with traditional predictors, improvement in overall prediction (eg, area under the curve) or risk reclassification is limited, and subject to methodological caveats.Despite very promising signals in terms of statistical significance, evidence for improvement in cardiovascular prediction by currently available markers derived from GWA studies is sparse. Clinical use of such markers currently would be premature.

    View details for DOI 10.1161/CIRCGENETICS.108.833392

    View details for Web of Science ID 000275960100003

    View details for PubMedID 20031562

  • STrengthening the REporting of Genetic Association Studies (STREGA) - An Extension of the STROBE Statement PLOS MEDICINE Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 6 (2): 151-163

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1371/journal.pmed.1000022

    View details for Web of Science ID 000263600000009

    View details for PubMedID 19192942

  • Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Thorlund, K., Devereaux, P. J., Wetterslev, J., Guyatt, G., Ioannidis, J. P., Thabane, L., Gluud, L., Als-Nielsen, B., Gluud, C. 2009; 38 (1): 276-286

    Abstract

    Results from apparently conclusive meta-analyses may be false. A limited number of events from a few small trials and the associated random error may be under-recognized sources of spurious findings. The information size (IS, i.e. number of participants) required for a reliable and conclusive meta-analysis should be no less rigorous than the sample size of a single, optimally powered randomized clinical trial. If a meta-analysis is conducted before a sufficient IS is reached, it should be evaluated in a manner that accounts for the increased risk that the result might represent a chance finding (i.e. applying trial sequential monitoring boundaries).We analysed 33 meta-analyses with a sufficient IS to detect a treatment effect of 15% relative risk reduction (RRR). We successively monitored the results of the meta-analyses by generating interim cumulative meta-analyses after each included trial and evaluated their results using a conventional statistical criterion (alpha = 0.05) and two-sided Lan-DeMets monitoring boundaries. We examined the proportion of false positive results and important inaccuracies in estimates of treatment effects that resulted from the two approaches.Using the random-effects model and final data, 12 of the meta-analyses yielded P > alpha = 0.05, and 21 yielded P alpha = 0.05. The monitoring boundaries eliminated all false positives. Important inaccuracies in estimates were observed in 6 out of 21 meta-analyses using the conventional P

    View details for DOI 10.1093/ije/dyn179

    View details for Web of Science ID 000263164400037

    View details for PubMedID 18824467

  • Meta-analysis in genome-wide association studies PHARMACOGENOMICS Zeggini, E., Ioannidis, J. P. 2009; 10 (2): 191-201

    Abstract

    The advent of genome-wide association studies has allowed considerable progress in the identification and robust replication of common gene variants that confer susceptibility to common diseases and other phenotypes of interest. These genetic effect sizes are almost invariably moderate to small in magnitude and single studies, even if large, are underpowered to detect them with confidence. Meta-analysis of many genome-wide association studies improves the power to detect more associations, and to investigate the consistency or heterogeneity of these associations across diverse datasets and study populations. In this review, we discuss the key methodological issues in the set-up, information gathering and processing, and analysis of meta-analyses of genome-wide association datasets. We illustrate, as an example, the application of meta-analysis methods in the elucidation of common genetic variants associated with Type 2 diabetes. Finally, we discuss the prospects and caveats for future application of meta-analysis methods in the genome-wide setting.

    View details for DOI 10.2217/14622416.10.2.191

    View details for Web of Science ID 000263811400005

    View details for PubMedID 19207020

  • How to Use an Article About Genetic Association C: What Are the Results and Will They Help Me in Caring for My Patients? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Attia, J., Ioannidis, J. P., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J., Infante-Rivard, C., Guyatt, G. 2009; 301 (3): 304-308

    Abstract

    In the first 2 articles of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies, and we enumerated the major issues in judging the validity of these studies. In this third article, we review the issues relating to the applicability of the results in the clinical situation. How large and precise are the associations? Many genetic effects are expected to be smaller in magnitude than traditional risk factors. Does the genetic association improve predictive power beyond easily measured clinical variables? In some cases, the additional genetic information adds only a small increment in the predictive ability of a diagnostic or prognostic test. What are the absolute vs relative effects? Even if the genetic risk is high in relative terms, the baseline risk may be very low in absolute terms. Is the risk-associated allele likely to be present in my patient? A risk allele may have a strong effect but be rare in a particular ethnic group. Is the patient likely better off knowing the genetic information? Given that genes cannot be modified, one must weigh whether the genetic information is likely to be helpful in planning other health interventions or initiating behavior change.

    View details for Web of Science ID 000262518700021

    View details for PubMedID 19155457

  • Personalized Genetic Prediction: Too Limited, Too Expensive, or Too Soon? ANNALS OF INTERNAL MEDICINE Ioannidis, J. P. 2009; 150 (2): 139-141

    View details for Web of Science ID 000262655200009

    View details for PubMedID 19153414

  • How to Use an Article About Genetic Association B: Are the Results of the Study Valid? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Attia, J., Ioannidis, J. P., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J., Infante-Rivard, C., Guyatt, G. 2009; 301 (2): 191-197

    Abstract

    In the first article of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies. In this second article, we enumerate the major issues in judging the validity of these studies, framed as critical appraisal questions. Was the disease phenotype properly defined and accurately recorded by someone blind to the genetic information? Have any potential differences between disease and nondisease groups, particularly ethnicity, been properly addressed? In genetic studies, one potential cause of spurious associations is differences between cases and controls in ethnicity, a situation termed population stratification. Was measurement of the genetic variants unbiased and accurate? Methods for determining DNA sequence variation are not perfect and may have some measurement error. Do the genotype proportions observe Hardy-Weinberg equilibrium? This simple mathematic rule about the distribution of genetic groups may be one way to check for errors in reading DNA information. Have the investigators adjusted their inferences for multiple comparisons? Given the thousands of genetic markers tested in genome-wide association studies, the potential for false-positive and false-negative results is much higher than in traditional medical studies, and it is particularly important to look for replication of results.

    View details for Web of Science ID 000262405500021

    View details for PubMedID 19141767

  • Reporting and interpretation of SF-36 outcomes in randomised trials: systematic review BRITISH MEDICAL JOURNAL Contopoulos-Ioannidis, D. G., Karvouni, A., Kouri, I., Ioannidis, J. P. 2009; 338

    Abstract

    To determine how often health surveys and quality of life evaluations reach different conclusions from those of primary efficacy outcomes and whether discordant results make a difference in the interpretation of trial findings.Systematic review.PubMed, contact with authors for missing information, and author survey for unpublished SF-36 data.Randomised trials with SF-36 outcomes (the most extensively validated and used health survey instrument for appraising quality of life) that were published in 2005 in 22 journals with a high impact factor.Analyses on the two composite and eight subdomain SF-36 scores that corresponded to the time and mode of analysis of the primary efficacy outcome.Of 1057 screened trials, 52 were identified as randomised trials with SF-36 results (66 separate comparisons). Only eight trials reported all 10 SF-36 scores in the published articles. For 21 of the 66 comparisons, SF-36 results were discordant for statistical significance compared with the results for primary efficacy outcomes. Of 17 statistically significant SF-36 scores where primary outcomes were not also statistically significant in the same direction, the magnitude of effect was small in six, moderate in six, large in three, and not reported in two. Authors modified the interpretation of study findings based on SF-36 results in only two of the 21 discordant cases. Among 100 additional randomly selected trials not reporting any SF-36 information, at least five had collected SF-36 data but only one had analysed it.SF-36 measurements sometimes produce different results from those of the primary efficacy outcomes but rarely modify the overall interpretation of randomised trials. Quality of life and health related survey information should be utilised more systematically in randomised trials.

    View details for DOI 10.1136/bmj.a3006

    View details for Web of Science ID 000263192800001

    View details for PubMedID 19139138

  • How to Use an Article About Genetic Association A: Background Concepts JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Attia, J., Ioannidis, J. P., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J., Infante-Rivard, C., Guyatt, G. 2009; 301 (1): 74-81

    Abstract

    This is the first in a series of 3 articles serving as an introduction to clinicians wishing to read and critically appraise genetic association studies. We summarize the key concepts in genetics that clinicians must understand to review these studies, including the structure of DNA, transcription and translation, patterns of inheritance, Hardy-Weinberg equilibrium, and linkage disequilibrium. We review the types of DNA variation, including single-nucleotide polymorphisms (SNPs), insertions, and deletions, and how these can affect protein function. We introduce the idea of genetic association for both single-candidate gene and genome-wide association studies, in which thousands of genetic variants are tested for association with disease. We use the APOE polymorphism and its association with dementia as a case study to demonstrate the concepts and introduce the terminology used in this field. The second and third articles will focus on issues of validity and applicability.

    View details for Web of Science ID 000262220400022

    View details for PubMedID 19126812

  • A Field Synopsis on Low-Penetrance Variants in DNA Repair Genes and Cancer Susceptibility JOURNAL OF THE NATIONAL CANCER INSTITUTE Vineis, P., Manuguerra, M., Kavvoura, F. K., Guarrera, S., Allione, A., Rosa, F., Di Gregorio, A., Polidoro, S., Saletta, F., Ioannidis, J. P., Matullo, G. 2009; 101 (1): 24-36

    Abstract

    Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair.We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were two-sided.Thirty-one nominally statistically significant (ie, P < .05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POLI, TP53, XPA, XRCC1, XRCC2, XRCC3, and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had modest credibility, and 24 had weak credibility based on Venice criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P

    View details for DOI 10.1093/jnci/djn437

    View details for Web of Science ID 000262333500009

    View details for PubMedID 19116388

  • The use of older studies in meta-analyses of medical interventions: a survey. Open medicine : a peer-reviewed, independent, open-access journal Patsopoulos, N. A., Ioannidis, J. P. 2009; 3 (2): e62-8

    Abstract

    Evidence for medical interventions sometimes derives from data that are no longer up to date. These data can influence the outcomes of meta-analyses, yet do not always reflect current clinical practice. We examined the age of the data used in meta-analyses contained within systematic reviews of medical interventions, and investigated whether authors consider the age of these data in their interpretations.From Issue 4, 2005, of the Cochrane Database of Systematic Reviews we randomly selected 10% of systematic reviews containing at least 1 meta-analysis. From this sample we extracted 1 meta-analysis per primary outcome. We calculated the number of years between the study's publication and 2005 (the year that the systematic review was published), as well as the number of years between the study's publication and the year of the literature search conducted in the study. We assessed whether authors discussed the implications of including less recent data, and, for systematic reviews containing meta-analyses of studies published before 1996, we calculated whether excluding the findings of those studies changed the significance of the outcomes. We repeated these calculations and assessments for 22 systematic reviews containing meta-analyses published in 6 high-impact general medical journals in 2005.For 157 meta-analyses (n = 1149 trials) published in 2005, the median year of the most recent literature search was 2003 (interquartile range [IQR] 2002-04). Two-thirds of these meta-analyses (103/157, 66%) involved no trials published in the preceding 5 years (2001-05). Forty-seven meta-analyses (30%) included no trials published in the preceding 10 years (1996-2005). In another 16 (10%), the statistical significance of the outcomes would have been different had the studies been limited to those published between 1996 and 2005, although in some cases this change in significance would have been due to loss of power. Only 12 (8%) of the meta-analyses discussed the potential implications of including older studies. Among the 22 meta-analyses considered in high-impact general medical journals, 2 included no studies published in the 5 years prior to the reference year (2005), and 18 included at least 1 study published before 1996. Only 4 meta-analyses discussed the implications of including older studies.In most systematic reviews containing meta-analyses of evidence for health care interventions, very recent studies are rare. Researchers who conduct systematic reviews with meta-analyses, and clinicians who read the outcomes of these studies, should be made aware of the potential implications of including less recent data.

    View details for PubMedID 19946395

  • Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement EUROPEAN JOURNAL OF EPIDEMIOLOGY Little, J., Higgins, J. P., Ioannidis, J. P., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R. E., Zou, G. Y., Hutchings, K., Johnson, C. Y., Tait, V., Wiens, M., Golding, J., Van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A. F., Birkett, N. 2009; 24 (1): 37-55

    Abstract

    Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

    View details for DOI 10.1007/s10654-008-9302-y

    View details for Web of Science ID 000263362000006

    View details for PubMedID 19189221

  • Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term COCHRANE DATABASE OF SYSTEMATIC REVIEWS Sotiriadis, A., Makrydimas, G., Papatheodorou, S., Ioannidis, J. P. 2009

    Abstract

    Infants born at term by elective caesarean delivery are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications.The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications.We searched the Cochrane Pregnancy and Chilbirth Group's Trials Register (30 June 2009).Randomised and quasi-randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation).The co-authors assessed the results of the only available trial independently to retrieve data on perinatal outcomes. Results were expressed as risk ratio (RR) or mean differences (MD), together with their 95% confidence intervals (CI).One study comparing prophylactic administration of betamethasone (N = 467) versus usual treatment without steroids (N = 475) in term elective caesarean section was included in the review. Women randomised to treatment group received two intramuscular doses of betamethasone in the 48 hours before delivery, whereas the control group received treatment as usual.Prophylactic betamethasone appeared to significantly decrease the risk of admission to the neonatal intensive care unit for respiratory morbidity (RR 0.15; 95% CI 0.03 to 0.64). However, no statistically significant reduction was found in the incidence of neonatal respiratory distress syndrome (RR 0.32; 95% CI 0.07 to 1.58), transient tachypnoea of the newborn (RR 0.52; 95% CI 0.25 to 1.11), need for mechanical ventilation (RR 4.07; 95% CI 0.46 to 36.27) and length of stay in neonatal intensive care unit (MD) -2.14 days; 95% CI -5.58 to 1.30).There were no reported events of neonatal sepsis, perinatal deaths or maternal trauma infection, therefore results on these outcomes are non-estimable. The study did not provide data on other pre-defined outcomes.The results from the single trial are promising, but more studies with larger samples are needed to investigate the effect of prophylactic steroids in the incidence of neonatal complications per se. Also more data and longer follow up would be needed for potential harms and complications.

    View details for DOI 10.1002/14651858.CD006614.pub2

    View details for Web of Science ID 000270686900058

    View details for PubMedID 19821379

  • Multiple-Treatments Meta-analysis of Chemotherapy and Targeted Therapies in Advanced Breast Cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Polyzos, N. P., Salanti, G., Pavlidis, N., Ioannidis, J. P. 2008; 100 (24): 1780-1791

    Abstract

    Many systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival.We performed a systematic review of all trials that compared different regimens involving chemotherapy and/or targeted therapy in advanced breast cancer (1973-2007). Regimens were categorized a priori into different treatment types. We performed multiple-treatments meta-analysis and calculated hazard ratios for each treatment category relative to monotherapy with old agents (ie, regimens not including anthracyclines, anthracenediones, vinorelbine, gemcitabine, capecitabine, taxanes, marimastat, thalidomide, trastuzumab, lapatinib, or bevacizumab).We identified 370 eligible randomized trials (54,189 patients), of which 172 (31,552 patients) compared different types of treatment. Survival data from 148 comparisons pertaining to 128 of the 172 trials (26,031 patients, 22 different types of treatment) were available for inclusion in the multiple-treatments meta-analysis. Compared with single-agent chemotherapy with old nonanthracycline drugs, anthracycline regimens achieved 22%-33% relative risk reductions in mortality (ie, hazard ratio [HR] for standard-dose anthracycline-based combination: 0.67, 95% credibility interval [CrI] 0.57-0.78). Several newer regimens achieved further benefits (eg, HR [95% CrI] 0.67 [0.55-0.81] for single-drug taxane, 0.64 [0.53-0.78] for combination of anthracyclines with taxane, 0.49 [0.37-0.67] for taxane-based combination with capecitabine or gemcitabine), and similar benefits were seen with several regimens including molecular targeted treatments. Most regimens had very similar efficacy profiles (<5% difference in HR) as first- and subsequent-line therapies.Stepwise improvements in efficacy of chemotherapy and targeted treatments cumulatively have achieved major improvements in the survival of patients with advanced breast cancer. Many options that can be used in first and subsequent lines of therapy have comparable efficacy profiles.

    View details for DOI 10.1093/jnci/djn414

    View details for Web of Science ID 000261902100013

    View details for PubMedID 19066278

  • Expectations and challenges stemming from genome-wide association studies MUTAGENESIS Vineis, P., Brennan, P., Canzian, F., Ioannidis, J. P., Matullo, G., Ritchie, M., Stromberg, U., Taioli, E., Thompson, J. 2008; 23 (6): 439-444

    Abstract

    There are considerable expectations about the ability of genome-wide association (GWA) studies to make exciting discoveries about the role of genes in common diseases. GWA studies may allow researchers to identify causal pathways that have not been unveiled before, thus opening new avenues to disease understanding, prevention and therapy. However, there are still many open challenges. One is how to analyse these studies. The problem of false positives and false negatives provides an interesting methodological stimulus to find optimal solutions. Once main genetic effects have been concretely documented, the next question is how to proceed with the investigation of gene-gene and gene-environment interactions. It is possible that what really counts is not the main effect of genes but complex interactions. Finding and interpreting such interactions is not straightforward. Finally, continuous updated integration of all evidence, from both old studies, current GWA investigations and future replication studies, and careful interpretation of the strength of the evidence are crucial to maximize transparency and lead to informative selection of the next steps of research in this field. The present Commentary is a report of an Environmental Cancer Risk, Nutrition and Individual Susceptibility network Workshop held in Venice in October 2007 and discusses some of the problems outlined above, with examples.

    View details for DOI 10.1093/mutage/gen042

    View details for Web of Science ID 000260557900002

    View details for PubMedID 18765424

  • Evaluation of the Potential Excess of Statistically Significant Findings in Published Genetic Association Studies: Application to Alzheimer's Disease AMERICAN JOURNAL OF EPIDEMIOLOGY Kavvoura, F. K., McQueen, M. B., Khoury, M. J., Tanzi, R. E., Bertram, L., Ioannidis, J. P. 2008; 168 (8): 855-865

    Abstract

    The authors evaluated whether there is an excess of statistically significant results in studies of genetic associations with Alzheimer's disease reflecting either between-study heterogeneity or bias. Among published articles on genetic associations entered into the comprehensive AlzGene database (www.alzgene.org) through January 31, 2007, 1,348 studies included in 175 meta-analyses with 3 or more studies each were analyzed. The number of observed studies (O) with statistically significant results (P = 0.05 threshold) was compared with the expected number (E) under different assumptions for the magnitude of the effect size. In the main analysis, the plausible effect size of each association was the summary effect presented in the respective meta-analysis. Overall, 19 meta-analyses (all with eventually nonsignificant summary effects) had a documented excess of O over E: Typically single studies had significant effects pointing in opposite directions and early summary effects were dissipated over time. Across the whole domain, O was 235 (17.4%), while E was 164.8 (12.2%) (P < 10(-6)). The excess showed a predilection for meta-analyses with nonsignificant summary effects and between-study heterogeneity. The excess was seen for all levels of statistical significance and also for studies with borderline P values (P = 0.05-0.10). The excess of significant findings may represent significance-chasing biases in a setting of massive testing.

    View details for DOI 10.1093/aje/kwn206

    View details for Web of Science ID 000259965800001

    View details for PubMedID 18779388

  • Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level BEHAVIORAL AND BRAIN FUNCTIONS Stefanis, N. C., Trikalinos, T. A., Avramopoulos, D., Smyrnis, N., Evdokimidis, I., Ntzani, E. E., Hatzimanolis, A., Ioannidis, J. P., Stefanis, C. N. 2008; 4

    Abstract

    While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level.Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts.SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model).Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders.

    View details for DOI 10.1186/1744-9081-4-46

    View details for Web of Science ID 000260435200001

    View details for PubMedID 18834502

  • Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patsopoulos, N. A., Evangelou, E., Ioannidis, J. P. 2008; 37 (5): 1148-1157

    Abstract

    Several approaches are available for evaluating heterogeneity in meta-analysis. Sensitivity analyses are often used, but these are often implemented in various non-standardized ways.We developed and implemented sequential and combinatorial algorithms that evaluate the change in between-study heterogeneity as one or more studies are excluded from the calculations. The algorithms exclude studies aiming to achieve either the maximum or the minimum final I(2) below a desired pre-set threshold. We applied these algorithms in databases of meta-analyses of binary outcome and >/=4 studies from Cochrane Database of Systematic Reviews (Issue 4, 2005, n = 1011) and meta-analyses of genetic associations (n = 50). Two I(2) thresholds were used (50% and 25%).Both algorithms have succeeded in achieving the pre-specified final I(2) thresholds. Differences in the number of excluded studies varied from 0% to 6% depending on the database and the heterogeneity threshold, while it was common to exclude different specific studies. Among meta-analyses with initial I(2) > 50%, in the large majority [19 (90.5%) and 208 (85.9%) in genetic and Cochrane meta-analyses, respectively] exclusion of one or two studies sufficed to decrease I(2) < 50%. Similarly, among meta-analyses with initial I(2) > 25%, in most cases [16 (57.1%) and 382 (81.3%), respectively) exclusion of one or two studies sufficed to decrease heterogeneity even <25%. The number of excluded studies correlated modestly with initial estimated I(2) (correlation coefficients 0.52-0.68 depending on algorithm used).The proposed algorithms can be routinely applied in meta-analyses as standardized sensitivity analyses for heterogeneity. Caution is needed evaluating post hoc which specific studies are responsible for the heterogeneity.

    View details for DOI 10.1093/ije/dyn065

    View details for Web of Science ID 000259771500031

    View details for PubMedID 18424475

  • Why Current Publication Practices May Distort Science PLOS MEDICINE Young, N. S., Ioannidis, J. P., Al-Ubaydi, O. 2008; 5 (10): 1418-1422

    View details for DOI 10.1371/journal.pmed.0050201

    View details for Web of Science ID 000260424100003

    View details for PubMedID 18844432

  • Interpretation of tests of heterogeneity and bias in meta-analysis JOURNAL OF EVALUATION IN CLINICAL PRACTICE Ioannidis, J. P. 2008; 14 (5): 951-957

    Abstract

    Statistical tests of heterogeneity and bias, in particular publication bias, are very popular in meta-analyses. These tests use statistical approaches whose limitations are often not recognized. Moreover, it is often implied with inappropriate confidence that these tests can provide reliable answers to questions that in essence are not of statistical nature. Statistical heterogeneity is only a correlate of clinical and pragmatic heterogeneity and the correlation may sometimes be weak. Similarly, statistical signals may hint to bias, but seen in isolation they cannot fully prove or disprove bias in general, let alone specific causes of bias, such as publication bias in particular. Both false-positive and false-negative signals of heterogeneity and bias can be common and their prevalence may be anticipated based on some rational considerations. Here I discuss the major common challenges and flaws that emerge in using and interpreting statistical tests of heterogeneity and bias in meta-analyses. I discuss misinterpretations that can occur at the level of statistical inference, clinical/pragmatic inference and specific cause attribution. Suggestions are made on how to avoid these flaws, use these tests properly and learn from them.

    View details for DOI 10.1111/j.1365-2753.2008.00986.x

    View details for Web of Science ID 000260544400050

    View details for PubMedID 19018930

  • Calibration of credibility of agnostic genome-wide associations AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Ioannidis, J. P. 2008; 147B (6): 964-972

    Abstract

    Genome-wide testing platforms are increasingly used to promote "agnostic" approaches to the discovery of gene variants associated with the risk of many common diseases and quantitative traits. The early track record of genome-wide association (GWA) studies suggests that some proposed associations are replicated quite consistently with large-scale subsequent evidence from multiple studies, others have a more inconsistent replication record, some have failed to be replicated by independent investigators and many more early proposed associations await further replication. An important question is how to calibrate the credibility of these postulated associations. A simple Bayesian method is applied here to achieve such calibration. The variability of the estimated credibility is examined under different assumptions. Empirical examples are drawn from existing GWA studies. It is demonstrated that the credibility of different proposed associations can cover a very wide range. The credibility of specific associations usually remains relatively robust when different plausible assumptions are made (within a reasonable range) for the prior odds of an association being true, or the magnitude of the anticipated effect size for genetic associations. Heterogeneity and bias assumptions can have a more major impact on the credibility estimates and thus they need very careful consideration in each case. Credibility calibration may be used in conjunction with qualitative criteria for the appraisal of the cumulative evidence that take into consideration the amount, consistency, and protection from bias in the data.

    View details for DOI 10.1002/ajmg.b.30721

    View details for Web of Science ID 000259050100040

    View details for PubMedID 18361430

  • Medicine - Life cycle of translational research for medical interventions SCIENCE Contopoulos-Ioannidis, D. G., Alexiou, G. A., Gouvias, T. C., Ioannidis, J. P. 2008; 321 (5894): 1298-1299

    View details for DOI 10.1126/science.1160622

    View details for Web of Science ID 000258914300031

    View details for PubMedID 18772421

  • Mortality in systemic sclerosis CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Karassa, F. B., Ioannidis, J. P. 2008; 26 (5): S85-S93

    Abstract

    Systemic sclerosis is a rare and potentially devastating connective tissue disease. It is highly heterogeneous in terms of clinical presentation, extent and severity of organ involvement, immunologic abnormalities, and clinical course. Although clinical outcomes appear to have improved in recent years, the disease continues to cause substantial excess mortality. In this review, we have systematically collected the published studies addressing the mortality burden in patients with scleroderma in comparison with the general population, as well as studies exploring the most important potential predictors of mortality. Results of these studies are presented and discussed, with emphasis on methodological limitations. Suggestions are made for the design, conduct, and reporting of further research on these themes.

    View details for Web of Science ID 000260467300011

    View details for PubMedID 19026149

  • Why most discovered true associations are inflated EPIDEMIOLOGY Ioannidis, J. P. 2008; 19 (5): 640-648

    Abstract

    Newly discovered true (non-null) associations often have inflated effects compared with the true effect sizes. I discuss here the main reasons for this inflation. First, theoretical considerations prove that when true discovery is claimed based on crossing a threshold of statistical significance and the discovery study is underpowered, the observed effects are expected to be inflated. This has been demonstrated in various fields ranging from early stopped clinical trials to genome-wide associations. Second, flexible analyses coupled with selective reporting may inflate the published discovered effects. The vibration ratio (the ratio of the largest vs. smallest effect on the same association approached with different analytic choices) can be very large. Third, effects may be inflated at the stage of interpretation due to diverse conflicts of interest. Discovered effects are not always inflated, and under some circumstances may be deflated-for example, in the setting of late discovery of associations in sequentially accumulated overpowered evidence, in some types of misclassification from measurement error, and in conflicts causing reverse biases. Finally, I discuss potential approaches to this problem. These include being cautious about newly discovered effect sizes, considering some rational down-adjustment, using analytical methods that correct for the anticipated inflation, ignoring the magnitude of the effect (if not necessary), conducting large studies in the discovery phase, using strict protocols for analyses, pursuing complete and transparent reporting of all results, placing emphasis on replication, and being fair with interpretation of results.

    View details for DOI 10.1097/EDE.0b013e31818131e7

    View details for Web of Science ID 000258712000001

    View details for PubMedID 18633328

  • Systematic Review of the Empirical Evidence of Study Publication Bias and Outcome Reporting Bias PLOS ONE Dwan, K., Altman, D. G., Arnaiz, J. A., Bloom, J., Chan, A., Cronin, E., Decullier, E., Easterbrook, P. J., von Elm, E., Gamble, C., Ghersi, D., Ioannidis, J. P., Simes, J., Williamson, P. R. 2008; 3 (8)

    Abstract

    The increased use of meta-analysis in systematic reviews of healthcare interventions has highlighted several types of bias that can arise during the completion of a randomised controlled trial. Study publication bias has been recognised as a potential threat to the validity of meta-analysis and can make the readily available evidence unreliable for decision making. Until recently, outcome reporting bias has received less attention.We review and summarise the evidence from a series of cohort studies that have assessed study publication bias and outcome reporting bias in randomised controlled trials. Sixteen studies were eligible of which only two followed the cohort all the way through from protocol approval to information regarding publication of outcomes. Eleven of the studies investigated study publication bias and five investigated outcome reporting bias. Three studies have found that statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). In comparing trial publications to protocols, we found that 40-62% of studies had at least one primary outcome that was changed, introduced, or omitted. We decided not to undertake meta-analysis due to the differences between studies.Recent work provides direct empirical evidence for the existence of study publication bias and outcome reporting bias. There is strong evidence of an association between significant results and publication; studies that report positive or significant results are more likely to be published and outcomes that are statistically significant have higher odds of being fully reported. Publications have been found to be inconsistent with their protocols. Researchers need to be aware of the problems of both types of bias and efforts should be concentrated on improving the reporting of trials.

    View details for DOI 10.1371/journal.pone.0003081

    View details for Web of Science ID 000264796600003

    View details for PubMedID 18769481

  • Effect of formal statistical significance on the credibility of observational associations AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2008; 168 (4): 374-383

    Abstract

    The author evaluated the implications of nominal statistical significance for changing the credibility of null versus alternative hypotheses across a large number of observational associations for which formal statistical significance (p < 0.05) was claimed. Calculation of the Bayes factor (B) under different assumptions was performed on 272 observational associations published in 2004-2005 and a data set of 50 meta-analyses on gene-disease associations (752 studies) for which statistically significant associations had been claimed (p < 0.05). Depending on the formulation of the prior, statistically significant results offered less than strong support to the credibility (B > 0.10) for 54-77% of the 272 epidemiologic associations for diverse risk factors and 44-70% of the 50 associations from genetic meta-analyses. Sometimes nominally statistically significant results even decreased the credibility of the probed association in comparison with what was thought before the study was conducted. Five of six meta-analyses with less than substantial support (B > 0.032) lost their nominal statistical significance in a subsequent (more recent) meta-analysis, while this did not occur in any of seven meta-analyses with decisive support (B < 0.01). In these large data sets of observational associations, formal statistical significance alone failed to increase much the credibility of many postulated associations. Bayes factors may be used routinely to interpret "significant" associations.

    View details for DOI 10.1093/aje/kwn156

    View details for Web of Science ID 000258329700004

    View details for PubMedID 18611956

  • Measuring Co-Authorship and Networking-Adjusted Scientific Impact PLOS ONE Ioannidis, J. P. 2008; 3 (7)

    Abstract

    Appraisal of the scientific impact of researchers, teams and institutions with productivity and citation metrics has major repercussions. Funding and promotion of individuals and survival of teams and institutions depend on publications and citations. In this competitive environment, the number of authors per paper is increasing and apparently some co-authors don't satisfy authorship criteria. Listing of individual contributions is still sporadic and also open to manipulation. Metrics are needed to measure the networking intensity for a single scientist or group of scientists accounting for patterns of co-authorship. Here, I define I(1) for a single scientist as the number of authors who appear in at least I(1) papers of the specific scientist. For a group of scientists or institution, I(n) is defined as the number of authors who appear in at least I(n) papers that bear the affiliation of the group or institution. I(1) depends on the number of papers authored N(p). The power exponent R of the relationship between I(1) and N(p) categorizes scientists as solitary (R>2.5), nuclear (R = 2.25-2.5), networked (R = 2-2.25), extensively networked (R = 1.75-2) or collaborators (R<1.75). R may be used to adjust for co-authorship networking the citation impact of a scientist. I(n) similarly provides a simple measure of the effective networking size to adjust the citation impact of groups or institutions. Empirical data are provided for single scientists and institutions for the proposed metrics. Cautious adoption of adjustments for co-authorship and networking in scientific appraisals may offer incentives for more accountable co-authorship behaviour in published articles.

    View details for DOI 10.1371/journal.pone.0002778

    View details for Web of Science ID 000264302900048

    View details for PubMedID 18648663

  • Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database NATURE GENETICS Allen, N. C., Bagade, S., McQueen, M. B., Ioannidis, J. P., Kavvoura, F. K., Khoury, M. J., Tanzi, R. E., Bertram, L. 2008; 40 (7): 827-834

    Abstract

    In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.

    View details for DOI 10.1038/ng.171

    View details for Web of Science ID 000257166500015

    View details for PubMedID 18583979

  • Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: The case of rosiglitazone AMERICAN HEART JOURNAL Hernandez, A. V., Walker, E., Ioannidis, J. P., Kattan, M. W. 2008; 156 (1): 23-30

    Abstract

    Rare cardiovascular events of commonly used drugs are important to document and investigate, but single trials are notoriously underpowered to provide conclusive evidence. Recently, meta-analyses have been used to improve on the power. A recent rosiglitazone meta-analysis heightened the debate about the usefulness and limitations of meta-analysis in this setting. In this review, we examined the methods used in previous published meta-analyses for harmful cardiovascular events, with special attention to the rosiglitazone meta-analyses, and give suggestions for the improvement of methods and interpretation of such meta-analyses. The conduct of meta-analysis in this context is particularly difficult and requires timely investigation, availability of high-quality data on harms, and statistical expertise. There are important decisions that need to be made about selecting the appropriate analytical methods and performing sensitivity analyses to evaluate whether the results are robust to different analytical choices.

    View details for DOI 10.1016/j.ahj.2008.03.002

    View details for Web of Science ID 000257329900004

    View details for PubMedID 18585493

  • Perfect study, poor evidence: Interpretation of biases preceding study design SEMINARS IN HEMATOLOGY Ioannidis, J. P. 2008; 45 (3): 160-166

    Abstract

    In the interpretation of research evidence, data that have been accumulated in a specific isolated study are typically examined. However, important biases may precede the study design. A study may be misleading, useless, or even harmful, even though it seems to be perfectly designed, conducted, analyzed, and reported. Some biases pertain to setting the wider research agenda and include poor scientific relevance, minimal clinical utility, or failure to consider prior evidence (non-consideration of prior evidence, biased consideration of prior evidence, or consideration of biased prior evidence). Other biases reflect issues in setting the specific research questions: examples include straw man effects, avoidance of head-to-head comparisons, head-to-head comparisons bypassing demonstration of effectiveness, overpowered studies, unilateral aims (focusing on benefits and neglecting harms), and the approach of the industry towards research as bulk advertisement (including ghost management of the literature). The concerted presence of such biases may have a multiplicative, detrimental impact on the scientific literature. These issues should be considered carefully when interpreting research results.

    View details for DOI 10.1053/j.seminhematol.2008.04.010

    View details for Web of Science ID 000257501600005

    View details for PubMedID 18582622

  • Interpretation of research results: An indispensable mission impossible? SEMINARS IN HEMATOLOGY Ioannidis, J. P. 2008; 45 (3): 133-134

    View details for DOI 10.1053/j.seminhematol.2008.04.009

    View details for Web of Science ID 000257501600001

    View details for PubMedID 18582618

  • Reasons or excuses for avoiding meta-analysis in forest plots. BMJ (Clinical research ed.) Ioannidis, J. P., Patsopoulos, N. A., Rothstein, H. R. 2008; 336 (7658): 1413-1415

    View details for DOI 10.1136/bmj.a117

    View details for PubMedID 18566080

  • Doctors' versus patients' global assessments of treatment effectiveness: empirical survey of diverse treatments in clinical trials BRITISH MEDICAL JOURNAL Evangelou, E., Tsianos, G., Ioannidis, J. P. 2008; 336 (7656): 1287-?

    Abstract

    To examine whether doctors' global assessments of treatment effects agree with patients' global assessments.Survey of trials included in systematic reviews of treatments for diverse conditions.Cochrane database of systematic reviews. Data extracted Data on patients' global assessments and on doctors' global assessment for the same treatment against the same comparator.Relative odds ratio (ratio of odds ratios of global improvement with the experimental intervention versus control according to doctors compared with patients), and improvement rates according to doctors and patients.Doctors' global assessments were compared with patients' global assessments for 63 different treatment comparisons (240 trials) in 18 conditions. The summary relative odds ratio across the comparisons was not significant (0.98, 95% confidence interval 0.88 to 1.08; I(2)=0%, 95% confidence interval 0% to 30%). In 62 of the 63 comparisons the effects of treatment rated by patients and by doctors did not differ beyond chance, but for single comparisons the confidence intervals were large. Rates of improvement on average did not differ between doctors' assessments and patients' assessments (summary relative odds ratio 0.98, 0.88 to 1.06; I(2)=0%, 0% to 24%).Doctors' global assessments of the effects of treatments are on average similar to those of patients.

    View details for DOI 10.1136/bmj.39560.759572.BE

    View details for Web of Science ID 000256705900032

    View details for PubMedID 18495634

  • Evaluation of networks of randomized trials STATISTICAL METHODS IN MEDICAL RESEARCH Salanti, G., Higgins, J. P., Ades, A. E., Ioannidis, J. P. 2008; 17 (3): 279-301

    Abstract

    Randomized trials may be designed and interpreted as single experiments or they may be seen in the context of other similar or relevant evidence. The amount and complexity of available randomized evidence vary for different topics. Systematic reviews may be useful in identifying gaps in the existing randomized evidence, pointing to discrepancies between trials, and planning future trials. A new, promising, but also very much debated extension of systematic reviews, mixed treatment comparison (MTC) meta-analysis, has become increasingly popular recently. MTC meta-analysis may have value in interpreting the available randomized evidence from networks of trials and can rank many different treatments, going beyond focusing on simple pairwise-comparisons. Nevertheless, the evaluation of networks also presents special challenges and caveats. In this article, we review the statistical methodology for MTC meta-analysis. We discuss the concept of inconsistency and methods that have been proposed to evaluate it as well as the methodological gaps that remain. We introduce the concepts of network geometry and asymmetry, and propose metrics for the evaluation of the asymmetry. Finally, we discuss the implications of inconsistency, network geometry and asymmetry in informing the planning of future trials.

    View details for DOI 10.1177/0962280207080643

    View details for Web of Science ID 000257244300006

    View details for PubMedID 17925316

  • Inflated numbers of authors over time have not been just due to increasing research complexity JOURNAL OF CLINICAL EPIDEMIOLOGY Papatheodorou, S. I., Trikalinos, T. A., Ioannidis, J. P. 2008; 61 (6): 546-551

    Abstract

    To examine trends in and determinants of the number of authors in clinical studies.We analyzed determinants of the number of authors in 633 articles of randomized trials and 313 articles of nonrandomized studies included in large meta-analyses (seven and six topics, respectively). Analyses were adjusted for topic. We also evaluated 310 randomly sampled case reports that had an abstract and described a single case.After adjusting for topic and other determinants, for both randomized trials and nonrandomized studies, the number of authors increased by 0.8 per decade (P<0.001). Topic was a strong determinant of the number of authors; other independent factors included journal impact factor, multinational authorship, and (for randomized trials) article length and sample size. Trials from South Europe (+1.1 authors) and North America (+0.9) and nonrandomized studies from South Europe (+1.8) had more authors than studies from North Europe (P<0.001). For case reports, only geographic location and article length were significantly related with author numbers.The number of authors in articles of randomized and nonrandomized studies has increased over time, even after adjusting for the topic, size, and visibility of a study. The academic coinage of authorship may be suffering from inflation.

    View details for DOI 10.1016/j.jclinepi.2007.07.017

    View details for Web of Science ID 000256164700006

    View details for PubMedID 18471658

  • F-18-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: A meta-analysis JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyzas, P. A., Evangelou, E., Denaxa-Kyza, D., Ioannidis, J. P. 2008; 100 (10): 712-720

    Abstract

    Positron emission tomography using 18F-fluorodeoxyglucose (18F-FDG PET) has been proposed to enhance preoperative assessment of cervical lymph node status in patients with head and neck squamous cell carcinoma (HNSCC). Management is most controversial for patients with a clinically negative (cN0) neck. We aimed to assess the diagnostic accuracy of 18F-FDG PET in detecting lymph node metastases in patients with HNSCC.We performed a meta-analysis of all available studies of the diagnostic performance of 18F-FDG PET in patients with HNSCC. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves using hierarchical regression models. We also compared the performance of 18F-FDG PET with that of conventional diagnostic methods (ie, computed tomography, magnetic resonance imaging, and ultrasound with fine-needle aspiration) by analyzing studies that had also used these diagnostic methods on the same patients.Across 32 studies (1236 patients), 18F-FDG PET sensitivity was 79% (95% confidence interval [CI] = 72% to 85%) and specificity was 86% (95% CI = 83% to 89%). For cN0 patients, sensitivity of 18F-FDG PET was only 50% (95% CI = 37% to 63%), whereas specificity was 87% (95% CI = 76% to 93%). Overall, LR+ was 5.84 (95% CI = 4.59 to 7.42) and LR- was 0.24 (95% CI = 0.17 to 0.33). In studies in which both 18F-FDG PET and conventional diagnostic tests were performed, sensitivity and specificity of 18F-FDG PET were 80% and 86%, respectively, and of conventional diagnostic tests were 75% and 79%, respectively.18F-FDG PET has good diagnostic performance in the overall pretreatment evaluation of patients with HNSCC but still does not detect disease in half of the patients with metastasis and cN0.

    View details for DOI 10.1093/jnci/djn125

    View details for Web of Science ID 000256172400008

    View details for PubMedID 18477804

  • Reporting of human genome epidemiology (HuGE) association studies: An empirical assessment BMC MEDICAL RESEARCH METHODOLOGY Yesupriya, A., Evangelou, E., Kavvoura, F. K., Patsopoulos, N. A., Clyne, M., Walsh, M. C., Lin, B. K., Yu, W., Gwinn, M., Ioannidis, J. P., Khoury, M. J. 2008; 8

    Abstract

    Several thousand human genome epidemiology association studies are published every year investigating the relationship between common genetic variants and diverse phenotypes. Transparent reporting of study methods and results allows readers to better assess the validity of study findings. Here, we document reporting practices of human genome epidemiology studies.Articles were randomly selected from a continuously updated database of human genome epidemiology association studies to be representative of genetic epidemiology literature. The main analysis evaluated 315 articles published in 2001-2003. For a comparative update, we evaluated 28 more recent articles published in 2006, focusing on issues that were poorly reported in 2001-2003.During both time periods, most studies comprised relatively small study populations and examined one or more genetic variants within a single gene. Articles were inconsistent in reporting the data needed to assess selection bias and the methods used to minimize misclassification (of the genotype, outcome, and environmental exposure) or to identify population stratification. Statistical power, the use of unrelated study participants, and the use of replicate samples were reported more often in articles published during 2006 when compared with the earlier sample.We conclude that many items needed to assess error and bias in human genome epidemiology association studies are not consistently reported. Although some improvements were seen over time, reporting guidelines and online supplemental material may help enhance the transparency of this literature.

    View details for DOI 10.1186/1471-2288-8-31

    View details for Web of Science ID 000256664800001

    View details for PubMedID 18492284

  • Large-scale analysis of association between polymorphisms in the transfonning growth factor beta 1 gene (TGFB1) and osteoporosis: The GENOMOS study BONE Langdahl, B. L., Uitterlinden, A. G., Ralston, S. H., Trikalinos, T. A., Balcells, S., Brandi, M. L., Scollen, S., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Reid, D. M., Armas, J. B., Arp, P. P., Bassiti, A., Bustamante, M., Husted, L. B., Carey, A. H., Cano, R. P., Dobnig, H., Dunning, A. M., Fahrleitner-Pammer, A., Falchetti, A., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P., Masi, L., van Meurs, J. B., Mangion, J., McGuigan, F. E., Mellibovsky, L., Mosekilde, L., Nogues, X., Pols, H. A., Reeve, J., Renner, W., Rivadeneira, F., van Schoor, N. M., Ioannidis, J. P. 2008; 42 (5): 969-981

    Abstract

    The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results.We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures.There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05.This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.

    View details for DOI 10.1016/j.bone.2007.11.007

    View details for Web of Science ID 000255260100016

    View details for PubMedID 18284942

  • Falsified papers in high-impact journals were slow to retract and indistinguishable from nonfraudulent papers JOURNAL OF CLINICAL EPIDEMIOLOGY Trikalinos, N. A., Evangelou, E., Ioannidis, J. P. 2008; 61 (5): 464-470

    Abstract

    The aim was to evaluate papers retracted due to falsification in high-impact journals.We selected articles retracted due to allegations of falsification in January 1, 1980 to March 1, 2006 from journals with impact factor >10 and >30,000 annual citations. We evaluated characteristics of these papers and misconduct-involved authors and assessed whether they correlated with time to retraction. We also compared retracted articles vs. matched nonretracted articles in the same journals.Fourteen eligible journals had 63 eligible retracted articles. Median time from publication to retraction was 28 months; it was 79 months for articles where a senior researcher was implicated in the misconduct vs. 22 months when junior researchers were implicated (log-rank P<0.001). For the 25 implicated authors, the median time from the first publication of a fraudulent paper to the first retraction was 34 months, again with a clear difference according to researcher rank (log-rank P=0.001). Retracted articles didn't differ from matched nonretracted papers in citations received within 12 months, number of authors, country, funding, or field, but were twofold more likely to have multinational authorship (P=0.049).Retractions due to falsification can take a long time, especially when senior researchers are implicated. Fraudulent articles are not obviously distinguishable from nonfraudulent ones.

    View details for DOI 10.1016/j.jclinepi.2007.11.019

    View details for Web of Science ID 000254978200008

    View details for PubMedID 18394539

  • Genome-wide association studies for complex traits: consensus, uncertainty and challenges NATURE REVIEWS GENETICS McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P., Hirschhorn, J. N. 2008; 9 (5): 356-369

    Abstract

    The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.

    View details for DOI 10.1038/nrg2344

    View details for Web of Science ID 000255057300012

    View details for PubMedID 18398418

  • Exploring the geometry of treatment networks ANNALS OF INTERNAL MEDICINE Salanti, G., Kavvoura, F. K., Ioannidis, J. P. 2008; 148 (7): 544-553

    Abstract

    Several treatment options exist for many conditions. Randomized trial evidence on the relative merits of various options may be missing or biased.To examine the patterns of trial evidence (network geometry) and explain their implications for the interpretation of the existing evidence on a treatment's relative effectiveness.PubMed and Thompson ISI Web of Knowledge (last search April 2007).Published networks of randomized trials that included at least 4 treatments were identified.For each network, data on the number of studies per treatment comparison were extracted by one investigator and verified by a second investigator.Indices were adopted from the ecological literature that measure diversity (number of treatments and how often they were tested) and co-occurrence (whether some treatment comparisons were preferred and others avoided). Eighteen eligible treatment networks were identified for different diseases, involving 4 to 16 alternative treatments and 10 to 84 trials. Networks in which 1 option (placebo or no treatment) was the typical comparator were star-shaped, even though several treatments might have had proven effectiveness. Other networks had different shapes. Some showed important co-occurrence that avoided specific head-to-head comparisons. Comparison choices sometimes seemed justified, such as when newer treatments were not compared with older ones already shown to be inferior, whereas other choices seemed to reflect preference bias.Networks evolve over time as new trials accumulate, and their geometry may change. Statistical testing for co-occurrence is underpowered when few trials exist.Evaluation of the geometry of a treatment network can offer valuable insights for the interpretation of total evidence when many treatment options are available.

    View details for Web of Science ID 000254701000007

    View details for PubMedID 18378949

  • KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease - Introduction KIDNEY INTERNATIONAL Alpers, C., Bloom, R. D., Fabrizi, F., Izopet, J., Jadoul, M., Lindley, E., Martin, P., Morales, J. M., Natov, S., Pol, S., Reddy, K. R., Rostaing, L., Roth, D., Wei, L., Alter, M., Lavanchy, D., Meyers, C., Seeff, L., Eknoyan, G., Lameire, N., Balk, E., Craig, J., Earley, A., Gordon, C., Ioannidis, J., Jadoul, M., Roth, D. 2008; 73: S6-S99

    View details for DOI 10.1038/ki.2008.83

    View details for Web of Science ID 000254559200002

  • Percutaneous coronary intervention after myocardial infarction and the late open artery hypothesis AMERICAN HEART JOURNAL Ioannidis, J. P., Katritsis, D. G. 2008; 155 (4)

    View details for DOI 10.1016/j.ahj.2007.12.030

    View details for Web of Science ID 000254808100038

  • Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION van Meurs, J. B., Trikalinos, T. A., Ralston, S. H., Balcells, S., Brandi, M. L., Brixen, K., Kiel, D. P., Langdahl, B. L., Lips, P., Ljunggren, O., Lorenc, R., Obermayer-Pietsch, B., Ohlsson, C., Pettersson, U., Reid, D. M., Rousseau, F., Scollen, S., Van Hul, W., Agueda, L., Akesson, K., Benevolenskaya, L. I., Ferrari, S. L., Hallmans, G., Hofman, A., Husted, L. B., Kruk, M., Kaptoge, S., Karasik, D., Karlsson, M. K., Lorentzon, M., Masi, L., McGuigan, F. E., Mellstrom, D., Mosekilde, L., Nogues, X., Pols, H. A., Reeve, J., Renner, W., Rivadeneira, F., van Schoor, N. M., Weber, K., Ioannidis, J. P., Uitterlinden, A. G. 2008; 299 (11): 1277-1290

    Abstract

    Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

    View details for Web of Science ID 000254079100019

    View details for PubMedID 18349089

  • Assessment of cumulative evidence on genetic associations: interim guidelines INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Boffetta, P., Little, J., O'Brien, T. R., Uitterlinden, A. G., Vineis, P., Balding, D. J., Chokkalingam, A., Dolan, S. M., Flanders, W. D., Higgins, J. P., McCarthy, M. I., McDermott, D. H., Page, G. P., Rebbeck, T. R., Seminara, D., Khoury, M. J. 2008; 37 (1): 120-132

    Abstract

    Established guidelines for causal inference in epidemiological studies may be inappropriate for genetic associations. A consensus process was used to develop guidance criteria for assessing cumulative epidemiologic evidence in genetic associations. A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility. In addition, we discuss how additional input and guidance can be derived from biological data. Future empirical research and consensus development are needed to develop an integrated model for combining epidemiological and biological evidence in the rapidly evolving field of investigation of genetic factors.

    View details for DOI 10.1093/ije/dym159

    View details for Web of Science ID 000252906600022

    View details for PubMedID 17898028

  • Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls HUMAN GENETICS Kavvoura, F. K., Ioannidis, J. P. 2008; 123 (1): 1-14

    Abstract

    Meta-analysis offers the opportunity to combine evidence from retrospectively accumulated or prospectively generated data. Meta-analyses may provide summary estimates and can help in detecting and addressing potential inconsistency between the combined datasets. Application of meta-analysis in genetic associations presents considerable potential and several pitfalls. In this review, we present basic principles of meta-analytic methods, adapted for human genome epidemiology. We describe issues that arise in the retrospective or the prospective collection of relevant data through various sources, common traps to consider in the appraisal of evidence and potential biases that may interfere. We describe the relative merits and caveats for common methods used to trace inconsistency across studies along with possible reasons for non-replication of proposed associations. Different statistical models may be employed to combine data and some common misconceptions may arise in the process. Several meta-analysis diagnostics are often applied or misapplied in the literature, and we comment on their use and limitations. An alternative to overcome limitations arising from retrospective combination of data from published studies is to create networks of research teams working in the same field and perform collaborative meta-analyses of individual participant data, ideally on a prospective basis. We discuss the advantages and the challenges inherent in such collaborative approaches. Meta-analysis can be a useful tool in dissecting the genetics of complex diseases and traits, provided its methods are properly applied and interpreted.

    View details for DOI 10.1007/s00439-007-0445-9

    View details for Web of Science ID 000252799200001

    View details for PubMedID 18026754

  • Meta-analysis for ranked discovery datasets: theoretical framework and empirical demonstration for microarrays. Computational biology and chemistry Zintzaras, E., Ioannidis, J. P. 2008; 32 (1): 38-46

    Abstract

    The combination of results from different large-scale datasets of multidimensional biological signals (such as gene expression profiling) presents a major challenge. Methodologies are needed that can efficiently combine diverse datasets, but can also test the extent of diversity (heterogeneity) across the combined studies. We developed METa-analysis of RAnked DISCovery datasets (METRADISC), a generalized meta-analysis method for combining information across discovery-oriented datasets and for testing between-study heterogeneity for each biological variable of interest. The method is based on non-parametric Monte Carlo permutation testing. The tested biological variables are ranked in each study according to the level of statistical significance. METRADISC tests for each biological variable of interest its average rank and the between-study heterogeneity of the study-specific ranks. After accounting for ties and differences in tested variables across studies, we randomly permute the ranks of each study and the simulated metrics of average rank and heterogeneity are calculated. The procedure is repeated to generate null distributions for the metrics. The use of METRADISC is demonstrated empirically using gene expression data from seven studies comparing prostate cancer cases and normal controls. We offer a new tool for combining complex datasets derived from massive testing, discovery-oriented research and for examining the diversity of results across the combined studies.

    View details for PubMedID 17988949

  • EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics ANNALS OF THE RHEUMATIC DISEASES Bertsias, G., Ioannidis, J. P., Boletis, J., Bombardieri, S., Cervera, R., Dostal, C., Font, J., Gilboe, I. M., Houssiau, F., Huizinga, T., Isenberg, D., Kallenberg, C. G., Khamashta, M., Piette, J. C., Schneider, M., Smolen, J., Sturfelt, G., Tincani, A., van Vollenhoven, R., Gordon, C., Boumpas, D. T. 2008; 67 (2): 195-205

    Abstract

    Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE.The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists.Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10.Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.

    View details for DOI 10.1136/ard.2007.070367

    View details for Web of Science ID 000252301700010

    View details for PubMedID 17504841

  • Meta-analysis for ranked discovery datasets: Theoretical framework and empirical demonstration for microarrays COMPUTATIONAL BIOLOGY AND CHEMISTRY Zintzaras, E., Ioannidis, J. P. 2008; 32 (1): 39-47

    View details for DOI 10.1016/j.compbiolchem.2007.09.003

    View details for Web of Science ID 000253028600005

  • Required sample size and nonreplicability thresholds for heterogeneous genetic associations PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Moonesinghe, R., Khoury, M. J., Liu, T., Ioannidis, J. P. 2008; 105 (2): 617-622

    Abstract

    Many gene-disease associations proposed to date have not been consistently replicated across different populations. Nonreplication often reflects false positives in the original claims. However, occasionally, nonreplication may be due to heterogeneity due to biases or even genuine diversity of the genetic effects in different populations. Here, we propose methods for estimating the required sample size to replicate an association across many studies with different amounts of between-study heterogeneity, when data are summarized through metaanalysis. We demonstrate thresholds of between-study heterogeneity (tau(0)(2)) above which one cannot reach adequate power to replicate a proposed association at a specified level of statistical significance when k studies are performed (regardless of how large these studies are). Based on empirical evidence from 91 proposed gene-disease associations (50 on candidate genes and 41 from genome-wide association efforts), the observed between-study heterogeneity is often close to or even surpasses nonreplicability thresholds. With more modest between-study heterogeneity, the required sample size increases considerably compared with when no between-study heterogeneity exists. Increases are steep as tau(0)(2) is approached. Therefore, some true associations may not be practically possible to replicate with consistency, no matter how large studies are conducted. Efforts should be made to minimize between-study heterogeneity in targeted genetic effects.

    View details for DOI 10.1073/pnas.0705554105

    View details for Web of Science ID 000252551100041

    View details for PubMedID 18174335

  • Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials? Philosophy, ethics, and humanities in medicine : PEHM Ioannidis, J. P. 2008; 3: 14-?

    Abstract

    Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval). However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second meta-analysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted reporting of results has built and nourished a seemingly evidence-based myth on antidepressant effectiveness and how higher evidence standards, with very large long-term trials and careful prospective meta-analyses of individual-level data may reach closer to the truth and clinically useful evidence.

    View details for DOI 10.1186/1747-5341-3-14

    View details for PubMedID 18505564

  • Meta-Analysis Methods GENETIC DISSECTION OF COMPLEX TRAITS, 2ND EDITION Trikalinos, T. A., Salanti, G., Zintzaras, E., Ioannidis, J. P. 2008; 60: 311-334

    Abstract

    Meta-analysis is the quantitative synthesis of information from several studies. It is applicable to a variety of study designs in genetics, from family-based linkage studies and population-based association studies to genome-wide scans and genome-wide association studies. By combining relevant evidence from many studies, statistical power is increased and more precise estimates may be obtained. Most importantly, meta-analysis provides a framework for the appreciation and assessment of between-study heterogeneity, that is, the methodological, epidemiological, clinical, and biological dissimilarity across the various studies. Being a retrospective research design in most cases, meta-analysis is subject to a variety of selection biases that may undermine its validity. A major challenge is to differentiate genuine between-study heterogeneity from systematic errors and biases.

    View details for DOI 10.1016/S0065-2660(07)00413-0

    View details for Web of Science ID 000280575900015

    View details for PubMedID 18358326

  • Nested Randomized trials in large cohorts and biobanks - Studying the health effects of lifestyle factors EPIDEMIOLOGY Ioannidis, J. P., Adami, H. 2008; 19 (1): 75-82

    Abstract

    Most diseases are likely to result largely from the interplay of lifestyle and genetic factors. However, both observational studies and randomized trials have faced major limitations in trying to address the impact of lifestyle on health. As large cohorts and biobanks are being developed, we need to find novel, efficient ways to address the effects of lifestyle interventions. We propose that this could be done using multiple lifestyle factorial experimental designs that combine characteristics of randomized trials and epidemiologic studies. Randomized trials of simple lifestyle interventions can be nested within large cohorts linked to reliable registries of outcomes. Participants can choose from a long list of simple lifestyle randomization options and many interventions may be tested concurrently with factorial randomization. Participants can tailor their own personal trial choosing several items among long laundry lists of randomization options. Participants are citizen-scientists rather than passive subjects and this may be attractive in modern societies of health-conscious people. These trials can use the existing machinery of the cohort for data collection and outcome linkage at no or minimal additional cost. We discuss a number of issues on the implementation of multiple lifestyle factorial experimental designs, as compared with the usual observational studies and randomized trials. These include participation, the number of allowed randomizations per participant, compliance/adherence, power, false-negatives, false-positives, composite lifestyle effects, selection of outcomes, follow-up and monitoring, masking and allocation concealment, age of participants, confounding, and cost. The aim should be to combine carefully the strengths of both observational epidemiology and randomized research without compounding their limitations.

    View details for DOI 10.1097/EDE.0b013e31815be01c

    View details for Web of Science ID 000251889400013

    View details for PubMedID 18090999

  • Some main problems eroding the credibility and relevance of randomized trials. Bulletin of the NYU hospital for joint diseases Ioannidis, J. P. 2008; 66 (2): 135-139

    Abstract

    Randomized trials are an excellent research design with major advantages. However, randomized trials are not immune to biases, and inferences from them may be sometimes flawed or irrelevant. The present review addresses, in brief, some of the major threats to the credibility and relevance of the results of clinical trials: power problems, biases affecting internal validity (poor design, conduct, and analysis), biases affecting the total randomized evidence on a specific topic (publication bias and selective outcome and analysis reporting bias), lack of relevance, poor generalizability, and biases in the interpretation of the results.

    View details for PubMedID 18537784

  • Claims of sex-gene interactions - Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Patsopoulos, N. A., Tatsioni, A., Ioannidis, J. P. 2007; 298 (23): 2742-2742

    View details for Web of Science ID 000251716000018

  • Persistence of contradicted claims in the literature JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tatsioni, A., Bonitsis, N. G., Ioannidis, J. P. 2007; 298 (21): 2517-2526

    Abstract

    Some research findings based on observational epidemiology are contradicted by randomized trials, but may nevertheless still be supported in some scientific circles.To evaluate the change over time in the content of citations for 2 highly cited epidemiological studies that proposed major cardiovascular benefits associated with vitamin E in 1993; and to understand how these benefits continued being defended in the literature, despite strong contradicting evidence from large randomized clinical trials (RCTs). To examine the generalizability of these findings, we also examined the extent of persistence of supporting citations for the highly cited and contradicted protective effects of beta-carotene on cancer and of estrogen on Alzheimer disease.For vitamin E, we sampled articles published in 1997, 2001, and 2005 (before, early, and late after publication of refuting evidence) that referenced the highly cited epidemiological studies and separately sampled articles published in 2005 and referencing the major contradicting RCT (HOPE trial). We also sampled articles published in 2006 that referenced highly cited articles proposing benefits associated with beta-carotene for cancer (published in 1981 and contradicted long ago by RCTs in 1994-1996) and estrogen for Alzheimer disease (published in 1996 and contradicted recently by RCTs in 2004).The stance of the citing articles was rated as favorable, equivocal, and unfavorable to the intervention. We also recorded the range of counterarguments raised to defend effectiveness against contradicting evidence.For the 2 vitamin E epidemiological studies, even in 2005, 50% of citing articles remained favorable. A favorable stance was independently less likely in more recent articles, specifically in articles that also cited the HOPE trial (odds ratio for 2001, 0.05 [95% confidence interval, 0.01-0.19; P < .001] and the odds ratio for 2005, 0.06 [95% confidence interval, 0.02-0.24; P < .001], as compared with 1997), and in general/internal medicine vs specialty journals. Among articles citing the HOPE trial in 2005, 41.4% were unfavorable. In 2006, 62.5% of articles referencing the highly cited article that had proposed beta-carotene and 61.7% of those referencing the highly cited article on estrogen effectiveness were still favorable; 100% and 96%, respectively, of the citations appeared in specialty journals; and citations were significantly less favorable (P = .001 and P = .009, respectively) when the major contradicting trials were also mentioned. Counterarguments defending vitamin E or estrogen included diverse selection and information biases and genuine differences across studies in participants, interventions, cointerventions, and outcomes. Favorable citations to beta-carotene, long after evidence contradicted its effectiveness, did not consider the contradicting evidence.Claims from highly cited observational studies persist and continue to be supported in the medical literature despite strong contradictory evidence from randomized trials.

    View details for Web of Science ID 000251361900017

    View details for PubMedID 18056905

  • Percutaneous coronary intervention for late reperfusion after myocardial infarction in stable patients AMERICAN HEART JOURNAL Ioannidis, J. P., Katritsis, D. G. 2007; 154 (6): 1065-1071

    Abstract

    Results of randomized trials that have compared mechanical coronary artery recanalization versus medical therapy for total occlusion late after myocardial infarction (MI) have been conflicting.We performed a meta-analysis of randomized trials comparing percutaneous coronary intervention (PCI) with medical therapy in stable patients with an occluded artery 1 to 45 days after MI. Six trials and one substudy were included with data on 2617 patients for the clinical outcomes and 653 patients for determination of ejection fraction (EF) during follow-up. Outcomes included death, MI, death or MI, congestive heart failure (CHF), and change in left ventricular EF.There were no statistically significant differences for any clinical outcome, with trends for an increase in MI (risk ratio 1.26, P = .19) and decrease in CHF (risk ratio 0.67, P = .19) in the PCI arm. The PCI arm showed a slight superiority in left ventricular EF (2%, 95% CI 0.1%-2.8%). Early smaller studies showed formally statistically significant benefits for CHF and EF, but the much larger Occluded Artery Trial and Total Occlusion Study of Canada 2 found no benefit. For CHF, the difference between early smaller studies and Occluded Artery Trial was beyond chance (P = .02).Percutaneous coronary intervention does not seem to confer any benefits when used for late revascularization of occluded arteries after MI in stable patients.

    View details for DOI 10.1016/j.ahj.2007.07.049

    View details for Web of Science ID 000251396200010

    View details for PubMedID 18035076

  • Osteomyelitis: Antigranulocyte scintigraphy with Tc-99m radiolabeled monoclonal antibodies for diagnosis-meta-analysis RADIOLOGY Pakos, E. E., Koumoulis, H. D., Fotopoulos, A. D., Ioannidis, J. P. 2007; 245 (3): 732-741

    Abstract

    To perform a meta-analysis of the sensitivity and specificity of antigranulocyte scintigraphy with monoclonal antibodies (MoAbs) in the diagnosis of osteomyelitis across different patient groups and clinical settings.MEDLINE and EMBASE searches were conducted. Data on the diagnostic performance of antigranulocyte scintigraphy with MoAbs were combined. Weighted sensitivities and specificities were estimated by using a random-effects model that incorporated between-study heterogeneity and by constructing summary receiver operating characteristic (ROC) curves. The weighted positive and negative likelihood ratios (LRs) across studies were estimated. Data syntheses were performed for all patients and for various subgroups. The reference standard used in each individual study was accepted.Nineteen nonoverlapping studies with a total of 714 examinations and reference standards of cell culture, histologic examination, clinical follow-up, and radiologic examination were eligible. The independent random-effects summary estimates of sensitivity and specificity were 81% (95% confidence interval [CI]: 70%, 88%) and 77% (95% CI: 66%, 86%), respectively, with statistically significant between-study heterogeneity (exact P < .001 for both metrics). In the summary ROC curve, a sensitivity of 81% corresponded to a specificity of 86%, and a specificity of 77% corresponded to a sensitivity of 87%. The weighted positive LR was 3.02 (95% CI: 2.07, 4.42), and the weighted negative LR was 0.26 (95% CI: 0.17, 0.39), with statistically significant between-study heterogeneity (exact P < .001 for both metrics). Sensitivity was better for peripheral than for axial skeleton lesions (87% vs 53%).Antigranulocyte scintigraphy with MoAbs has a sensitivity of 81% and a specificity of 77% in the diagnosis of osteomyelitis.

    View details for DOI 10.1148/radiol.2452061877

    View details for Web of Science ID 000251070700014

    View details for PubMedID 17898328

  • Uncertainty in heterogeneity estimates in meta-analyses BRITISH MEDICAL JOURNAL Ioannidis, J. P., Patsopoulos, N. A., Evangelou, E. 2007; 335 (7626): 914-916

    View details for Web of Science ID 000250848300029

    View details for PubMedID 17974687

  • Almost all articles on cancer prognostic markers report statistically significant results EUROPEAN JOURNAL OF CANCER Kyzas, P. A., Denaxa-Kyza, D., Ioannidis, J. P. 2007; 43 (17): 2559-2579

    Abstract

    We aimed to understand the extent of the pursuit for statistically significant results in the prognostic literature of cancer. We evaluated 340 articles included in prognostic marker meta-analyses (Database 1) and 1575 articles on cancer prognostic markers published in 2005 (Database 2). For each article, we examined whether the abstract reported any statistically significant prognostic effect for any marker and any outcome ('positive' articles). 'Negative' articles were further examined for statements made by the investigators to overcome the absence of prognostic statistical significance. We also examined how the articles of Database 1 had presented the relative risks that were included in the respective meta-analyses. 'Positive' prognostic articles comprised 90.6% and 95.8% in Databases 1 and 2, respectively. Most of the 'negative' prognostic articles claimed significance for other analyses, expanded on non-significant trends or offered apologies that were occasionally remote from the original study aims. Only five articles in Database 1 (1.5%) and 21 in Database 2 (1.3%) were fully 'negative' for all presented results in the abstract and without efforts to expand on non-significant trends or to defend the importance of the marker with other arguments. Of the statistically non-significant relative risks in the meta-analyses, 25% had been presented as statistically significant in the primary papers using different analyses compared with the respective meta-analysis. We conclude that almost all articles on cancer prognostic marker studies highlight some statistically significant results. Under strong reporting bias, statistical significance loses its discriminating ability for the importance of prognostic markers.

    View details for DOI 10.1016/j.ejca.2007.08.030

    View details for Web of Science ID 000251706000027

    View details for PubMedID 17981458

  • International ranking systems for universities and institutions: a critical appraisal BMC MEDICINE Ioannidis, J. P., Patsopoulos, N. A., Kavvoura, F. K., Tatsioni, A., Evangelou, E., Kouri, I., Contopoulos-Ioannidis, D. G., Liberopoulos, G. 2007; 5

    Abstract

    Ranking of universities and institutions has attracted wide attention recently. Several systems have been proposed that attempt to rank academic institutions worldwide.We review the two most publicly visible ranking systems, the Shanghai Jiao Tong University 'Academic Ranking of World Universities' and the Times Higher Education Supplement 'World University Rankings' and also briefly review other ranking systems that use different criteria. We assess the construct validity for educational and research excellence and the measurement validity of each of the proposed ranking criteria, and try to identify generic challenges in international ranking of universities and institutions.None of the reviewed criteria for international ranking seems to have very good construct validity for both educational and research excellence, and most don't have very good construct validity even for just one of these two aspects of excellence. Measurement error for many items is also considerable or is not possible to determine due to lack of publication of the relevant data and methodology details. The concordance between the 2006 rankings by Shanghai and Times is modest at best, with only 133 universities shared in their top 200 lists. The examination of the existing international ranking systems suggests that generic challenges include adjustment for institutional size, definition of institutions, implications of average measurements of excellence versus measurements of extremes, adjustments for scientific field, time frame of measurement and allocation of credit for excellence.Naïve lists of international institutional rankings that do not address these fundamental challenges with transparent methods are misleading and should be abandoned. We make some suggestions on how focused and standardized evaluations of excellence could be improved and placed in proper context.

    View details for DOI 10.1186/1741-7015-5-30

    View details for Web of Science ID 000252409300001

    View details for PubMedID 17961208

  • Turning the pump handle: Evolving methods for integrating the evidence on gene-disease association AMERICAN JOURNAL OF EPIDEMIOLOGY Higgins, J. P., Little, J., Ioannidis, J. P., Bray, M. S., Manolio, T. A., Smeeth, L., Sterne, J. A., Anagnostelis, B., Butterworth, A. S., Danesh, J., Dezateux, C., Gallacher, J. E., Gwinn, M., Lewis, S. J., Minelli, C., Pharoah, P. D., Salanti, G., Sanderson, S., Smith, L. A., Taioli, E., Thompson, J. R., Thompson, S. G., Walker, N., Zimmern, R. L., Khoury, M. J. 2007; 166 (8): 863-866

    View details for DOI 10.1093/aje/kwm248

    View details for Web of Science ID 000250143200001

    View details for PubMedID 17804859

  • Effects of glycoprotein IIb/IIIa blockers - Reply HEART Hernandez, A. V., Westerhout, C. M., Steyerberg, E. W., Ioannidis, J. P., Bueno, H., White, H., Theroux, P., Moliterno, D. J., Armstrong, P. W., Califf, R. M., Wallentin, L. C., Simoons, M. L., Boersma, E. 2007; 93 (10): 1293-1293

    View details for Web of Science ID 000249621500027

  • Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level BIOLOGICAL PSYCHIATRY Stefanis, N. C., Trikalinos, T. A., Avramopoulos, D., Smyrnis, N., Evdokimidis, I., Ntzani, E. E., Ioannidis, J. P., Stefanis, C. N. 2007; 62 (7): 784-792

    Abstract

    Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia.We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated.The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected.The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.

    View details for DOI 10.1016/j.biopsych.2006.11.015

    View details for Web of Science ID 000249511500010

    View details for PubMedID 17336946

  • Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis LANCET ONCOLOGY Golfinopoulos, V., Salanti, G., Pavlidis, N., Ioannidis, J. P. 2007; 8 (10): 898-911

    Abstract

    Many randomised trials have compared different systemic treatment regimens in patients with advanced colorectal cancer. While survival advances have apparently been achieved, the magnitude of these incremental benefits across diverse regimens is less clear. The aim of our study was to estimate the magnitude of survival and disease progression benefits with the use of different regimens in patients with advanced colorectal cancer.We systematically reviewed randomised trials comparing systemic treatment regimens in advanced colorectal cancer. Treatment was categorised by use of or no use of fluorouracil-based regimens, irinotecan, oxaliplatin, bevacizumab, and cetuximab. We used multiple-treatment meta-analysis methodology to combine information from direct comparisons (ie, treatments compared within a randomised trial) and indirect comparisons (ie, treatments compared between trials by combining results on how effective they are against a common comparator treatment) of different chemotherapy regimens. The primary endpoint was death and the secondary endpoint was disease progression. Monte Carlo simulations were used to establish which regimen offered the most benefit for these endpoints. We did analyses of all trials and analysed separately trials that studied first-line treatments and non-first-line treatments.242 trials published in 1967-2007 (N=56 677 patients) involved 137 different chemotherapy regimens. 37 of these trials were eligible for the multiple-treatment meta-analysis, according to our categorisation, including 47 comparisons of data on death (N=13 875 patients) and 48 comparisons of data on disease progression (N=15 158 patients). Compared with fluorouracil plus leucovorin alone, the risk of death was most decreased with the addition of irinotecan plus bevacizumab (hazard ratio [HR] 0.60, 95% credibility intervals (CrI) 0.44-0.84) and considerable benefits were also noted with addition of irinotecan plus oxaliplatin (HR 0.72 [95% CrI 0.54-0.97]); oxaliplatin plus bevacizumab (HR 0.72 [0.57-0.90]); bevacizumab alone (HR 0.78 [0.60-1.03]); and oxaliplatin alone (HR 0.87 [0.78-0.98]). The disease progression benefits were even more prominent for the addition of irinotecan plus bevacizumab (HR 0.41 [0.28-0.60]); irinotecan plus oxaliplatin (0.53 [0.38-0.73]); oxaliplatin plus bevacizumab (0.46 [0.34-0.61]); bevacizumab alone (0.56 [0.41-0.76]); oxaliplatin alone (0.64 [0.56-0.73]); irinotecan plus cetuximab (HR 0.62 [0.42-0.92]); and irinotecan alone (HR 0.73 [0.65-0.82]). Findings were similar for first-line and non-first-line treatment analyses although data were sparse for non-first-line treatment analyses. Compared with a patient with an anticipated 1-year survival who is treated with fluorouracil and leucovorin, the absolute survival benefit is estimated at 8 months' prolongation with addition of irinotecan plus bevacizumab, 4.7 months' prolongation with addition of oxaliplatin plus bevacizumab or irinotecan plus oxaliplatin, and 1-1.8 months' prolongation with addition of irinotecan alone or oxaliplatin alone.Distinct incremental benefits are noted for diverse chemotherapy regimens in patients with advanced colorectal cancer, with more prominent effects on disease progression than on death. More data are needed at least for the newest drugs to estimate more accurately the magnitude of the benefit derived from their use.

    View details for DOI 10.1016/S1470-2045(07)70281-4

    View details for Web of Science ID 000250249000028

    View details for PubMedID 17888735

  • Heterogeneity in Meta-Analyses of Genome-Wide Association Investigations PLOS ONE Ioannidis, J. P., Patsopoulos, N. A., Evangelou, E. 2007; 2 (9)

    Abstract

    Meta-analysis is the systematic and quantitative synthesis of effect sizes and the exploration of their diversity across different studies. Meta-analyses are increasingly applied to synthesize data from genome-wide association (GWA) studies and from other teams that try to replicate the genetic variants that emerge from such investigations. Between-study heterogeneity is important to document and may point to interesting leads.To exemplify these issues, we used data from three GWA studies on type 2 diabetes and their replication efforts where meta-analyses of all data using fixed effects methods (not incorporating between-study heterogeneity) have already been published. We considered 11 polymorphisms that at least one of the three teams has suggested as susceptibility loci for type 2 diabetes. The I2 inconsistency metric (measuring the amount of heterogeneity not due to chance) was different from 0 (no detectable heterogeneity) for 6 of the 11 genetic variants; inconsistency was moderate to very large (I2 = 32-77%) for 5 of them. For these 5 polymorphisms, random effects calculations incorporating between-study heterogeneity revealed more conservative p-values for the summary effects compared with the fixed effects calculations. These 5 associations were perused in detail to highlight potential explanations for between-study heterogeneity. These include identification of a marker for a correlated phenotype (e.g. FTO rs8050136 being associated with type 2 diabetes through its effect on obesity); differential linkage disequilibrium across studies of the identified genetic markers with the respective culprit polymorphisms (e.g., possibly the case for CDKAL1 polymorphisms or for rs9300039 and markers in linkage disequilibrium, as shown by additional studies); and potential bias. Results were largely similar, when we treated the discovery and replication data from each GWA investigation as separate studies.Between-study heterogeneity is useful to document in the synthesis of data from GWA investigations and can offer valuable insights for further clarification of gene-disease associations.

    View details for DOI 10.1371/journal.pone.0000841

    View details for Web of Science ID 000207455500024

    View details for PubMedID 17786212

  • Selective discussion and transparency in microarray research findings for cancer outcomes EUROPEAN JOURNAL OF CANCER Ioannidis, J. P., Polyzos, N. P., Trikalinos, T. A. 2007; 43 (13): 1999-2010

    Abstract

    We examined the interpretation of research findings and public availability of transparent information on data and processing for 46 articles of microarray studies that had addressed major cancer outcomes. Unsupervised and supervised methods selected molecular signatures with a median of 675 and 50 genes, respectively, but only a median of eight genes or groups thereof were further discussed. Across 479 genes or groups thereof discussed in all 46 studies, 65% reflected specific comments (reflecting external relevant data from other studies or other lines of reasoning relevant to the gene of interest), and 59% of the comments were referenced. Among specific comments, supportive ones outnumbered comments against the research findings by nine to one (270 versus 29). Discussion was similarly selective in early studies and in studies published in 2006. Even in 2006 only 10 of 15 studies had publicly deposited data. Only three studies had scanned images, raw and processed data available. Processing details varied. Public transparency and unbiased interpretation of findings can be improved in microarray research.

    View details for DOI 10.1016/j.ejca.2007.05.019

    View details for Web of Science ID 000250128300026

    View details for PubMedID 17629475

  • Genetic and molecular epidemiology JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Ioannidis, J. P. 2007; 61 (9): 757-758

    Abstract

    Genetic and molecular epidemiology covers a vast area of research. Given the rapid changes in this field, discussing a research agenda is a precarious and ambitious task. A representative set of high-priority concepts will be presented here, each of which alone could be the topic of a long series of essays. The wish list includes issues of full transparency and integration of information, dealing efficiently with complex multidimensional biology, juxtaposing the genome and environmental exposures, and using robust randomised trials to advance our knowledge and its application in this field.

    View details for DOI 10.1136/jech.2006.059055

    View details for Web of Science ID 000248743600003

    View details for PubMedID 17699527

  • Claims of sex differences - An empirical assessment in genetic associations JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Patsopoulos, N. A., Tatsioni, A., Ioannidis, J. P. 2007; 298 (8): 880-893

    Abstract

    Many studies try to probe for differences in risks between men and women, and this is a major challenge in the expanding literature of associations between genetic variants and common diseases or traits.To evaluate whether prominently claimed sex differences for genetic effects have sufficient internal and external validity.We searched PubMed through July 6, 2007, for genetic association studies claiming sex-related differences in the articles' titles. Titles and abstracts and, if necessary, the full text of the article were assessed for eligibility.Two hundred fifteen articles were retrieved by the search. We considered eligible all retrieved association studies that claimed different genetic effects across sexes of 1 or more gene variants for any human disease or phenotype. We considered both biallelic and multiallelic markers (including haplotypes) and both binary and continuous phenotypes and traits. We excluded non-English-language studies; studies evaluating only 1 sex; studies in which sex was treated only as an independent predictor of disease; studies that did not address any association of the investigated genetic variant with a disease or trait; studies not involving humans; and studies in which the authors did not claim any sex difference.Two evaluators independently extracted data with a third evaluator arbitrating their discrepancies. Data evaluation included whether analyses were stated to have been specified a priori; whether sex effects were evaluated in the whole study or subgroups thereof; and whether the claims were appropriately documented, insufficiently documented, or spurious. For appropriately and insufficiently documented claims we performed the calculations for gene-sex interaction whenever raw data were available. Finally, we compared the sex-difference claims with the best internal validity against the results of other studies addressing the same interaction.We appraised 432 sex-difference claims in 77 eligible articles. Authors stated that sex comparisons were decided a priori for 286 claims (66.2%), while the entire sample size was used in 210 (48.6%) claims. Appropriate documentation of gene-sex interaction was recorded in 55 claims (12.7%); documentation was insufficient for 303 claims and spurious for the other 74. Data for reanalysis of claims were available for 188 comparisons. Of these, 83 (44.1%) were nominally statistically significant at a P = .05 threshold, and more than half of them (n = 44) had modest P values between .01 and .05. Of 60 claims with seemingly the best internal validity, only 1 was consistently replicated in at least 2 other studies.In this sample of highly prominent claims of sex-related differences in genetic associations, most claims were insufficiently documented or spurious, and claims with documented good internal and external validity were uncommon.

    View details for Web of Science ID 000248880200022

    View details for PubMedID 17712072

  • Pharmacogenetics of the response to beta 2 agonist drugs: a systematic overview of the field. Pharmacogenomics Contopoulos-Ioannidis, D. G., Kouri, I., Ioannidis, J. P. 2007; 8 (8): 933-958

    Abstract

    The response to beta2-agonist treatment shows large repeatability within individuals and may thus be determined by genetic influences. Here we present a systematic overview of the available genetic association and linkage data for beta2-agonist treatment response. Systematic searches identified 66 eligible articles, as of March 2007, pertaining either to B2AR gene polymorphisms and short-acting or long-acting beta2-agonists or to another 29 different genes. We systematize these study results according to gene, agent and type of outcomes addressed. The systematic review highlights major challenges in the field, including extreme multiplicity of analyses; lack of consensus for main phenotypes of interest; typically small sample sizes; and poor replicability of the proposed genetic variants. Future studies will benefit from standardization of analyses and outcomes, hypothesis-free genome-wide association testing platforms, potentially additional fine mapping around new discovered variants, and large-scale collaborative studies with prospective plans for replication among several teams, with transparent public recording of all data.

    View details for PubMedID 17716228

  • Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: A meta-analysis JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Kavvoura, F. K., Akamizu, T., Awata, T., Ban, Y., Chistiakov, D. A., Frydecka, I., Ghaderi, A., Gough, S. C., Hiromatsu, Y., Ploski, R., Wang, P., Ban, Y., Bednarczuk, T., Chistiakova, E. I., Chojm, M., Heward, J. M., Hiratani, H., Juo, S. H., Karabon, L., Katayama, S., Kurihara, S., Liu, R., Miyake, I., Omrani, G. R., Pawlak, E., Taniyama, M., Tozaki, T., Ioannidis, J. P. 2007; 92 (8): 3162-3170

    Abstract

    Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) polymorphisms have been widely examined for their associations with autoimmune thyroid diseases [Graves' disease (GD) and Hashimoto thyroiditis (HT)], but their relative population effect remains unclear.The aim was to generate large-scale evidence on whether the CTLA-4 polymorphisms (A49G and CT60) and haplotypes thereof increase the susceptibility to GD and/or HT.Meta-analyses of group-level data were reviewed from 32 (11,019 subjects) and 12 (4,479) published and unpublished studies for the association of the A49G polymorphism with GD and HT, respectively (PubMed and HuGeNet search until July 2006). There were 15 (n = 7246) and six (n = 3086) studies available for the CT60 polymorphism, respectively. Meta-analyses of individual-level data from 10 (4906 subjects) and five (2386) collaborating teams for GD and HT, respectively, were also reviewed.Association of gene variants and haplotypes with GD and HT was measured.Group-level data suggested significant associations with GD and HT for both A49G [odds ratios 1.49 (P = 6 x 10(-14)) and 1.29 (P = 0.001) per G allele, respectively] and CT60 [1.45 (P = 2 x 10(-9)) and 1.64 (P = 0.003) per G allele, respectively]. Results were consistent between Asian and Caucasian descent subjects. Individual-level data showed that compared with the AA haplotype, the risk conferred by the GG haplotype was 1.49 (95% confidence interval 1.31,1.70) and 1.36 (95% confidence interval 1.16,1.59) for GD and HT, respectively. Data were consistent with a dose-response effect for the G allele of CT60.The CT60 polymorphism of CTLA-4 maps an important genetic determinant for the risk of both GD and HT across diverse populations.

    View details for DOI 10.1210/jc.2007-0147

    View details for Web of Science ID 000248570600052

    View details for PubMedID 17504905

  • PCI for stable coronary disease NEW ENGLAND JOURNAL OF MEDICINE Katritsis, D. G., Ioannidis, J. P. 2007; 357 (4): 414-415

    View details for Web of Science ID 000248283500017

    View details for PubMedID 17652659

  • Why most published research findings are false: Author's reply to Goodman and Greenland PLOS MEDICINE Ioannidis, J. P. 2007; 4 (6): 1132-1133

    View details for DOI 10.1371/journal.pmed.0040215

    View details for Web of Science ID 000247476300030

    View details for PubMedID 17593900

  • Reporting of systematic reviews: The challenge of genetic association studies PLOS MEDICINE Khoury, M. J., Little, J., Higgins, J., Ioannidis, J. P., Gwinn, M. 2007; 4 (6): 1129-1129

    View details for DOI 10.1371/journal.pmed.0040211

    View details for Web of Science ID 000247476300024

    View details for PubMedID 17593896

  • Genetic effects versus bias for candidate polymorphisms in myocardial infarction: Case study and overview of large-scale evidence AMERICAN JOURNAL OF EPIDEMIOLOGY Ntzani, E. E., Rizos, E. C., Ioannidis, J. P. 2007; 165 (9): 973-984

    Abstract

    Several genetic polymorphisms have been proposed to be associated with myocardial infarction (MI). The authors examined the evidence and biases underlying such associations using a case-study meta-analysis and an overview of large-scale data. In a meta-analysis of 27 studies addressing the association of the angiotensin type 1 receptor (AT1R)+1166A/C polymorphism with MI (10,180 cases, 17,129 controls), the *C allele conferred an increase in MI risk (odds ratio = 1.13 per allele, p = 0.005). However, there was large between-study heterogeneity; the largest study showed no effect, contradicting smaller studies; and studies with blinded genotyping showed no effect. The authors conducted an overview of meta-analyses of genetic associations for MI or coronary artery disease, including at least three studies and 3,000 subjects. In their latest meta-analysis, another 14 polymorphisms were found to have formally significant associations. If true, these associations would already explain 42% of the MI risk for Caucasian populations. Significant between-study heterogeneity was common. Across the 32 largest studies, only two found formally significant results (nine would be expected if each meta-analysis showed a true association). Even with large-scale evidence from meta-analyses, significant associations for MI may be subject to bias. Large-scale single studies and prospective consortia should be used for detecting and validating the genetic determinants of MI.

    View details for DOI 10.1093/aje/kwk085

    View details for Web of Science ID 000245896900001

    View details for PubMedID 17293603

  • Molecular evidence-based medicine - Evolution and integration of information in the genomic era EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P. 2007; 37 (5): 340-349

    Abstract

    Evidence-based medicine and molecular medicine have both been influential in biomedical research in the last 15 years. Despite following largely parallel routes to date, the goals and principles of evidence-based and molecular medicine are complementary and they should be converging. I define molecular evidence-based medicine as the study of medical information that makes sense of the advances of molecular biological disciplines and where errors and biases are properly appreciated and placed in context. Biomedical measurement capacity improves very rapidly. The exponentially growing mass of hypotheses being tested requires a new approach to both statistical and biological inference. Multidimensional biology requires careful exact replication of research findings, but indirect corroboration is often all that is achieved at best. Besides random error, bias remains a major threat. It is often difficult to separate bias from the spirit of scientific inquiry to force data into coherent and 'significant' biological stories. Transparency and public availability of protocols, data, analyses and results may be crucial to make sense of the complex biology of human disease and avoid being flooded by spurious research findings. Research efforts should be integrated across teams in an open, sharing environment. Most research in the future may be designed, performed, and integrated in the public cyberspace.

    View details for Web of Science ID 000245986300002

    View details for PubMedID 17461979

  • The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey CANADIAN MEDICAL ASSOCIATION JOURNAL Ioannidis, J. P., Trikalinos, T. A. 2007; 176 (8): 1091-1096

    Abstract

    Statistical tests for funnel-plot asymmetry are common in meta-analyses. Inappropriate application can generate misleading inferences about publication bias. We aimed to measure, in a survey of meta-analyses, how frequently the application of these tests would be not meaningful or inappropriate.We evaluated all meta-analyses of binary outcomes with é 3 studies in the Cochrane Database of Systematic Reviews (2003, issue 2). A separate, restricted analysis was confined to the largest meta-analysis in each of the review articles. In each meta-analysis, we assessed whether criteria to apply asymmetry tests were met: no significant heterogeneity, I2 < 50%, é 10 studies (with statistically significant results in at least 1) and ratio of the maximal to minimal variance across studies > 4. We performed a correlation and 2 regression asymmetry tests and evaluated their concordance. Finally, we sampled 60 meta-analyses from print journals in 2005 that cited use of the standard regression test.A total of 366 of 6873 (5%) and 98 of 846 meta-analyses (12%) in the wider and restricted Cochrane data set, respectively, would have qualified for use of asymmetry tests. Asymmetry test results were significant in 7%-18% of the meta-analyses. Concordance between the 3 tests was modest (estimated k 0.33-0.66). Of the 60 journal meta-analyses, 7 (12%) would qualify for asymmetry tests; all 11 claims for identification of publication bias were made in the face of large and significant heterogeneity.Statistical conditions for employing asymmetry tests for publication bias are absent from most meta-analyses; yet, in medical journals these tests are performed often and interpreted erroneously.

    View details for DOI 10.1503/cmaj.060410

    View details for Web of Science ID 000245303100012

    View details for PubMedID 17420491

  • Evidence from crossover trials: empirical evaluation and comparison against parallel arm trials INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Lathyris, D. N., Trikalinos, T. A., Ioannidis, J. P. 2007; 36 (2): 422-430

    Abstract

    We aimed to evaluate empirically how crossover trial results are analysed in meta-analyses of randomized evidence and whether their results agree with parallel arm studies on the same questions.We used a systematic sample of Cochrane meta-analyses including crossover trials. We evaluated the methods of analysis for crossover results and compared the concordance of the estimated effect sizes in crossover vs parallel arm trials.Of 334 screened reviews, 62 had crossover trials. Of those, 33 meta-analyses performed quantitative syntheses involving two-arm two-period crossover trials. There was large variability on how these trials were analysed; only one of the 33 meta-analyses stated that they used the data from both the first and second period with an appropriate paired approach. Nine meta-analyses used the first period data only and 14 gave no information at all on what they had done. Twenty-eight meta-analyses had both crossover (n = 137, sample size n = 7,162) and parallel arm (n = 132, sample size n = 11,398) trials. Effect sizes correlated well with the two types of designs (rho = 0.72). Differences on whether the summary effect had a P < 0.05 or not were common due to limited sample sizes. The summary relative odds ratio for parallel arm vs crossover designs for favourable outcomes was 0.87 (95% CI, 0.74-1.02).Crossover designs may contribute evidence in a fifth of systematic reviews, but few meta-analyses make use of their full data. The results of crossover trials tend to agree with those of parallel arm trials, although there was a trend for more conservative treatment effect estimates in parallel arm trials.

    View details for DOI 10.1093/ije/dym001

    View details for Web of Science ID 000248084200034

    View details for PubMedID 17301102

  • Limitations are not properly acknowledged in the scientific literature JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P. 2007; 60 (4): 324-329

    Abstract

    Limitations are important to understand for placing research findings in context, interpreting the validity of the scientific work, and ascribing a credibility level to the conclusions of published research. This goes beyond listing the magnitude and direction of random and systematic errors and validity problems. Acknowledgment of limitations requires an interpretation of the meaning and influence of errors and validity problems on the published findings. An examination of the full-text files of the first 50 articles published in 2005 in the six most-cited research journals and in two recently launched leading open-access journals showed that only 67 articles (17%) used at least one word denoting limitations in the context of the presented scientific work. Only four articles (1%) used the word limitation in their abstract; none referred to limitations of the present work that materially affected conclusions. Only five articles had a separate section on limitations. Conversely, 243 articles (61%) used words detected by the roots error, valid, bias, reproducib, or false and 289 articles (72%) used words with the root importan. Among the 25 top-cited journals' instructions to the authors and editorial policies, only one encourages discussion of limitations; importance, novelty, and lack of error are typically encouraged. Limitations should be better covered and discussed in research articles. To facilitate this, journals should give better guidance and promote the discussion of limitations. Otherwise, we are facing an important loss of context for the scientific literature.

    View details for DOI 10.1016/j.jclinepi.2006.09.011

    View details for Web of Science ID 000245094200002

    View details for PubMedID 17346604

  • Effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups HEART Hernandez, A. V., Westerhout, C. M., Steyerberg, E. W., Ioannidis, J. P., Bueno, H., White, H., Theroux, P., Moliterno, D. J., Armstrong, P. W., Califf, R. M., Wallentin, L. C., Simoons, M. L., Boersma, E. 2007; 93 (4): 450-455

    Abstract

    To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST elevation acute coronary syndromes (NSTE-ACS) depend on age.A meta-analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE-ACS (PRISM, PRISM-PLUS, PARAGON-A, PURSUIT, PARAGON-B, GUSTO IV-ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non-fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60-69, 70-79, > or =80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH).Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein IIb/IIIa receptor blockers did not differ significantly (p = 0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97 (0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1.6 (1.2 to 2.1) and 2.5 (1.5-4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients > or =80 years had half of the NNT and a third of the NNH of patients <60 years.In patients with NSTE-ACS, the relative reduction of death or non-fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted.

    View details for DOI 10.1136/hrt.2006.098657

    View details for Web of Science ID 000245350000010

    View details for PubMedID 17065179

  • On the synthesis and interpretation of consistent but weak gene-disease associations in the era of genome-wide association studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Khoury, M. J., Little, J., Gwinn, M., Ioannidis, J. P. 2007; 36 (2): 439-445

    Abstract

    Emerging technologies are allowing researchers to study hundreds of thousands of genetic variants simultaneously as risk factors for common complex diseases. Both theoretical considerations and empirical evidence suggest that specific genetic variants causally associated with common diseases will have small effects (risk ratios mostly <2.0). However, the combination of even a few small effects (e.g. effects of fewer than 20 common genetic variants) could account for a sizeable population attributable fraction of common diseases and shed important light on disease pathogenesis and environmental determinants. Nevertheless, the inauguration of genome-wide association studies only magnifies the challenge of differentiating between the expected, true weak associations from the numerous spurious effects caused by misclassification, confounding and significance-chasing biases. Standards are urgently needed for presenting and interpreting cumulative evidence on gene-disease associations, especially for consistent but weak associations. Criteria for synthesis of the evidence should include sound methods for study conduct and analysis, biological plausibility, experimental evidence and adequate replication in large-scale, collaborative studies. Efforts by the Human Genome Epidemiology Network (HuGENet) are currently ongoing to streamline and operationalize these criteria for data on genetic associations with common diseases.

    View details for DOI 10.1093/ije/dyl253

    View details for Web of Science ID 000248084200036

    View details for PubMedID 17182636

  • Selection in reported epidemiological risks: An empirical assessment PLOS MEDICINE Kavvoura, F. K., Liberopoulos, G., Ioannidis, J. P. 2007; 4 (3): 456-465

    Abstract

    Epidemiological studies may be subject to selective reporting, but empirical evidence thereof is limited. We empirically evaluated the extent of selection of significant results and large effect sizes in a large sample of recent articles.We evaluated 389 articles of epidemiological studies that reported, in their respective abstracts, at least one relative risk for a continuous risk factor in contrasts based on median, tertile, quartile, or quintile categorizations. We examined the proportion and correlates of reporting statistically significant and nonsignificant results in the abstract and whether the magnitude of the relative risks presented (coined to be consistently > or =1.00) differs depending on the type of contrast used for the risk factor. In 342 articles (87.9%), > or =1 statistically significant relative risk was reported in the abstract, while only 169 articles (43.4%) reported > or =1 statistically nonsignificant relative risk in the abstract. Reporting of statistically significant results was more common with structured abstracts, and was less common in US-based studies and in cancer outcomes. Among 50 randomly selected articles in which the full text was examined, a median of nine (interquartile range 5-16) statistically significant and six (interquartile range 3-16) statistically nonsignificant relative risks were presented (p = 0.25). Paradoxically, the smallest presented relative risks were based on the contrasts of extreme quintiles; on average, the relative risk magnitude was 1.41-, 1.42-, and 1.36-fold larger in contrasts of extreme quartiles, extreme tertiles, and above-versus-below median values, respectively (p < 0.001).Published epidemiological investigations almost universally highlight significant associations between risk factors and outcomes. For continuous risk factors, investigators selectively present contrasts between more extreme groups, when relative risks are inherently lower.

    View details for DOI 10.1371/journal.pmed.0040079

    View details for Web of Science ID 000245243700013

    View details for PubMedID 17341129

  • Meta-analysis of fractional flow reserve versus quantitative coronary angiography and noninvasive imaging for evaluation of myocardial ischemia AMERICAN JOURNAL OF CARDIOLOGY Christou, M. A., Siontis, G. C., Katritsis, D. G., Ioannidis, J. P. 2007; 99 (4): 450-456

    Abstract

    We performed a meta-analysis of 31 studies comparing the results of fractional flow reserve (FFR) against quantitative coronary angiography (QCA) and/or noninvasive imaging of the same lesions. Studies were retrieved from PubMed (last search February 2006). Across 18 studies (1,522 lesions), QCA had a random effects sensitivity of 78% (95% confidence interval [CI] 67 to 86) and specificity of 51% (95% CI 40 to 61) against FFR (0.75 cutoff). Overall concordances were 61% for lesions with diameter stenosis 30% to 70%, 67% for stenoses >70%, and 95% for stenoses <30%. Compared with noninvasive imaging (21 studies, 1,249 lesions), FFR had a sensitivity of 76% (95% CI 69 to 82) and specificity of 76% (95% CI 71 to 81) by random effects. Summary receiver-operator characteristic estimates were similar. Most data addressed comparisons with perfusion scintigraphy (976 lesions, sensitivity 75%, specificity 77%), and some data were also available for dobutamine stress echocardiography (273 lesions, sensitivity 82%, specificity 74%). In conclusion, QCA does not predict the functional significance of coronary lesions. FFR shows modest concordance with noninvasive imaging tests. The prognostic implications of discordant FFR and imaging results need further study.

    View details for DOI 10.1016/j.amjcard.2006.09.092

    View details for Web of Science ID 000244514500005

    View details for PubMedID 17293182

  • Bayesian meta-analysis and meta-regression for gene-disease associations and deviations from Hardy-Weinberg equilibrium STATISTICS IN MEDICINE Salanti, G., Higgins, J. P., Trikalinos, T. A., Ioannidis, J. P. 2007; 26 (3): 553-567

    Abstract

    Violation of Hardy-Weinberg equilibrium (HWE) can raise doubts about the validity of the conclusions from genetic association studies. However, for most currently performed gene-disease association studies, the available tests have low power to detect deviations from HWE. We consider this issue from a meta-analysis perspective, and suggest an approach to estimate the deviation and investigate its relationship with the observed genetic effects. Different degrees of deviation from HWE have previously been proposed as a potential source of heterogeneity across studies. We present a hierarchical meta-regression model that can be applied to test this assumption, using the concept of the fixation coefficient. We re-analyse seven meta-analyses to illustrate these methods. The uncertainty in the genetic effect estimate tended to increase once the fixation coefficient was taken into account. Dependence of the genetic effect size on the deviation from HWE was found in one meta-analysis, while in the other six examples, deviations from HWE did not clearly explain between-study heterogeneity in the genetic effects. The proposed hierarchical models allow the synthesis of data across gene-disease association studies with appropriate consideration of HWE issues.

    View details for DOI 10.1002/sim.2575

    View details for Web of Science ID 000243511400007

    View details for PubMedID 16685693

  • Meta-Analysis in Genome-Wide Association Datasets: Strategies and Application in Parkinson Disease PLOS ONE Evangelou, E., Maraganore, D. M., Ioannidis, J. P. 2007; 2 (2)

    Abstract

    Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques.Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1) enhancement of replication data and (2) enhancement of first-stage data, and then, we also considered (3) joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets) on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I(2) = 0, 0 and 15%, respectively). Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets).Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies.

    View details for DOI 10.1371/journal.pone.0000196

    View details for Web of Science ID 000207444300009

    View details for PubMedID 17332845

  • Quality of reporting of cancer prognostic marker studies: Association with reported prognostic effect JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyzas, P. A., Denaxa-Kyza, D., Ioannidis, J. P. 2007; 99 (3): 236-243

    Abstract

    Issues of reported study quality have not been addressed empirically with large-scale data in the cancer prognostic literature.Eight quality measures pertaining to study design and assay methods (i.e., blinding, prospective versus retrospective design, power calculations, outcomes' definitions, time of enrollment, reporting of variables, assay description, and assay reference) were evaluated in cancer prognostic marker studies included in meta-analyses identified in Medline and EMBASE. To be eligible, meta-analyses had to include at least six studies and to examine binary outcomes. We estimated the ratios of relative risks, which compared the overall prognostic effects (summary relative risks) between poor-quality and good-quality studies for each quality item. Between-study heterogeneity was tested with the Q statistic (statistically significant at P<.10). All statistical tests were two-sided.We identified 20 meta-analyses that included 331 cancer prognostic marker studies published between 1987 and 2005. Only three (0.9%) of the 331 studies presented power calculations, 129 (39.0%) studies stated that analyses were blinded, and 73 (21.5%) stated that they were prospective. Time of enrollment was defined in 232 (70.0%), 234 (70.7%) gave lists of candidate variables, and 254 (76.7%) defined outcomes. The assay used was described in 317 (95.8%), but only 177 (53.5%) provided the assay reference. Estimates of prognostic effects from poor-quality studies varied considerably and could be larger or smaller than summary estimates derived from meta-analyses. Summary ratios of relative risks of poor- versus good-quality studies for the seven quality measures ranged from 0.95 to but 1.26, but none was statistically significantly. There was statistically significant heterogeneity (P<.10) between the ratios of relative risk estimates across meta-analyses for blinding, defining endpoints, and stating variables and assay references.Among cancer prognostic marker studies, reporting quality of design and assay information often appears suboptimal, indicating that this literature may be largely unreliable. Given the potential clinical importance of prognostic marker information, improved design and reporting of these studies are warranted.

    View details for DOI 10.1093/jnci/djk032

    View details for Web of Science ID 000244223400011

    View details for PubMedID 17284718

  • Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass JOURNAL OF BONE AND MINERAL RESEARCH Ioannidis, J. P., Ng, M. Y., Sham, P. C., Zintzaras, E., Lewis, C. M., Deng, H., Econs, M. J., Karasik, D., Devoto, M., Kammerer, C. M., Spector, T., Andrew, T., Cupples, L. A., Duncan, E. L., Foroud, T., Kiel, D. P., Koller, D., Langdahl, B., Mitchell, B. D., Peacock, M., Recker, R., Shen, H., Sol-Church, K., Spotila, L. D., Uitterlinden, A. G., Wilson, S. G., Kung, A. W., Ralston, S. H. 2007; 22 (2): 173-183

    Abstract

    Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner.BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied.Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing.For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.

    View details for DOI 10.1359/JBMR.060806

    View details for Web of Science ID 000243668800001

    View details for PubMedID 17228994

  • Effects of different chemotherapy regimens on survival for advanced cervical cancer: Systematic review and meta-analysis CANCER TREATMENT REVIEWS Tzioras, S., Pavlidis, N., Paraskevaidis, E., Ioannidis, J. P. 2007; 33 (1): 24-38

    Abstract

    A large number of trials have assessed various chemotherapy regimens for the treatment of advanced cervical cancer, but there is uncertainty about the magnitude of survival benefits.We searched (last update January 2006) for trials in women with locally advanced or disseminated cervical cancer that compared neo-adjuvant or concurrent chemotherapy plus radiotherapy versus radiotherapy alone; or different chemotherapy regimens among themselves (with or without background radiotherapy in both arms). Sixty-five trials were identified with survival data on 11,180 women. Results for survival were combined with fixed and random effects models and between-study heterogeneity was estimated. Separate results were obtained for different regimens, cycle length, and type of chemotherapy (neo-adjuvant, concurrent, without radiotherapy).Twenty two comparisons had survival data on 3837 women randomized to receive chemotherapy plus radiotherapy versus radiotherapy alone; the summary relative hazard for mortality was 0.95, 95% CI, 0.83-1.08. Modest between-study heterogeneity (I2=38%) seemed to be due to contradictory results in early trials; trials published in the last decade had a summary relative hazard 0.89 (95% CI, 0.78-1.02) and no between-study heterogeneity (I2=0%). Results were similar for neo-adjuvant chemotherapy and for concurrent chemo-radiotherapy. Cisplatin or cisplatin-based combinations had no significant benefit overall, but a potential benefit was seen with short-length cycles (14 days) and a marginally significant harm with longer-length cycles (summary relative hazards 0.80, 95% CI, 0.66-0.99 and 1.18, 95% CI, 1.02-1.38, respectively). The summary relative hazard was 1.02, (95% CI, 0.84-1.24) for trials using neo-adjuvant chemotherapy and 0.85 (95% CI, 0.73-1.00) for trials using concurrent chemotherapy.Evidence on chemotherapy in women with advanced cervical cancer is not encouraging for major survival benefits. However, small benefits have been observed in some trials, especially with short-length cycles of cisplatin-based regimens and concurrent chemotherapy and radiotherapy.

    View details for DOI 10.1016/j.ctrv.2006.09.007

    View details for Web of Science ID 000244178700003

    View details for PubMedID 17112673

  • Open letter to the leader of academic medicine. BMJ (Clinical research ed.) Ioannidis, J. P., Ahmed, T., Awasthi, S., Clarfield, A. M., Clark, J., Dandona, L., Howe, A., Lozano, J. M., Li, Y., Madani, H., Marusic, A., Mohammed, I., Purcell, G. P., Rhoads, M., Sliwa-Hähnle, K., Straus, S. E., Edejer, T. T., Tugwell, P., Ward, R., Wilkes, M. S., Smith, R. 2007; 334 (7586): 191-193

    View details for PubMedID 17255613

  • Re: Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis - Response JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P., Mauri, D., Polyzos, N. P., Pavlidis, N. 2007; 99 (2): 176-177

    View details for DOI 10.1093/jnci/djk023

    View details for Web of Science ID 000243528300016

  • Genetic predisposition to asthma and atopy RESPIRATION Contopoulos-Ioannidis, D. G., Kouri, I. N., Ioannidis, J. P. 2007; 74 (1): 8-12

    Abstract

    A large number of studies have tried to identify heritable components in the susceptibility to asthma and atopy phenotypes. This review examines the evidence of multigenetic inheritance for these conditions. We identified in the literature at least 372 gene-disease association studies for asthma and 124 for atopy published in the last 6 years. Gene-environment analyses were performed in 41 and 14 articles, respectively, in the same time period. Many postulated associations have been probed with limited sample sizes and will require more extensive replication and large-scale evidence. Meta-analyses have been performed for polymorphisms in 5 genes and provide modest evidence for genetic association of asthma with ADAM33 and TNFA gene polymorphisms. Meta-analyses of linkage studies show that it is unlikely to detect strong linkage peaks for asthma susceptibility. However, linkage was claimed between loci on chromosomes 2, 4, 6, 9, 10, 11 and 15 and total serum IgE levels. Careful definitions and standardization of phenotypes across teams of investigators are important to endorse. New large-scale testing platforms may offer new opportunities for discovering susceptibility gene variants, but they need to be coupled with careful study design, international collaboration, and possibly also dissection of gene-environment interactions.

    View details for DOI 10.1159/000096833

    View details for Web of Science ID 000244565400003

    View details for PubMedID 17190999

  • Is molecular profiling ready for use in clinical decision making? ONCOLOGIST Ioannidis, J. P. 2007; 12 (3): 301-311

    Abstract

    Molecular profiling, the classification of tissue or other specimens for diagnostic, prognostic, and predictive purposes based on multiple gene expression, is a technology that holds major promise for optimizing the management of patients with cancer. However, the use of these tests for clinical decision making presents many challenges to overcome. Assay development and data analysis in this field have been largely exploratory, and leave numerous possibilities for the introduction of bias. Standardization of profiles remains the exception. Classifier performance is usually overinterpreted by presenting the results as p-values or multiplicative effects (e.g., relative risks), while the absolute sensitivity and specificity of classification remain modest at best, especially when tested in large validation samples. Validation has often been done with suboptimal attention to methodology and protection from bias. The postulated classifier performance may be inflated compared to what these profiles can achieve. With the exception of breast cancer, we have little evidence about the incremental discrimination that molecular profiles can provide versus classic risk factors alone. Clinical trials have started to evaluate the utility of using molecular profiles for breast cancer management. Until we obtain data from these trials, the impact of these tests and the net benefit under real-life settings remain unknown. Optimal incorporation into clinical practice is not straightforward. Finally, cost-effectiveness is difficult to appreciate until these other challenges are addressed. Overall, molecular profiling is a fascinating and promising technology, but its incorporation into clinical decision making requires careful planning and robust evidence.

    View details for DOI 10.1634/theoncologist.12-3-301

    View details for Web of Science ID 000245543600008

    View details for PubMedID 17405894

  • An exploratory test for an excess of significant findings CLINICAL TRIALS Ioannidis, J. P., Trikalinos, T. A. 2007; 4 (3): 245-253

    Abstract

    The published clinical research literature may be distorted by the pursuit of statistically significant results.We aimed to develop a test to explore biases stemming from the pursuit of nominal statistical significance.The exploratory test evaluates whether there is a relative excess of formally significant findings in the published literature due to any reason (e.g., publication bias, selective analyses and outcome reporting, or fabricated data). The number of expected studies with statistically significant results is estimated and compared against the number of observed significant studies. The main application uses alpha = 0.05, but a range of alpha thresholds is also examined. Different values or prior distributions of the effect size are assumed. Given the typically low power (few studies per research question), the test may be best applied across domains of many meta-analyses that share common characteristics (interventions, outcomes, study populations, research environment).We evaluated illustratively eight meta-analyses of clinical trials with >50 studies each and 10 meta-analyses of clinical efficacy for neuroleptic agents in schizophrenia; the 10 meta-analyses were also examined as a composite domain. Different results were obtained against commonly used tests of publication bias. We demonstrated a clear or possible excess of significant studies in 6 of 8 large meta-analyses and in the wide domain of neuroleptic treatments.The proposed test is exploratory, may depend on prior assumptions, and should be applied cautiously.An excess of significant findings may be documented in some clinical research fields.

    View details for DOI 10.1177/1740774507079441

    View details for Web of Science ID 000249489200005

    View details for PubMedID 17715249

  • Prosthesis infection: Diagnosis after total joint arthroplasty with antigranulocyte scintigraphy with Tc-99m-labeled monoclonal antibodies - A meta-analysis RADIOLOGY Pakos, E. E., Trikalinos, T. A., Fotopoulos, A. D., Ioannidis, J. P. 2007; 242 (1): 101-108

    Abstract

    To perform a meta-analysis of diagnostic studies regarding the accuracy of antigranulocyte scintigraphy (AGS) with monoclonal antibodies in the identification of prosthesis infection after total hip or knee arthroplasty.PubMed and EMBASE searches were conducted for the identification of relevant studies. Data on the diagnostic performance of AGS with monoclonal antibodies were combined quantitatively across eligible studies, and the overall sensitivity and specificity, along with summary receiver operating characteristic (ROC) curves and likelihood ratios (LRs), were estimated. The above parameters were evaluated for all patients and for various subgroups among the eligible studies. The reference standard used in the individual studies was accepted.Thirteen eligible studies on nonoverlapping patient groups were included in the meta-analysis; there was a total sample size of 522 implants. The independent random effects summary estimates of sensitivity and specificity were 83% and 80%, respectively. The summary ROC curve estimate for weighted analysis was a sensitivity of 90% for a specificity of 80%. LR syntheses gave a weighted positive LR of 3.99 (95% confidence interval [CI]: 3.13, 5.09) and a weighted negative LR of 0.22 (95% CI: 0.15, 0.34); there was no statistically significant between-study heterogeneity for either metric. Various subgroup analyses did not reveal any statistically significant differences.AGS with monoclonal antibodies had a reasonably high discriminating ability to identify prosthesis infection in patients who underwent total joint arthroplasty.

    View details for DOI 10.1148/radiol.2421052011

    View details for Web of Science ID 000243842500014

    View details for PubMedID 17090716

  • The emergence of networks in human genome epidemiology - Challenges and opportunities EPIDEMIOLOGY Seminara, D., Khoury, M. J., O'Brien, T. R., Manolio, T., Gwinn, M. L., Little, J., T Higgins, J. P., Bernstein, J. L., Boffetta, P., Bondy, M., Bray, M. S., Brenchley, P. E., Buffler, P. A., Casas, J. P., Chokkalingam, A. P., Danesh, J., Smith, G. D., Dolan, S., Duncan, R., Gruis, N. A., Hashibe, M., Hunter, D., Jarvelin, M., Malmer, B., Maraganore, D. M., Newton-Bishop, J. A., Riboli, E., Salanti, G., Taioli, E., Timpson, N., Uitterlinden, A. G., Vineis, P., Wareham, N., Winn, D. M., Zimmern, R., Ioannidis, J. P. 2007; 18 (1): 1-8

    View details for DOI 10.1097/01.ede.0000249540.17855.b7

    View details for Web of Science ID 000242836700001

    View details for PubMedID 17179752

  • Non-replication and inconsistency in the genome-wide association setting HUMAN HEREDITY Ioannidis, J. P. 2007; 64 (4): 203-213

    Abstract

    Non-replication and inconsistency had been common features in the search for common variants of candidate genes affecting the risk of complex diseases. They may continue to require attention in the current era, when massive hypothesis-free testing of genetic variants is feasible. An empirical evaluation of the early experience with genome-wide association (GWA) studies suggests several examples where proposed associations have failed to be replicated by subsequent investigations. Non-replication and inconsistency is defined here in the framework of cumulative meta-analysis. Ideally, associations exist, GWA finds them, and subsequent investigations should replicate them. However, a number of other possibilities need to be considered. No common genetic variants may associate with the phenotype of interest and GWA may find nothing; or associations may exist, but GWA may miss them. Associations that do not exist may be falsely selected by the GWA and subsequent studies may appropriately refute them or falsely replicate them. Finally, GWA may find true associations that are nevertheless falsely non-replicated in the subsequent studies; or associations may be genuinely inconsistent across study populations. A list of options is presented for consideration in each of these scenarios.

    View details for DOI 10.1159/000103512

    View details for Web of Science ID 000247824800001

    View details for PubMedID 17551261

  • Concentration of the Most-Cited Papers in the Scientific Literature: Analysis of Journal Ecosystems PLOS ONE Ioannidis, J. P. 2006; 1 (1)

    Abstract

    A minority of scientific journals publishes the majority of scientific papers and receives the majority of citations. The extent of concentration of the most influential articles is less well known.The 100 most-cited papers in the last decade in each of 21 scientific fields were analyzed; fields were considered as ecosystems and their "species" (journal) diversity was evaluated. Only 9% of journals in Journal Citation Reports had published at least one such paper. Among this 9%, half of them had published only one such paper. The number of journals that had published a larger number of most-cited papers decreased exponentially according to a Lotka law. Except for three scientific fields, six journals accounted for 53 to 94 of the 100 most-cited papers in their field. With increasing average number of citations per paper (citation density) in a scientific field, concentration of the most-cited papers in a few journals became even more prominent (p<0.001). Concentration was unrelated to the number of papers published or number of journals available in a scientific field. Multidisciplinary journals accounted for 24% of all most-cited papers, with large variability across fields. The concentration of most-cited papers in multidisciplinary journals was most prominent in fields with high citation density (correlation coefficient 0.70, p<0.001). Multidisciplinary journals had published fewer than eight of the 100 most-cited papers in eight scientific fields (none in two fields). Journals concentrating most-cited original articles often differed from those concentrating most-cited reviews. The concentration of the most-influential papers was stronger than the already prominent concentration of papers published and citations received.Despite a plethora of available journals, the most influential papers are extremely concentrated in few journals, especially in fields with high citation density. Existing multidisciplinary journals publish selectively most-cited papers from fields with high citation density.

    View details for DOI 10.1371/journal.pone.0000005

    View details for Web of Science ID 000207443600005

    View details for PubMedID 17183679

  • Evolution and translation of research findings: From to where? PLOS CLINICAL TRIALS Ioannidis, J. P. 2006; 1 (7)

    Abstract

    The credibility and replication of research findings evolve over time, as data accumulate. However, translation of postulated research promises to real-life biomedical applications is uncommon. In some fields of research, we may observe diminishing effects for the strength of research findings and rapid alternations of exaggerated claims and extreme contradictions--the "Proteus Phenomenon." While these phenomena are probably more prominent in the basic sciences, similar manifestations have been documented even in clinical trials and they may undermine the credibility of clinical research. Significance-chasing bias may be in part responsible, but the greatest threat may come from the poor relevance and scientific rationale and thus low pre-study odds of success of research efforts. Given that we currently have too many research findings, often with low credibility, replication and rigorous evaluation become as important as or even more important than discovery. Credibility, replication, and translation are all desirable properties of research findings, but are only modestly correlated. In this essay, I discuss some of the evidence (or lack thereof) for the process of evolution and translation of research findings, with emphasis on the biomedical sciences.

    View details for DOI 10.1371/journal.pctr.0010036

    View details for Web of Science ID 000245239000003

    View details for PubMedID 17111044

  • Survival benefits with diverse chemotherapy regimens for ovarian cancer: Meta-analysis of multiple treatments JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyrgiou, M., Salanti, G., Pavlidis, N., Paraskevaidis, E., Ioannidis, J. P. 2006; 98 (22): 1655-1663

    Abstract

    Numerous randomized trials have compared different chemotherapy regimens in women with ovarian cancer. Although ovarian cancer survival has improved in recent years, the magnitude of these incremental benefits across diverse regimens is unclear.We used multiple-treatment meta-analysis methodology to combine information from direct and indirect comparisons of all chemotherapy regimens used in randomized trials of ovarian cancer in the last 40 years. Chemotherapy was categorized by the use or not of platinum and/or taxanes, combinations of agents, and intraperitoneal administration. Monte Carlo simulations were used to determine which regimen most improved survival. Analyses of trials that examined first- and second-line treatments were also performed separately.We found 198 trials (N = 38,440 women) involving 120 different chemotherapy regimens published in 1971-2006. Eighty-two trials compared different types of chemotherapy, among which 60 had usable survival information (N = 15,609 women). Monte Carlo simulations showed a 92% probability that the regimen that best prolonged survival is a platinum and taxane combination with intraperitoneal administration; this regimen resulted in a 55% relative risk reduction (95% confidence interval [CI] = 39% to 67%) for mortality as compared with nonintraperitoneal monotherapy using neither platinum nor taxane. Against that same monotherapy comparator, platinum-based combinations with and without intraperitoneal administration achieved 40% (95% CI = 21% to 54%) and 30% (95% CI = 20% to 38%) relative risk reductions for mortality, respectively, and combinations involving platinum and taxane without intraperitoneal administration achieved a 42% (95% CI = 31% to 51%) relative risk reduction. Results were similar when analyses were limited to first-line treatment. Data on second-line treatment were consistent with the superiority of platinum and taxane combinations.Distinct incremental improvements in survival have been achieved for ovarian cancer chemotherapy over time, with the possibility to achieve a doubling or more of time to mortality with platinum and taxane combinations, especially when intraperitoneal administration is used.

    View details for DOI 10.1093/jnci/djj443

    View details for Web of Science ID 000242379700012

    View details for PubMedID 17105988

  • Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study LANCET NEUROLOGY Elbaz, A., Nelson, L. M., Payami, H., Ioannidis, J. P., Fiske, B. K., Annesi, G., Belin, A. C., Factor, S. A., Ferrarese, C., Hadjigeorgiou, G. M., Higgins, D. S., Kawakami, H., Krueger, R., Marder, K. S., Mayeux, R. P., Mellick, G. D., Nutt, J. G., Ritz, B., Samii, A., Tanner, C. M., Van Broeckhoven, C., Van Den Eeden, S. K., Wirdefeldt, K., Zabetian, C. P., Dehem, M., Montimurro, J. S., Southwick, A., Myers, R. M., Trikalinos, T. A. 2006; 5 (11): 917-923

    Abstract

    A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain.Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies.In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966.Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

    View details for DOI 10.1016/S1474-4422(06)70579-8

    View details for Web of Science ID 000241591600014

    View details for PubMedID 17052658

  • Indirect comparisons: the mesh and mess of clinical trials LANCET Ioannidis, J. P. 2006; 368 (9546): 1470-1472

    View details for Web of Science ID 000241582700005

    View details for PubMedID 17071265

  • Common genetic variants for breast cancer: 32 largely refuted candidates and larger prospects JOURNAL OF THE NATIONAL CANCER INSTITUTE Ioannidis, J. P. 2006; 98 (19): 1350-1353

    View details for DOI 10.1093/jnci/djj392

    View details for Web of Science ID 000241721200003

    View details for PubMedID 17018776

  • Gene expression profiling for individualized breast cancer chemotherapy: success or not? NATURE CLINICAL PRACTICE ONCOLOGY Ioannidis, J. P. 2006; 3 (10): 538-539

    View details for DOI 10.1038/ncponc0631

    View details for Web of Science ID 000241054700006

    View details for PubMedID 17019431

  • Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Trikalinos, T. A., Khoury, M. J. 2006; 164 (7): 609-614

    Abstract

    Accumulated evidence from searching for candidate gene-disease associations of complex diseases can offer some insights as the field moves toward discovery-oriented approaches with massive genome-wide testing. Meta-analyses of 50 non-human lymphocyte antigen gene-disease associations with documented overall statistical significance (752 studies) show summary odds ratios with a median of 1.43 (interquartile range, 1.28-1.65). Many different biases may operate in this field, for both single studies and meta-analyses, and these biases could invalidate some of these seemingly "validated" associations. Studies with a sample size of >500 show a median odds ratio of only 1.15. The median sample size required to detect the observed summary effects in each population addressed in the 752 studies is estimated to be 3,535 (interquartile range, 1,936-9,119 for cases and controls combined). These estimates are steeply inflated in the presence of modest bias. Population heterogeneity, as well as gene-gene and gene-environment interactions, could steeply increase these estimates and may be difficult to address even by very large biobanks and observational cohorts. The one visible solution is for a large number of teams to join forces on the same research platforms. These collaborative studies ideally should be designed up front to also assess more complex gene-gene and gene-environment interactions.

    View details for DOI 10.1093/aje/kwj259

    View details for Web of Science ID 000240698000001

    View details for PubMedID 16893921

  • Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: A meta-analysis BONE Fang, Y., Rivadeneira, F., van Meurs, J. B., Pols, H. A., Ioannidis, J. P., Uitterlinden, A. G. 2006; 39 (4): 938-945

    Abstract

    Fracture is the major clinical outcome of osteoporosis. The vitamin D receptor (VDR) gene is thought to be a candidate gene for osteoporosis. Many genetic studies have suggested an association of VDR polymorphisms and osteoporosis, but evidence remains conflicting.We searched published studies from 1996 to September 2005 through PubMed and evaluated the genetic effect of the BsmI and TaqI polymorphism of VDR on fracture risk in a meta-analysis. Thirteen studies with a total of 20 eligible comparisons (1632 fracture cases and 5203 controls) were analyzed with fixed and random effects models.No evidence of relationship between the VDR BsmI or TaqI polymorphism and fracture risk was observed with any genetic model. The odds ratio (95% confidence interval) of b-allele versus B-allele was 0.98 (0.86-1.12) with random effects calculations. There was significant between-study heterogeneity. Small studies did not differ significantly from larger ones.No relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data.

    View details for DOI 10.1016/j.bone.2006.04.016

    View details for Web of Science ID 000240792700030

    View details for PubMedID 16769262

  • Heterogeneity-based genome search meta-analysis for preeclampsia HUMAN GENETICS Zintzaras, E., Kitsios, G., Harrison, G. A., Laivuori, H., Kivinen, K., Kere, J., Messinis, I., Stefanidis, I., Ioannidis, J. P. 2006; 120 (3): 360-370

    Abstract

    Preeclampsia is a pregnancy-related disorder that causes maternal and fetal morbidity and mortality. Its exact inheritance pattern is still unknown, and genome searches for identifying susceptibility loci for preeclampsia have thus far produced inconclusive or inconsistent results. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) that synthesized the available genome scan data on preeclampsia. HEGESMA identifies genetic regions (bins) that rank highly on average in terms of linkage statistics across genome scans (searches). The significance of each bin's average rank and heterogeneity across scans was calculated using Monte Carlo tests. The meta-analysis involved four genome-scans on general preeclampsia and five scans on severe preeclampsia. In general preeclampsia, 13 bins had significantly high average rank (Prank< 0.05) by either unweighted or weighted analyses, while four of them (2p11.2-2q21.1, 9q21.32-9q31.2, 2p15-2p11.2, 2q32.1-2q35) were formally significant by both analyses. Heterogeneity of bin 2.8 (2q32.1-2q35) was significantly low in both unweighted and weighted analysis (PQ< 0.01). In severe preeclampsia, 10 bins had significantly high average rank by either unweighted or weighted analyses and five of them (3q11.1-3q21.2, 2q37.1-2q37.3, 18p11.32-18p11.22, 2p15-2p11.2, 7q34-7q36.3) were significant by both analyses. Bin 2q37.1-2q37.3 showed marginal low heterogeneity in unweighted and weighted analysis (PQ= 0.06). Results should be interpreted with caution as the p values were modest. Further investigation of these regions by genotyping with additional markers and families may help to direct the identification of candidate genes for preeclampsia.

    View details for DOI 10.1007/s00439-006-0214-1

    View details for Web of Science ID 000240613900004

    View details for PubMedID 16868762

  • An empirical evaluation of multifarious outcomes in pharmacogenetics: beta-2 adrenoceptor gene polymorphisms in asthma treatment PHARMACOGENETICS AND GENOMICS Contopoulos-Ioannidis, D. G., Alexiou, G. A., Gouvias, T. C., Ioannidis, J. P. 2006; 16 (10): 705-711

    Abstract

    Pharmacogenetics promises to individualize therapeutics. Concerns, however, exist about the lack of replication of discoveries. Selective use of different endpoints, times of assessment, types of interventions and genetic groups across studies may lead to spurious results. Here, we examined the variability of definitions of endpoints and analyses reported across studies addressing the association of the Arg16Gly and/or Gln27Glu polymorphisms of the beta2-adrenergic receptor gene with clinical response to beta2-agonist therapy in asthma.We systematically calculated the number and type of endpoints and analyses reported across studies and recorded the appraisal of their statistical significance.Across 21 studies, the total number of probed and reported associations was 487 when the multiple endpoints and types of comparisons presented by multiple comparisons were considered (337 for Arg16Gly, 98 for Gln27Glu and 52 for their haplotypes): 465 (95%) were probed only once; only six associations were probed twice and two associations were probed five times, for the same endpoint, time of assessment, type of interventions and genetic group. Most studies (17/21) claimed at least one significant association. Overall, however, 243/487 (49.9%) probed and reported associations were not statistically significant, 120 (24.6%) were of unspecified statistical significance, 86 (17.7%) were statistically significant only for specific selected genetic contrasts and only 38 (7.8%) were genuinely statistically significant for the comparison between all available genetic groups.The multifarious outcomes in this literature are inconsistent across studies and susceptible to selective reporting. The lack of standardization hinders the evaluation of replication validity for reported discoveries.

    View details for Web of Science ID 000203009100002

    View details for PubMedID 17001289

  • Extreme between-study homogeneity in meta-analyses could offer useful insights JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Trikalinos, T. A., Zintzaras, E. 2006; 59 (10): 1023-1032

    Abstract

    Meta-analyses are routinely evaluated for the presence of large between-study heterogeneity. We examined whether it is also important to probe whether there is extreme between-study homogeneity.We used heterogeneity tests with left-sided statistical significance for inference and developed a Monte Carlo simulation test for testing extreme homogeneity in risk ratios across studies, using the empiric distribution of the summary risk ratio and heterogeneity statistic. A left-sided P=0.01 threshold was set for claiming extreme homogeneity to minimize type I error.Among 11,803 meta-analyses with binary contrasts from the Cochrane Library, 143 (1.21%) had left-sided P-value <0.01 for the asymptotic Q statistic and 1,004 (8.50%) had left-sided P-value <0.10. The frequency of extreme between-study homogeneity did not depend on the number of studies in the meta-analyses. We identified examples where extreme between-study homogeneity (left-sided P-value <0.01) could result from various possibilities beyond chance. These included inappropriate statistical inference (asymptotic vs. Monte Carlo), use of a specific effect metric, correlated data or stratification using strong predictors of outcome, and biases and potential fraud.Extreme between-study homogeneity may provide useful insights about a meta-analysis and its constituent studies.

    View details for DOI 10.1016/j.jclinepi.2006.02.013

    View details for Web of Science ID 000241064500003

    View details for PubMedID 16980141

  • Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Pavlidis, N., Polyzos, N. P., Ioannidis, J. P. 2006; 98 (18): 1285-1291

    Abstract

    Aromatase inhibitors and inactivators have been extensively tested in patients with advanced breast cancer, but it is unclear whether they offer any survival benefits compared with standard hormonal treatment with tamoxifen or progestagens. We performed a meta-analysis of randomized controlled trials that compared several generations of aromatase inhibitors and inactivators with standard hormonal treatment in patients with advanced breast cancer.The endpoint that we assessed was survival. Trials were located through searches of PubMed and Cochrane Library (last update March 2006). Relative hazards (RHs) were summarized across trials through fixed- and random-effects analyses, and heterogeneity was assessed with the Q and I2 statistics. All statistical tests were two-sided.Twenty-five different comparisons, with a total of 8504 patients, were included in the meta-analysis. We found statistically significant survival benefits with third-generation aromatase inhibitors and inactivators (vorozole, letrozole, examestane, and anastrazole) (RH = 0.87, 95% confidence interval [CI] = 0.82 to 0.93; P<.001) but not with first-generation (aminoglutethimide) or second-generation (formestane and fadrozole) agents. The difference in the summary effects between these two groups of trials was statistically significant (P = .04). The survival benefit with third-generation agents in first-line trials, in which these agents were compared with tamoxifen (11% RH reduction, 95% CI = 1% to 19%; P = .03), was identical to their benefit in second- and subsequent-line trials in which these agents were compared with other treatments (14% RH reduction, 95% CI = 6% to 21%; P<.001).Inhibition of the aromatase system, in particular with third-generation aromatase inhibitors and inactivators, appears to be associated with statistically significant improved survival of patients with advanced breast cancer compared with standard hormonal treatments.

    View details for DOI 10.1093/jnci/djj357

    View details for Web of Science ID 000241721100008

    View details for PubMedID 16985247

  • The case of the misleading funnel plot. BMJ (Clinical research ed.) Lau, J., Ioannidis, J. P., Terrin, N., Schmid, C. H., Olkin, I. 2006; 333 (7568): 597-600

    View details for PubMedID 16974018

  • Concordance of functional in vitro data and epidemiological associations in complex disease genetics GENETICS IN MEDICINE Ioannidis, J. P., Kavvoura, F. K. 2006; 8 (9): 583-593

    Abstract

    We aimed to assess whether epidemiological evidence on genetic associations for complex diseases concord with in vitro functional data.We examined 36 studies on bi-allelic markers and 23 studies on haplotypes where investigators had addressed both epidemiological associations and the functional effect of the same gene variants in luciferase reporter systems in vitro.There was no correlation between epidemiological odds ratios and luciferase activity ratios (-0.09, P = 0.60). Luciferase activity ratios could not tell whether a probed epidemiologic association would be significant or not (area under receiver operating characteristics curve, 0.52). Luciferase results usually were qualitatively similar across cell lines and experimental conditions, with some exceptions. A luciferase activity ratio of 1.44 adequately separated statistically significant from non-significant functional differences (area under receiver operating characteristics curve, 0.95). Binary and continuous disease outcomes usually gave concordant results; other in vitro methods, in particular EMSA, agreed with luciferase results. Selective reporting and use of different variants and contrasts between functional and epidemiological analyses were common in these studies.In vitro biological data and epidemiology provide independent lines of evidence on complex diseases. We provide suggestions for improving the design and reporting of studies addressing both in vitro and epidemiological effects.

    View details for DOI 10.1097/01.gim.0000237775.93658.0c

    View details for Web of Science ID 000240917600007

    View details for PubMedID 16980815

  • The importance of independent risk-factors for long-term mortality prediction after cardiac surgery EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Toumpoulis, I. K., Anagnostopoulos, C. E., Ioannidis, J. P., Toumpoulis, S. K., Chamogeorgakis, T., Swistel, D. G., DeRose, J. J. 2006; 36 (9): 599-607

    Abstract

    The purpose of the present study was to determine independent predictors for long-term mortality after cardiac surgery. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to score in-hospital mortality and recent studies have shown its ability to predict long-term mortality as well. We compared forecasts based on EuroSCORE with other models based on independent predictors. Medical records of patients with cardiac surgery who were discharged alive (n = 4852) were retrospectively reviewed. Their operative surgical risks were calculated according to EuroSCORE. Patients were randomly divided into two groups: training dataset (n = 3233) and validation dataset (n = 1619). Long-term survival data (mean follow-up 5.1 years) were obtained from the National Death Index. We compared four models: standard EuroSCORE (M1); logistic EuroSCORE (M2); M2 and other preoperative, intra-operative and post-operative selected variables (M3); and selected variables only (M4). M3 and M4 were determined with multivariable Cox regression analysis using the training dataset. The estimated five-year survival rates of the quartiles in compared models in the validation dataset were: 94.5%, 87.8%, 77.1%, 64.9% for M1; 95.1%, 88.0%, 80.5%, 64.4% for M2; 93.4%, 89.4%, 80.8%, 64.1% for M3; and 95.8%, 90.9%, 81.0%, 59.9% for M4. In the four models, the odds of death in the highest-risk quartile was 8.4-, 8.5-, 9.4- and 15.6-fold higher, respectively, than the odds of death in the lowest-risk quartile (P < 0.0001 for all). EuroSCORE is a good predictor of long-term mortality after cardiac surgery. We developed and validated a model using selected preoperative, intra-operative and post-operative variables that has better discriminatory ability.

    View details for Web of Science ID 000239636000001

    View details for PubMedID 16919041

  • Patient outcomes with teaching versus nonteaching healthcare: A systematic review PLOS MEDICINE Papanikolaou, P. N., Christidi, G. D., Ioannidis, J. P. 2006; 3 (9): 1603-1615

    Abstract

    Extensive debate exists in the healthcare community over whether outcomes of medical care at teaching hospitals and other healthcare units are better or worse than those at the respective nonteaching ones. Thus, our goal was to systematically evaluate the evidence pertaining to this question.We reviewed all studies that compared teaching versus nonteaching healthcare structures for mortality or any other patient outcome, regardless of health condition. Studies were retrieved from PubMed, contact with experts, and literature cross-referencing. Data were extracted on setting, patients, data sources, author affiliations, definition of compared groups, types of diagnoses considered, adjusting covariates, and estimates of effect for mortality and for each other outcome. Overall, 132 eligible studies were identified, including 93 on mortality and 61 on other eligible outcomes (22 addressed both). Synthesis of the available adjusted estimates on mortality yielded a summary relative risk of 0.96 (95% confidence interval [CI], 0.93-1.00) for teaching versus nonteaching healthcare structures and 1.04 (95% CI, 0.99-1.10) for minor teaching versus nonteaching ones. There was considerable heterogeneity between studies (I(2) = 72% for the main analysis). Results were similar in studies using clinical and those using administrative databases. No differences were seen in the 14 studies fully adjusting for volume/experience, severity, and comorbidity (relative risk 1.01). Smaller studies did not differ in their results from larger studies. Differences were seen for some diagnoses (e.g., significantly better survival for breast cancer and cerebrovascular accidents in teaching hospitals and significantly better survival from cholecystectomy in nonteaching hospitals), but these were small in magnitude. Other outcomes were diverse, but typically teaching healthcare structures did not do better than nonteaching ones.The available data are limited by their nonrandomized design, but overall they do not suggest that a healthcare facility's teaching status on its own markedly improves or worsens patient outcomes. Differences for specific diseases cannot be excluded, but are likely to be small.

    View details for DOI 10.1371/journal.pmed.0030341

    View details for Web of Science ID 000241923800028

    View details for PubMedID 16968119

  • The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis ANNALS OF INTERNAL MEDICINE Uitterlinden, A. G., Ralston, S. H., Brandi, M. L., Carey, A. H., Grinberg, D., Langdahl, B. L., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Reeve, J., Reid, D. M., Amidei, A., Bassiti, A., Bustamante, M., Husted, U. B., Diez-Perez, A., Dobnig, H., Dunning, A. M., Enjuanes, A., Fahrleitner-Pammer, A., Fang, Y., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P., Mavilia, C., van Meurs, J. B., Mangion, J., McGuigan, F. E., Pols, H. A., Renner, W., Rivadeneira, F., van Schoor, N. M., Scollen, S., Sherlock, R. E., Ioannidis, J. P. 2006; 145 (4): 255-264

    Abstract

    Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear.To evaluate the relation between VDR polymorphisms, BMD, and fractures.Prospective multicenter large-scale association study.The Genetic Markers for Osteoporosis consortium, involving 9 European research teams.26,242 participants (18,405 women).Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures.Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model).The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis.The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

    View details for Web of Science ID 000239858800003

    View details for PubMedID 16908916

  • Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease 58th Annual Meeting of the American-Academy-of-Neurology Maraganore, D. M., de Andrade, M., Elbaz, A., Farrer, M. J., Ioannidis, J. P., Krueger, R., Rocca, W. A., Schneider, N. K., Lesnick, T. G., Lincoln, S. J., Hulihan, M. M., Aasly, J. O., Ashizawa, T., Chartier-Harlin, M., Checkoway, H., Ferrarese, C., Hadjigeorgiou, G., Hattori, N., Kawakami, H., Lambert, J., Lynch, T., Mellick, G. D., Papapetropoulos, S., Parsian, A., Quattrone, A., Riess, O., Tan, E., Van Broeckhoven, C. AMER MEDICAL ASSOC. 2006: 661–70

    Abstract

    Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking.To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset.We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally.Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset.Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55).This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

    View details for Web of Science ID 000239603800028

    View details for PubMedID 16896109

  • Family-based versus unrelated case-control designs for genetic associations PLOS GENETICS Evangelou, E., Trikalinos, T. A., Salanti, G., Ioannidis, J. P. 2006; 2 (8): 1147-1155

    Abstract

    The most simple and commonly used approach for genetic associations is the case-control study design of unrelated people. This design is susceptible to population stratification. This problem is obviated in family-based studies, but it is usually difficult to accumulate large enough samples of well-characterized families. We addressed empirically whether the two designs give similar estimates of association in 93 investigations where both unrelated case-control and family-based designs had been employed. Estimated odds ratios differed beyond chance between the two designs in only four instances (4%). The summary relative odds ratio (ROR) (the ratio of odds ratios obtained from unrelated case-control and family-based studies) was close to unity (0.96 [95% confidence interval, 0.91-1.01]). There was no heterogeneity in the ROR across studies (amount of heterogeneity beyond chance I(2) = 0%). Differences on whether results were nominally statistically significant (p < 0.05) or not with the two designs were common (opposite classification rates 14% and 17%); this reflected largely differences in power. Conclusions were largely similar in diverse subgroup analyses. Unrelated case-control and family-based designs give overall similar estimates of association. We cannot rule out rare large biases or common small biases.

    View details for DOI 10.1371/journal.pgen.0020123

    View details for Web of Science ID 000240006900004

    View details for PubMedID 16895437

  • Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study BRITISH MEDICAL JOURNAL Tiihonen, J., Wahlbeck, K., Lonnqvist, J., Klaukka, T., Ioannidis, J. P., Volavka, J., Haukka, J. 2006; 333 (7561): 224-227

    Abstract

    To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community.Prospective cohort study using national central registers.Community care in Finland.Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001.Rates of discontinuation of drugs (all causes), rates of rehospitalisation, and mortality associated with monotherapy with the 10 most commonly used antipsychotic drugs. Multivariate models and propensity score methods were used to adjust estimates of effectiveness.Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276).The effectiveness of first and second generation antipsychotics varies greatly in the community. Patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation or discontinuation (for any reason) of their initial treatment than do patients treated with haloperidol. Excess mortality is seen mostly in patients not using antipsychotic drugs.

    View details for DOI 10.1136/bmj.38881.382755.2F

    View details for Web of Science ID 000239496900018

    View details for PubMedID 16825203

  • Not-so-surprising findings - Response CANADIAN MEDICAL ASSOCIATION JOURNAL Ioannidis, J. P., Papanikolaou, P. 2006; 175 (2): 172-172

    View details for DOI 10.1503/cmaj.1060113

    View details for Web of Science ID 000238850100016

  • Commentary: Grading the credibility of molecular evidence for complex diseases INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2006; 35 (3): 572-577

    View details for DOI 10.1093/ije/dyl003

    View details for Web of Science ID 000238763100019

    View details for PubMedID 16540537

  • Origin and funding of the most frequently cited papers in medicine: database analysis BRITISH MEDICAL JOURNAL Patsopoulos, N. A., Analatos, A. A., Ioannidis, J. P. 2006; 332 (7549): 1061-1063

    Abstract

    To evaluate changes in the role of academics and the sources of funding for the medical research cited most frequently over the past decade.Database analysis.Web of Knowledge database.For each year from 1994 to 2003, articles in the domain of clinical medicine that had been cited most often by the end of 2004 were identified. Changes in authors' affiliations and funding sources were evaluated.Of the 289 frequently cited articles, most had at least one author with a university (76%) or hospital (57%) affiliation, and the proportion of articles with each type of affiliation was constant over time. Government or public funding was most common (60% of articles), followed by industry (36%). The proportion of most frequently cited articles funded by industry increased over time (odds ratio 1.17 per year, P = 0.001) and was equal to the proportion funded by government or public sources by 2001. 65 of the 77 most cited randomised controlled trials received funding from industry, and the proportion increased significantly over time (odds ratio 1.59 per year, P = 0.003). 18 of the 32 most cited trials published after 1999 were funded by industry alone.Academic affiliations remain prominent among the authors of the most frequently cited medical research. Such research is increasingly funded by industry, often exclusively so. Academics may be losing control of the clinical research agenda.

    View details for DOI 10.1136/bmj.38768.420139.80

    View details for Web of Science ID 000237518400015

    View details for PubMedID 16547014

  • Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: The GENOMOS study PLOS MEDICINE Ralston, S. H., Uitterlinden, A. G., Brandi, M. L., Balcells, S., Langdahl, B. L., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Scollen, S., Bustamante, M., Husted, L. B., Carey, A. H., Diez-Perez, A., Dunning, A. M., Falchetti, A., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P., van Meurs, J. B., Mangion, J., McGuigan, F. E., Mellibovsky, L., del Monte, F., Pols, H. A., Reeve, J., Reid, D. M., Renner, W., Rivadeneira, F., van Schoor, N. M., Sherlock, R. E., Ioannidis, J. P. 2006; 3 (4): 515-523

    Abstract

    Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

    View details for DOI 10.1371/journal.pmed.0030090

    View details for Web of Science ID 000237548200020

    View details for PubMedID 16475872

  • Self-reported health in high and very high incomes QUALITY OF LIFE RESEARCH Mantzavinis, G. D., Trikalinos, T. A., Dimoliatis, I. D., Ioannidis, J. P. 2006; 15 (3): 547-558

    Abstract

    The objective of the present study was to investigate whether self-reported health (SRH), an overall health indicator, continues to improve as individual income increases to very high levels or whether there is a threshold above which this relationship changes direction. We used data from the 2003 US Current Population Survey, focusing on the upper income decile. We modelled the relationship between income and SRH before and after adjustment for other socio-demographic parameters that are known to influence SRH. In the unadjusted model, SRH increased with increasing income up to the threshold of $326,000, above which SRH declined. After adjustment for all major socio-demographic parameters (age, gender, race, education, and marital status), the adjusted curve showed monotonically increasing SRH with increasing income. Adjustment for each of these parameters separately revealed that the threshold effect was lost only after adjusting for education. There were more people with low levels of educational attainment among those receiving more than $500,000 per year, compared to other people in the upper income decile. Increasing income does not always improve SRH. People in the very high income bracket tend to report slightly worse health, which may be explained by their lower education.

    View details for DOI 10.1007/s11136-005-1770-x

    View details for Web of Science ID 000236100300024

    View details for PubMedID 16547793

  • Comparison of evidence on harms of medical interventions in randomized and nonrandomized studies CANADIAN MEDICAL ASSOCIATION JOURNAL Papanikolaou, P. N., Christidi, G. D., Ioannidis, J. P. 2006; 174 (5): 635-641

    Abstract

    Information on major harms of medical interventions comes primarily from epidemiologic studies performed after licensing and marketing. Comparison with data from large-scale randomized trials is occasionally feasible. We compared evidence from randomized trials with that from epidemiologic studies to determine whether they give different estimates of risk for important harms of medical interventions.We targeted well-defined, specific harms of various medical interventions for which data were already available from large-scale randomized trials (> 4000 subjects). Nonrandomized studies involving at least 4000 subjects addressing these same harms were retrieved through a search of MEDLINE. We compared the relative risks and absolute risk differences for specific harms in the randomized and nonrandomized studies.Eligible nonrandomized studies were found for 15 harms for which data were available from randomized trials addressing the same harms. Comparisons of relative risks between the study types were feasible for 13 of the 15 topics, and of absolute risk differences for 8 topics. The estimated increase in relative risk differed more than 2-fold between the randomized and nonrandomized studies for 7 (54%) of the 13 topics; the estimated increase in absolute risk differed more than 2-fold for 5 (62%) of the 8 topics. There was no clear predilection for randomized or nonrandomized studies to estimate greater relative risks, but usually (75% [6/8]) the randomized trials estimated larger absolute excess risks of harm than the nonrandomized studies did.Nonrandomized studies are often conservative in estimating absolute risks of harms. It would be useful to compare and scrutinize the evidence on harms obtained from both randomized and nonrandomized studies.

    View details for Web of Science ID 000235402600020

    View details for PubMedID 16505459

  • Adverse events: The more you search, the more you find ANNALS OF INTERNAL MEDICINE Ioannidis, J. P., Mulrow, C. D., Goodman, S. N. 2006; 144 (4): 298-300

    View details for Web of Science ID 000235543100010

    View details for PubMedID 16490917

  • Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations AMERICAN JOURNAL OF EPIDEMIOLOGY Trikalinos, T. A., Salanti, G., Khoury, M. J., Ioannidis, J. P. 2006; 163 (4): 300-309

    Abstract

    The authors evaluated whether statistically significant violations of Hardy-Weinberg equilibrium (HWE) or the magnitude of deviations from HWE may contribute to the problem of replicating postulated gene-disease associations across different studies. Forty-two gene-disease associations assessed in meta-analyses of 591 studies were examined. Studies with disease-free controls in which HWE was violated gave significantly different results from HWE-conforming studies in five instances. Exclusion of the former studies resulted in loss of statistical significance of the overall meta-analysis in three instances and more than a 10% change in the summary odds ratio in six. Exclusion of HWE-violating studies changed the formal significance of the estimated between-study heterogeneity in three instances. After adjustment for the magnitude of the deviation from HWE for the controls, formal significance was lost in another three instances. Studies adjusted for the magnitude of deviation from HWE tended to become more heterogeneous among themselves, and, for seven gene-disease associations, between-study heterogeneity became significant, while it was not so in the unadjusted analyses. Gene-disease association studies and meta-analyses thereof should routinely scrutinize the potential impact of HWE violations as well as nonsignificant deviations from the exact frequencies expected under HWE. Postulated genetic associations with modest-sized odds ratios and borderline statistical significance may not be robust in such sensitivity analyses.

    View details for DOI 10.1093/aje/kwj046

    View details for Web of Science ID 000235276600001

    View details for PubMedID 16410351

  • Randomized evidence on chemotherapy and hormonal therapy regimens for advanced endometrial cancer: An overview of survival data EUROPEAN JOURNAL OF CANCER Polyzos, N. P., Pavlidis, N., Paraskevaidis, E., Ioannidis, J. P. 2006; 42 (3): 319-326

    Abstract

    Several chemotherapy and hormonal therapy regimens have been used in advanced endometrial cancer. In this review we have systematically evaluated the available data from randomized trials on survival. We searched MEDLINE, EMBASE and the Cochrane Library (last search April 2005) for randomized controlled trials evaluating various chemotherapy or hormonal therapy regimens in locally advanced or metastatic endometrial cancer. We focused on survival outcomes and examined trial characteristics pertaining to quality and potential biases. Across 17 eligible trials (2964 patients randomized), only 4 regimens were involved in more than one trial, and only two trials had used the same comparison of regimens. A statistically significant effect in survival was seen only in one recent trial, but it was borderline (P = 0.032) and amounted to only 3 months difference in median survival. Three more trials reported some survival benefits, but these were seen only after specific adjustments, and the difference was against the experimental arm in one of these three trials. Only four trials (24%) apparently analyzed all randomized patients and none of the trials were blinded. Median survival was seemingly longer in more recent compared with older trials, but this effect was driven by the inclusion of significantly fewer patients with poor performance status in more recent trials (P < 0.001). Overall, randomized evidence on systemic treatment in advanced endometrial cancer is fragmented and survival benefits for specific regimens are questionable.

    View details for DOI 10.1016/j.ejca.2005.09.026

    View details for Web of Science ID 000235508100015

    View details for PubMedID 16376072

  • beta(2)-adrenergic receptor polymorphism in asthma: Prospective versus retrospective perspective - Reply JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2006; 117 (1): 222-223

    View details for DOI 10.1016/j.jaci.2005.09.005

    View details for Web of Science ID 000235687100045

  • Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus - An international meta-analysis ARTHRITIS AND RHEUMATISM Karassa, F. B., Afeltra, A., Ambrozic, A., Chang, D. M., De Keyser, F., DORIA, A., Galeazzi, M., Hirohata, S., Hoffman, I. E., Inanc, M., Massardo, L., Mathieu, A., Mok, C. C., Morozzi, G., Sanna, G., Spindler, A. J., Tzioufas, A. G., Yoshio, T., Ioannidis, J. P. 2006; 54 (1): 312-324

    Abstract

    To quantitatively evaluate the diagnostic accuracy of antibodies to ribosomal P proteins (anti-P) for neuropsychiatric systemic lupus erythematosus (NPSLE) in general, for psychosis, mood disorder, or both, and for other diffuse manifestations.This international meta-analysis combined standardized data from 1,537 lupus patients contributed by 14 research teams. Weighted estimation of sensitivity and specificity with fixed-effects and random-effects models, as well as summary receiver operating characteristic (SROC) curve analysis, was used to summarize test performance. The robustness of the overall estimates was examined in sensitivity analyses that included additional studies published up to November 1, 2004 in the Medline, EMBase, and Cochrane databases.Combining the data from the 14 teams, the weighted sensitivity and specificity estimates for the diagnosis of NPSLE were 26% (95% confidence interval [95% CI] 15-42%) and 80% (95% CI 74-85%), respectively. For psychosis, mood disorder, or both, the sensitivity and specificity were 27% (95% CI 14-47%) and 80% (95% CI 74-85%), respectively. For other diffuse manifestations, the sensitivity was 24% (95% CI 12-42%), and the specificity was 80% (95% CI 73-85%). The proportion of patients with anti-P antibodies did not vary markedly across different presentations of NPSLE. Between-study heterogeneity was substantial, but the SROC curves were consistent with the weighted estimates. In further analyses that included another 24 published studies, only the sensitivity for psychosis and/or mood disorder was slightly improved, but it was still suboptimal (42% [95% CI 30-53%]); the specificity remained essentially the same (81% [95% CI 76-85%]).Anti-P antibody testing has limited diagnostic value for NPSLE, and it is not helpful in differentiating among various disease phenotypes.

    View details for DOI 10.1002/art.21539

    View details for Web of Science ID 000234605200038

    View details for PubMedID 16385548

  • Susceptibility to HIV infection - Disentangling host genetics and host behavior JOURNAL OF INFECTIOUS DISEASES Telenti, A., Ioannidis, J. P. 2006; 193 (1): 4-6

    View details for Web of Science ID 000234182800002

    View details for PubMedID 16323124

  • Journals should publish all "null" results and should sparingly publish "positive" results CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ioannidis, J. P. 2006; 15 (1): 186-186

    View details for Web of Science ID 000234866200038

    View details for PubMedID 16434613

  • A road map for efficient and reliable human genome epidemiology NATURE GENETICS Ioannidis, J. P., Gwinn, M., Little, J., Higgins, J. P., Bernstein, J. L., Boffetta, P., Bondy, M., Bray, M. S., Brenchley, P. E., Buffler, P. A., Casas, J. P., Chokkalingam, A., Danesh, J., Smith, G. D., Dolan, S., DUNCAN, R., Gruis, N. A., Hartge, P., Hashibe, M., Hunter, D. J., Jarvelin, M. R., Malmer, B., Maraganore, D. M., Newton-Bishop, J. A., O'Brien, T. R., Petersen, G., Riboli, E., Salanti, G., Seminara, D., Smeeth, L., Taioli, E., Timpson, N., Uitterlinden, A. G., Vineis, P., Wareham, N., Winn, D. M., Zimmern, R., Khoury, M. J. 2006; 38 (1): 3-5

    Abstract

    Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.

    View details for DOI 10.1038/ng0106-3

    View details for Web of Science ID 000234227200002

    View details for PubMedID 16468121

  • A heterogeneity-based genome search meta-analysis for autism-spectrum disorders MOLECULAR PSYCHIATRY Trikalinos, T. A., Karvouni, A., Zintzaras, E., Ylisaukko-oja, T., Peltonen, L., Jarvela, I., Ioannidis, J. P. 2006; 11 (1): 29-36

    Abstract

    Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtained through Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. For autism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestive significance was reached for the chromosomal regions 17p11.2-q12 and 10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggests that the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.

    View details for DOI 10.1038/sj.mp.4001750

    View details for Web of Science ID 000233971300007

    View details for PubMedID 16189507

  • Local literature bias in genetic epidemiology: An empirical evaluation of the Chinese literature PLOS MEDICINE Pan, Z. L., Trikalinos, T. A., Kavvoura, F. K., Lau, J., Ioannidis, J. P. 2005; 2 (12): 1309-1317

    Abstract

    Postulated epidemiological associations are subject to several biases. We evaluated whether the Chinese literature on human genome epidemiology may offer insights on the operation of selective reporting and language biases.We targeted 13 gene-disease associations, each already assessed by meta-analyses, including at least 15 non-Chinese studies. We searched the Chinese Journal Full-Text Database for additional Chinese studies on the same topics. We identified 161 Chinese studies on 12 of these gene-disease associations; only 20 were PubMed-indexed (seven English full-text). Many studies (14-35 per topic) were available for six topics, covering diseases common in China. With one exception, the first Chinese study appeared with a time lag (2-21 y) after the first non-Chinese study on the topic. Chinese studies showed significantly more prominent genetic effects than non-Chinese studies, and 48% were statistically significant per se, despite their smaller sample size (median sample size 146 versus 268, p < 0.001). The largest genetic effects were often seen in PubMed-indexed Chinese studies (65% statistically significant per se). Non-Chinese studies of Asian-descent populations (27% significant per se) also tended to show somewhat more prominent genetic effects than studies of non-Asian descent (17% significant per se).Our data provide evidence for the interplay of selective reporting and language biases in human genome epidemiology. These biases may not be limited to the Chinese literature and point to the need for a global, transparent, comprehensive outlook in molecular population genetics and epidemiologic studies in general.

    View details for DOI 10.1371/journal.pmed.0020334

    View details for Web of Science ID 000234714700019

    View details for PubMedID 16285839

  • Unavailability of online supplementary scientific information from articles published in major journals FASEB JOURNAL Evangelou, E., Trikalinos, T. A., Ioannidis, J. P. 2005; 19 (14): 1943-1944

    Abstract

    Printed articles increasingly rely on online supplements to store critical scientific information, but such data may eventually become unavailable. We checked the current availability of online supplementary scientific information published in six top-cited scientific journals (Science, Nature, Cell, New England Journal of Medicine, Lancet, Proceedings of the National Academy of Sciences USA). Here we show that in 4.7% and 9.6% of articles with online supplementary material, some of the supplements became unavailable within 2 and 5 years of their publication, respectively.

    View details for DOI 10.1096/fj.05-4784lsf

    View details for Web of Science ID 000234405500004

    View details for PubMedID 16319137

  • HEGESMA: genome search meta-analysis and heterogeneity testing BIOINFORMATICS Zintzaras, E., Ioannidis, J. P. 2005; 21 (18): 3672-3673

    Abstract

    Heterogeneity and genome search meta-analysis (HEGESMA) is a comprehensive software for performing genome scan meta-analysis, a quantitative method to identify genetic regions (bins) with consistently increased linkage score across multiple genome scans, and for testing the heterogeneity of the results of each bin across scans. The program provides as an output the average of ranks and three heterogeneity statistics, as well as corresponding significance levels. Statistical inferences are based on Monte Carlo permutation tests. The program allows both unweighted and weighted analysis, with the weights for each study as specified by the user. Furthermore, the program performs heterogeneity analyses restricted to the bins with similar average ranks.http://biomath.med.uth.gr.

    View details for DOI 10.1093/bioinformatics/bti536

    View details for Web of Science ID 000231694600015

    View details for PubMedID 15955784

  • Molecular bias EUROPEAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P. 2005; 20 (9): 739-745

    Abstract

    Bias is ubiquitous in research. The advent of the molecular era provides a unique opportunity to study the consequences of bias with large-scale empirical evidence accumulated in the massive data produced by the current discovery-oriented scientific effort, rather than just with theoretical speculations and constructs. Here I discuss some empirical evidence about manifestations of bias in molecular epidemiology. Bias may manifest as either heterogeneity or as deviation from the true estimates. The failure to translate molecular knowledge and the failure to replicate information are some typical hallmarks of bias at action. The acquired knowledge about the behaviour and manifestations of bias in molecular fields can be transferred back also to more traditional fields of epidemiology and medical research. Getting rid of false claims of the past is at least as important as producing new scientific discoveries. In many fields, the observed effects sizes that circulate as established knowledge are practically estimating only the net bias that has operated in the field all along. Issues of plausibility (in particular biological plausibility), replication, and credibility that form the theoretical basis of epidemiology and etiological inference can now be approached with large-scale empirical data.

    View details for DOI 10.1007/s10654-005-2028-1

    View details for Web of Science ID 000231974100001

    View details for PubMedID 16170656

  • A network of investigator networks in human genome epidemiology AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Bernstein, J., Boffetta, P., Danesh, J., Dolan, S., Hartge, P., Hunter, D., Inskip, P., Jarvelin, M. R., Little, J., Maraganore, D. M., Bishop, J. A., O'Brien, T. R., Petersen, G., Riboli, E., Seminara, D., Taioli, E., Uitterlinden, A. G., Vineis, P., Winn, D. M., Salanti, G., Higgins, J. P., Khoury, M. J. 2005; 162 (4): 302-304

    Abstract

    The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort.

    View details for DOI 10.1093/aje/kwi201

    View details for Web of Science ID 000231150600002

    View details for PubMedID 16014777

  • Reply to Badri et al. on 'Limited benefit of antiretroviral resistance testing in treatment-experienced patients: a meta-analvsis' AIDS Trikalinos, T. A., Panidou, E. T., Ioannidis, J. P. 2005; 19 (12): 1336-1337

    View details for Web of Science ID 000231316800019

    View details for PubMedID 16052096

  • Why most published research findings are false PLOS MEDICINE Ioannidis, J. P. 2005; 2 (8): 696-701

    Abstract

    There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

    View details for DOI 10.1371/journal.pmed.0020124

    View details for Web of Science ID 000231676900008

    View details for PubMedID 16060722

  • Selective reporting biases in cancer prognostic factor studies JOURNAL OF THE NATIONAL CANCER INSTITUTE Kyzas, P. A., Loizou, K. T., Ioannidis, J. P. 2005; 97 (14): 1043-1055

    Abstract

    Nonreported and selectively reported information and the use of different definitions may introduce biases in the literature of prognostic factors. We probed these biases in a meta-analysis of a prognostic factor for head and neck squamous cell cancer (HNSCC) mortality that has drawn wide attention--the status of the tumor suppressor protein TP53.We compared results of meta-analyses that included published data plus unpublished data retrieved from investigators; published data; and only published data indexed with "survival" or "mortality" in MEDLINE/EMBASE, with or without standardized definitions. We also evaluated whether previously published meta-analyses on mortality predictors for various malignancies addressed issues of retrieval and standardized information. All statistical tests were two-sided.For the 18 studies with 1364 patients that included published and indexed data, we obtained a highly statistically significant association between TP53 status and mortality. When we used the definitions preferred by each publication, the association was stronger (risk ratio [RR] = 1.38, 95% confidence interval [CI] = 1.13 to 1.67; P = .001) than when we standardized definitions (RR = 1.27, 95% CI = 1.06 to 1.53; P = .011). The addition of 13 studies with 1028 subjects that included published but not indexed data reduced the observed association (RR = 1.23, 95% CI = 1.03 to 1.47; P = .02). Finally, when we obtained data from investigators (11 studies with 996 patients) and analyzed it with all other data, statistical significance was lost (RR = 1.16, 95% CI = 0.99 to 1.35; P = .06). Among 18 published meta-analyses of 37 cancer prognostic factors, 13 (72%) did not use standardized definitions and 16 (89%) did not retrieve additional information.Selective reporting may spuriously inflate the importance of postulated prognostic factors for various malignancies. We recommend that meta-analyses thereof should maximize retrieval of information and standardize definitions.

    View details for DOI 10.1093/jnci/dji184

    View details for Web of Science ID 000230523400009

    View details for PubMedID 16030302

  • Contradicted and initially stronger effects in highly cited clinical research JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2005; 294 (2): 218-228

    Abstract

    Controversy and uncertainty ensue when the results of clinical research on the effectiveness of interventions are subsequently contradicted. Controversies are most prominent when high-impact research is involved.To understand how frequently highly cited studies are contradicted or find effects that are stronger than in other similar studies and to discern whether specific characteristics are associated with such refutation over time.All original clinical research studies published in 3 major general clinical journals or high-impact-factor specialty journals in 1990-2003 and cited more than 1000 times in the literature were examined.The results of highly cited articles were compared against subsequent studies of comparable or larger sample size and similar or better controlled designs. The same analysis was also performed comparatively for matched studies that were not so highly cited.Of 49 highly cited original clinical research studies, 45 claimed that the intervention was effective. Of these, 7 (16%) were contradicted by subsequent studies, 7 others (16%) had found effects that were stronger than those of subsequent studies, 20 (44%) were replicated, and 11 (24%) remained largely unchallenged. Five of 6 highly-cited nonrandomized studies had been contradicted or had found stronger effects vs 9 of 39 randomized controlled trials (P = .008). Among randomized trials, studies with contradicted or stronger effects were smaller (P = .009) than replicated or unchallenged studies although there was no statistically significant difference in their early or overall citation impact. Matched control studies did not have a significantly different share of refuted results than highly cited studies, but they included more studies with "negative" results.Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes. The extent to which high citations may provoke contradictions and vice versa needs more study. Controversies are most common with highly cited nonrandomized studies, but even the most highly cited randomized trials may be challenged and refuted over time, especially small ones.

    View details for Web of Science ID 000230406100026

    View details for PubMedID 16014596

  • CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: A HuGE review and meta-analysis AMERICAN JOURNAL OF EPIDEMIOLOGY Kavvoura, F. K., Ioannidis, J. P. 2005; 162 (1): 3-16

    Abstract

    The authors performed a meta-analysis of 33 studies examining the association of type 1 diabetes mellitus with polymorphisms in the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene, including the A49G (29 comparisons), C(-318)T (three comparisons), and (AT)n microsatellite (six comparisons) polymorphisms. The studies included 5,637 cases of type 1 diabetes and 6,759 controls (4,775 and 5,829, respectively, for analysis of the A49G polymorphism). The random-effects odds ratio for the *G (Ala) allele versus the *A (Thr) allele was 1.45 (95% confidence interval (CI): 1.28, 1.65), with significant between-study heterogeneity (p < 0.001). The effect size tended to be higher in type 1 diabetes cases with age of onset <20 years (odds ratio (OR) = 1.61), and there was a significant association between the presence of glutamic acid decarboxylase-65 autoantibodies and the *G allele among type 1 diabetes cases (OR = 1.49). Larger studies showed more conservative results (p = 0.011). After exclusion of studies with fewer than 150 subjects and studies with significant deviation from Hardy-Weinberg equilibrium in the controls, the summary odds ratio was 1.40 (95% CI: 1.28, 1.54). Available data showed no strong association for the 106-base-pair allele of the microsatellite polymorphism (OR = 0.99, 95% CI: 0.64, 1.55) or the *T allele of the C(-318)T polymorphism (OR = 0.92, 95% CI: 0.45, 1.89). This meta-analysis demonstrates that the CTLA-4*G genotype is associated with type 1 diabetes.

    View details for DOI 10.1093/aje/kwi165

    View details for Web of Science ID 000230088300002

    View details for PubMedID 15961581

  • Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power EUROPEAN JOURNAL OF HUMAN GENETICS Salanti, G., Amountza, G., Ntzani, E. E., Ioannidis, J. P. 2005; 13 (7): 840-848

    Abstract

    We evaluated the testing and reporting of Hardy-Weinberg equilibrium (HWE) in recent genetic association studies, detected how frequently HWE was violated and estimated the power for HWE testing in this literature. Genetic association studies published in 2002 in Nature Genetics, American Journal of Human Genetics, and American Journal of Medical Genetics were assessed. Data were analyzed on 239 biallelic associations using 154 distinct genotype distribution data sets where HWE could be tested. Any information on HWE was given only for 150 (62.8%) associations (92 (59.7%) data sets). Reanalysis of the data showed significant deviation from HWE in the disease-free controls of 20 associations (13 data sets), but only four of them (two data sets) were admitted in the published articles. Another four deviations (in two data sets) were observed in the combined sample of cases and controls of studies where both cases and controls were diseased, and none were reported in the papers. In all six tested multiallelic associations (six data sets), there was violation of HWE, but this was not admitted in the published articles. Power calculations showed that most studies conforming to HWE simply were largely underpowered to detect HWE deviation; for example, power to detect an inbreeding of magnitude F=0.10 exceeded 80% in only 11 (7%) of the data sets being tested. This empirical evidence suggests that, even in high profile genetics journals, testing and reporting for HWE is often neglected and deviations are rarely admitted in the published reports. Moreover, power is limited for HWE testing in most current genetic association studies.

    View details for Web of Science ID 000229977200010

    View details for PubMedID 15827565

  • International collaboration, funding and association with burden of disease in randomized controlled trials in Africa BULLETIN OF THE WORLD HEALTH ORGANIZATION Swingler, G. H., Pillay, V., Pienaar, E. D., Ioannidis, J. P. 2005; 83 (7): 511-517

    Abstract

    This study aimed to assess whether randomized controlled trials conducted in Africa with collaborators from outside Africa were more closely associated with health conditions that have a burden of disease that is of specific importance to Africa than with conditions of more general global importance or with conditions important to developed countries. We also assessed whether the source of funding influenced a study's relevance to Africa.We compared randomized controlled trials performed in Africa that looked at diseases specifically relevant to Africa (as determined by burden of disease criteria) with trials classified as looking at diseases of global importance or diseases important to developed countries in order to assess differences in collaboration and funding.Of 520 trials assessed, 347 studied diseases that are specifically important to Africa; 99 studied globally important diseases and 74 studied diseases that are important to developed countries. The strongest independent predictor of whether a study was of specifically African or global importance was the corresponding author's country of origin: African importance was negatively associated with a corresponding author being from South Africa (odds ratio (OR) = 0.04; 95% confidence interval (CI) = 0.02-0.10) but there was little difference between corresponding authors from other African countries and corresponding authors from countries outside Africa. The importance of a study to Africa was independently associated with having more non-African authors (OR per author = 1.31; 95% CI = 1.08-1.58), fewer trial sites (OR per site = 0.69; 95% CI = 0.50-0.96), and reporting of funding (OR = 2.14; 95% CI = 1.15-4.00). Similar patterns were present in the comparisons of trials studying diseases important to Africa versus those studying diseases important to developed countries with stronger associations overall. When funding was reported, private industry funding was negatively associated with African importance compared with global importance (OR = 0.31, P= 0.008 for African importance and OR = 0.51, P= 0.57 for importance for developed countries).The relevance to Africa of trials conducted in Africa was not adversely affected by collaboration with non-African researchers but funding from private industry was associated with a decreased emphasis on diseases relevant to Africa.

    View details for Web of Science ID 000230466700008

    View details for PubMedID 16175825

  • Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease - A meta-analysis CIRCULATION Katritsis, D. G., Ioannidis, J. P. 2005; 111 (22): 2906-2912

    Abstract

    Percutaneous coronary intervention (PCI) has been shown to improve symptoms compared with conservative medical treatment in patients with stable coronary artery disease (CAD); however, there is limited evidence on the effect of PCI on the risk of death, myocardial infarction, and subsequent revascularization. Therefore, we performed a meta-analysis of 11 randomized trials comparing PCI to conservative treatment in patients with stable CAD.A total of 2950 patients were included in the meta-analysis (1476 received PCI, and 1474 received conservative treatment). There was no significant difference between the 2 treatment strategies with regard to mortality, cardiac death or myocardial infarction, nonfatal myocardial infarction, CABG, or PCI during follow-up. By random effects, the risk ratios (95% CIs) for the PCI versus conservative treatment arms were 0.94 (0.72 to 1.24), 1.17 (0.88 to 1.57), 1.28 (0.94 to 1.75), 1.03 (0.80 to 1.33), and 1.23 (0.80 to 1.90) for these 5 outcomes, respectively. A possible survival benefit was seen for PCI only in trials of patients who had a relatively recent myocardial infarction (risk ratio 0.40, 95% CI 0.17 to 0.95). Except for PCI during follow-up, there was no significant between-study heterogeneity for any outcome.In patients with chronic stable CAD, in the absence of a recent myocardial infarction, PCI does not offer any benefit in terms of death, myocardial infarction, or the need for subsequent revascularization compared with conservative medical treatment.

    View details for DOI 10.1161/CIRCULATIONAHA.104.521864

    View details for Web of Science ID 000229600700008

    View details for PubMedID 15927966

  • Creatine kinase-MB elevation following stent implantation JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ioannidis, J. P., Karvouni, E., Katritsis, D. G. 2005; 45 (11): 1908-1908

    View details for DOI 10.1016/j.jacc.2005.03.006

    View details for Web of Science ID 000229593000034

    View details for PubMedID 15936632

  • Re: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis - Response JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Pavlidis, N., Ioannidis, J. P. 2005; 97 (11): 858-859

    View details for DOI 10.1093/jnci/dji148

    View details for Web of Science ID 000229939000017

  • F-18-FDG PET for evaluation of bone marrow infiltration in staging of lymphoma: A meta-analysis JOURNAL OF NUCLEAR MEDICINE Pakos, E. E., Fotopoulos, A. D., Ioannidis, J. P. 2005; 46 (6): 958-963

    Abstract

    The ability of PET with (18)F-FDG to evaluate bone marrow infiltration in patients with lymphoma has been a matter of extensive investigation with controversial results. Therefore, we aimed to evaluate systematically, with a meta-analysis, the diagnostic performance of (18)F-FDG PET in this setting.Relevant studies were identified with MEDLINE and EMBASE searches (last update, August 2004). Data on the diagnostic performance of (18)F-FDG PET were combined quantitatively across eligible studies. We estimated weighted summary sensitivities and specificities, summary receiver-operating-characteristic (SROC) curves, and weighted summary likelihood ratios. We also conducted separate analyses according to various subgroups. Bone marrow biopsy (BMB) was used as the reference standard.Thirteen eligible nonoverlapping studies, which enrolled a total of 587 patients, were included in the meta-analysis. The independent random-effects weighted estimates of sensitivity and specificity against BMB were 51% (95% confidence interval [CI], 38%-64%) and 91% (95% CI, 85%-95%), respectively. Results were consistent in the SROC curve: a sensitivity of 51% corresponds to a specificity of 92%, whereas a specificity of 91% corresponds to a sensitivity of 55%. The weighted positive likelihood ratio (LR+) was 5.75 (95% CI, 348-9.48) and the negative likelihood ratio (LR-) was 0.67 (95% CI, 0.55-0.82). Six of 12 patients with positive (18)F-FDG PET and negative initial biopsy were found to have bone marrow involvement when biopsy was performed at the sites with positive imaging signals. Subgroup analyses showed better sensitivity in patients with Hodgkin's disease and in aggressive histologic types of non-Hodgkin's lymphoma than in patients with less aggressive histologic types and in studies using unilateral BMB compared with those using bilateral biopsy.This meta-analysis showed that (18)F-FDG PET has good, but not excellent, concordance with the results of BMB for the detection of bone marrow infiltration in the staging of patients with lymphoma. (18)F-FDG PET may complement the results of BMB and its performance may vary according to the type of lymphoma.

    View details for Web of Science ID 000229644000017

    View details for PubMedID 15937306

  • Early extreme contradictory estimates may appear in published research: The Proteus phenomenon in molecular genetics research and randomized trials JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Trikalinos, T. A. 2005; 58 (6): 543-549

    Abstract

    Divergent results on the same scientific question generate controversy. We hypothesized that controversial data are attractive to investigators and editors, and thus the most extreme, opposite results would appear very early rather than late, as data accumulate, provided data can be generated rapidly.We used data from MEDLINE-indexed meta-analyses of case-control studies on genetic associations (retrospective, hypothesis-generating research with usually rapid turnaround) and meta-analyses of randomized trials of health care interventions (prospective, targeted research that usually takes longer) sampled from the Cochrane Library. Using cumulative meta-analysis, we evaluated how the between-study variance for studies on the same question changed over time and at what point the studies with the most extreme results ever observed had been published.The maximal between-study variance was more likely to be recorded early in the 44 eligible meta-analyses of genetic associations than in the 37 meta-analyses of health care interventions (P = .013). At the time of the first heterogeneity assessment, the most favorable-ever result in support of a specific association was more likely to appear than the least favorable-ever result (22 vs. 10, P = .017); the opposite was seen at the second heterogeneity assessment (15 vs. 5, P = .031). Such a sequence of extreme opposite results was not seen in the clinical trials meta-analyses. The estimated between-study variance decreased over time in genetic association studies (P = .010), but not in clinical trials (P = .30).In contrast to prospective trials, a rapid early sequence of extreme, opposite results is frequent in retrospective hypothesis-generating molecular research.

    View details for DOI 10.1016/j.jclinepi.2004.10.019

    View details for Web of Science ID 000229350000001

    View details for PubMedID 15878467

  • Relative citation impact of various study designs in the health sciences JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Patsopoulos, N. A., Analatos, A. A., Ioannidis, J. P. 2005; 293 (19): 2362-2366

    Abstract

    The relative merits of various study designs and their placement in hierarchies of evidence are often discussed. However, there is limited knowledge about the relative citation impact of articles using various study designs.To determine whether the type of study design affects the rate of citation in subsequent articles.We measured the citation impact of articles using various study designs--including meta-analyses, randomized controlled trials, cohort studies, case-control studies, case reports, nonsystematic reviews, and decision analysis or cost-effectiveness analysis--published in 1991 and in 2001 for a sample of 2646 articles.The citation count through the end of the second year after the year of publication and the total received citations.Meta-analyses received more citations than any other study design both in 1991 (P<.05 for all comparisons) and in 2001 (P<.001 for all comparisons) and both in the first 2 years and in the longer term. More than 10 citations in the first 2 years were received by 32.4% of meta-analyses published in 1991 and 43.6% of meta-analyses published in 2001. Randomized controlled trials did not differ significantly from epidemiological studies and nonsystematic review articles in 1991 but clearly became the second-cited study design in 2001. Epidemiological studies, nonsystematic review articles, and decision and cost-effectiveness analyses had relatively similar impact; case reports received negligible citations. Meta-analyses were cited significantly more often than all other designs after adjusting for year of publication, high journal impact factor, and country of origin. When limited to studies addressing treatment effects, meta-analyses received more citations than randomized trials.Overall, the citation impact of various study designs is commensurate with most proposed hierarchies of evidence.

    View details for Web of Science ID 000229120600023

    View details for PubMedID 15900006

  • Expectant, medical, or surgical management of first-trimester miscarriage: A meta-analysis OBSTETRICS AND GYNECOLOGY Sotiriadis, A., Makrydimas, G., Papatheodorou, S., Ioannidis, J. P. 2005; 105 (5): 1104-1113

    Abstract

    To quantify the relative benefits and harms of different management options for first-trimester miscarriage.MEDLINE, EMBASE, and Cochrane Controlled Trials Register searches (1966 to July 2004), including references of retrieved articles.Randomized trials assigning women with first-trimester missed or incomplete miscarriage to surgical, medical, or expectant management were included. Primary outcomes were successful treatment and patient satisfaction. Secondary outcomes included moderate or severe bleeding, blood transfusion, emergency curettage, pelvic inflammatory disease, nausea, vomiting, and diarrhea. Comparisons used the risk difference. Between-study heterogeneity and random effects summary estimates were calculated.Complete evacuation of the uterus was significantly more common with surgical than medical management (risk difference 32.8%, number needed to treat 3, success rate of medical management 62%) and with medical than expectant management (risk difference 49.7%, number needed to treat 2). Success rate with expectant management was spuriously low (39%) in the latter comparison. Analysis of cases with incomplete miscarriage only showed that medical management still had two thirds the chance to induce complete evacuation compared with surgical management, but it was better than expectant management. Data from studies that evaluated outcome at 48 hours or more after allocation indicated again that medical management had a better success rate than expectant management but a worse success rate than surgical management; expectant management probably had much lower success rates than surgical evacuation, but data were very sparse. Patient satisfaction data were sparse. Moderate or severe bleeding was less common with medical than expectant management (risk difference 3.2%) and possibly surgical management (risk difference 2.1%). There was a considerable amount of missing information, in particular for secondary outcomes.One additional success can be achieved among 3 women treated surgically rather than medically. Expectant management has had remarkably variable success rates across these studies, depending probably on the type of miscarriage. Greater standardization of outcomes should be a goal of future research.

    View details for DOI 10.1097/01.AOG.0000158857.44046.a4

    View details for Web of Science ID 000228674200026

    View details for PubMedID 15863551

  • Multivariate models of self-reported health often neglected essential candidate determinants and methodological issues JOURNAL OF CLINICAL EPIDEMIOLOGY Mantzavinis, G. D., Pappas, N., Dimoliatis, L. D., Ioannidis, J. P. 2005; 58 (5): 436-443

    Abstract

    Self-reported health is an important indicator of overall well-being that may be influenced by diverse parameters. We intended to evaluate the variety of candidate determinants used in models of self-reported health (SRH) and to examine the methodological problems encountered in multivariate models used in recent studies in this field.Medline searches identified articles published in 2002 in which SRH was included as an outcome, at least one other variable was used as a determinant of SRH, and the study population was not defined by the presence of specific diseases.Of 1,991 initially identified reports, 56 were eligible. In 91% of the eligible articles, multivariate models were used. In total, 133 different determinants of SRH were considered (median 7 determinants considered per study with multivariate models). The proportions of studies with problems in multivariate modeling were: overfitting, 10%; nonconformity to a linear gradient, 29%; no report of tests for interactions, 63%; unspecified coding of variables, 49%; and unspecified selection of variables, 29%.Models that try to identify what influences SRH should consider appropriate lists of candidate determinants, with proper attention to methodological aspects of multivariate modeling.

    View details for DOI 10.1016/j.jclinepi.2004.08.016

    View details for Web of Science ID 000229008000002

    View details for PubMedID 15845329

  • Meta-analysis of the association of beta 2-adrenergic receptor polymorphisms with asthma phenotypes JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Contopoulos-Ioannidis, D. G., Manoli, E. N., Ioannidis, J. P. 2005; 115 (5): 963-972

    Abstract

    Two common polymorphisms of the beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu ) have been extensively studied for their possible association with asthma-related phenotypes, but the results of individual studies have been inconclusive.We aimed to integrate quantitatively the available evidence on the association of the Arg16Gly and the Gln27Glu polymorphisms with asthma, nocturnal asthma, asthma severity, and bronchial hyperresponsiveness.Meta-analysis of case-control and cohort studies using random effects models.A total of 28 studies were included in the meta-analysis. The summary estimates suggested that neither the Gly16 nor the Glu27 allele contributes to asthma susceptibility overall (odds ratio [OR], 1.01; 95% CI, 0.90-1.13; and OR, 0.95; 95% CI, 0.83-1.09, respectively) or to bronchial hyperresponsiveness (OR, 0.90; 95% CI, 0.77-1.05; and OR, 1.07; 95% CI, 0.94-1.22, respectively). There was a strong association of Gly16 with nocturnal asthma (OR, 2.20; 95% CI, 1.56-3.11) and a less strong association with severe or moderate rather than milder asthma (OR, 1.42; 95% CI, 1.04-1.94). No such effects were seen for the Glu27 allele (OR, 1.02; 95% CI, 0.74-1.40; and OR, 0.82; 95% CI, 0.59-1.14, respectively). Moreover, there was evidence that Gly16 homozygotes had a much higher risk for nocturnal asthma (OR, 5.15; 95% CI, 2.44-10.84) and asthma severity (OR, 2.84; 95% CI, 1.62-4.96) than the Arg16 homozygotes.The Gly16 allele of the beta2-adrenergic receptor gene predisposes to nocturnal asthma, and this may also explain the association with asthma severity. Neither polymorphism modulates the risk for bronchial hyperresponsiveness or mild asthma.

    View details for DOI 10.1016/j.jaci.2004.12.1119

    View details for Web of Science ID 000229055100011

    View details for PubMedID 15867853

  • Comparison of large versus smaller randomized trials for mental health-related interventions AMERICAN JOURNAL OF PSYCHIATRY Contopoulos-Ioannidis, D. G., Gilbody, S. M., Trikalinos, T. A., Churchill, R., Wahlbeck, K., Ioannidis, J. P. 2005; 162 (3): 578-584

    Abstract

    The extent of disagreement between large and smaller randomized, controlled trials on mental health issues is unknown. The authors aimed to compare the results of large versus smaller trials on mental health-related interventions.The authors screened 161 Cochrane and 254 Database of Abstracts of Reviews of Effectiveness systematic reviews on mental health-related interventions. They identified 16 meta-analyses with at least one "large" randomized trial with sample size >800 and at least one "smaller" trial. Effect sizes were calculated separately for large and smaller trials. Heterogeneity was assessed between all studies, within each group (large and smaller studies), and between large and smaller studies.Significant between-study heterogeneity was seen in five meta-analyses. By random-effects calculations, the results of large and smaller trials differed beyond chance in four meta-analyses (25%). In three of these disagreements (effect of day care on IQ, discontinuation of antidepressants, risperidone versus typical antipsychotics for schizophrenia), the smaller trials showed greater effect sizes than the large trials. The inverse was seen in one case (olanzapine versus typical antipsychotics for schizophrenia). With fixed-effects models, disagreements beyond chance occurred in five cases (31%). In four meta-analyses, the effect size differed over twofold between large and smaller trials. Various quality and design parameters were identified as potential explanations for some disagreements.Large trials are uncommon in mental health. Their results are usually comparable with the results of smaller studies, but major disagreements do occur. Both large and smaller trials should be scrutinized as they offer a continuum of randomized evidence.

    View details for Web of Science ID 000227523500022

    View details for PubMedID 15741476

  • Extended-interval aminoglycosides in children: More guidance is needed - Reply PEDIATRICS Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2005; 115 (3): 828-828

    View details for DOI 10.1542/peds.2004-2721

    View details for Web of Science ID 000227596900058

  • Meta-analysis comparing drug-eluting stents with bare metal stents AMERICAN JOURNAL OF CARDIOLOGY Katritsis, D. G., Karvouni, E., Ioannidis, J. P. 2005; 95 (5): 640-643

    Abstract

    We performed a meta-analysis of 10 randomized trials of 5,066 patients with 6 to 12 months of follow-up. The summary risk differences excluded any major differences between the 2 types of stents for death (0.12%, 95% confidence interval [CI] -0.34% to 0.58%, p = 0.60) and overall myocardial infarction (0.04%, 95% CI -0.72% to 0.81%, p = 0.91). There was a modest increase in the risk of Q-wave myocardial infarction with drug-eluting stents (0.36%, 95% CI -0.04% to 0.77%, p = 0.080) but no difference in non-Q-wave myocardial infarction (-0.26%, 95% CI -0.95% to 0.43%, p = 0.47). The trend for increased risk of Q-wave myocardial infarction was seen for paclitaxel and sirolimus stents (risk differences 0.28% and 0.58%, respectively). Drug-eluting stents also had a nonsignificant trend for higher risk of thrombosis (0.29%, 95% CI -0.08% to 0.66%, p = 0.13). We conclude that sirolimus- and paclitaxel-eluting stents are equivalent to bare-metal stents in terms of mortality and overall myocardial infarction risk for the first year of follow-up; the meta-analysis excludes with considerable confidence the presence of large, clinically relevant differences for these outcomes.

    View details for DOI 10.1016/j.amjcard.2004.10.041

    View details for Web of Science ID 000227156400020

    View details for PubMedID 15721109

  • CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis PHARMACOGENETICS AND GENOMICS Patsopoulos, N. A., Ntzani, E. E., Zintzaras, E., Ioannidis, J. P. 2005; 15 (3): 151-158

    Abstract

    The present study aimed to evaluate whether there is any association between CYP2D6 alleles and susceptibility to tardive dyskinesia in patients with schizophrenia under treatment. A meta-analysis considered case-control studies determining the distribution of genotypes for any CYP2D6 polymorphism in unrelated tardive dyskinesia cases and controls without tardive dyskinesia among patients with schizophrenia who were treated with antipsychotic agents. Loss of function alleles were grouped together in a single comparison, whereas other alleles (2 and 10) were examined separately. Data were available for eight (n=569 patients), three (n=325 patients) and four (n=556) studies evaluating the effect of the loss of function alleles, the 2 allele and the 10 allele, respectively. Summary odds ratios (ORs) suggested that loss of function alleles increased the risk of tardive dyskinesia significantly [OR=1.43, 95% confidence interval (CI) 1.06-1.93, P=0.021], whereas there was no effect for 2 and inconclusive evidence for 10 (OR=0.82, 95% CI 0.50-1.32, P=0.41 and OR=1.19, 95% CI, 0.89-1.60, P=0.24, respectively). Patients who were homozygotes for loss of function alleles (poor metabolizers) had 1.64-fold greater odds of suffering tardive dyskinesia compared to other patients with schizophrenia, but the effect was not formally significant (95% CI 0.79-3.43). For the risk conferred by loss of function alleles, large studies provided more conservative estimates of a genetic effect than smaller studies (P=0.003). CYP2D6 loss of function alleles may predispose to tardive dyskinesia in patients with schizophrenia under treatment, but bias cannot be excluded.

    View details for Web of Science ID 000228902600003

    View details for PubMedID 15861039

  • Meta-analysis: Test performance of ultrasonography for giant-cell arteritis ANNALS OF INTERNAL MEDICINE Karassa, F. B., Matsagas, M. I., Schmidt, W. A., Ioannidis, J. P. 2005; 142 (5): 359-369

    Abstract

    Giant-cell arteritis is a diagnostic challenge.To determine the diagnostic performance of ultrasonography for giant-cell arteritis.Studies published up to April 2004 in the MEDLINE, EMBASE, and Cochrane databases; reference lists; and direct contact with investigators.Studies in any language that examined temporal artery ultrasonography for diagnosis of giant-cell arteritis, enrolled at least 5 patients, and used biopsy or the American College of Rheumatology (ACR) criteria as the reference standard.Two reviewers independently graded methodologic quality and abstracted data on sensitivity and specificity of ultrasonography for giant-cell arteritis. Diagnostic performance was determined for the halo sign, stenosis, or occlusion and for any of these ultrasonographic abnormalities.Weighted sensitivity and specificity estimates and summary receiver-operating characteristic (ROC) curve analysis were used. Twenty-three studies, involving a total of 2036 patients, met the inclusion criteria. The weighted sensitivity and specificity of the halo sign were 69% (95% CI, 57% to 79%) and 82% (CI, 75% to 87%), respectively, compared with biopsy and 55% (CI, 36% to 73%) and 94% (CI, 82% to 98%), respectively, compared with ACR criteria. Stenosis or occlusion was an almost equally sensitive marker compared with either biopsy (sensitivity, 68% [CI, 49% to 82%]) or ACR criteria (sensitivity, 66% [CI, 32% to 89%]). Consideration of any vessel abnormality nonsignificantly improved diagnostic performance compared with ACR criteria. Between-study heterogeneity was significant, but summary ROC curves were consistent with weighted estimates. When the pretest probability of giant-cell arteritis is 10%, negative results on ultrasonography practically exclude the disease (post-test probability, 2% to 5% for various analyses).The primary studies were small and of modest quality and had considerable heterogeneity.Ultrasonography may be helpful in diagnosing giant-cell arteritis, but cautious interpretation of the test results based on clinical presentation and pretest probability of the disease is imperative.

    View details for Web of Science ID 000227325100006

    View details for PubMedID 15738455

  • Large scale evidence and replication: insights from rheumatology and beyond ANNALS OF THE RHEUMATIC DISEASES Ioannidis, J. P. 2005; 64 (3): 345-346

    View details for DOI 10.1136/ard.2004.027979

    View details for Web of Science ID 000226980700001

    View details for PubMedID 15458962

  • Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: A meta-analysis CLINICAL CANCER RESEARCH Kyzas, P. A., Cunha, I. W., Ioannidis, J. P. 2005; 11 (4): 1434-1440

    Abstract

    Vascular endothelial growth factor (VEGF) is considered as a prime mediator of angiogenesis. Various studies examining the relationship between VEGF protein overexpression with the clinical outcome in patients with head and neck squamous cell carcinoma have yielded inconclusive results.We conducted a meta-analysis of 12 studies (n = 1.002 patients) that evaluated the correlation between VEGF (detected by immunohistochemistry) and 2-year overall survival. The relation between VEGF and lymph node involvement (11 studies, n = 722) was also examined. Data were synthesized with random effect and fixed effect risk ratios.The estimated risk of death in 2 years was 1.88-fold higher in the VEGF-positive patients [95% confidence interval, 1.43-2.45; P < 0.001 random effect calculations]. Between-study heterogeneity was nonsignificant (P = 0.15) but larger studies tended to provide more conservative estimates (P = 0.097). VEGF overexpression was not significantly associated with the presence of lymph node metastasis (risk ratio, 1.20; 95% confidence interval, 0.97-1.49; P = 0.087) and there was significant between-study heterogeneity (P = 0.08).Although some modest bias cannot be excluded, VEGF positivity seems to be associated with worse overall survival in patients with head and neck squamous cell carcinoma.

    View details for Web of Science ID 000227266600013

    View details for PubMedID 15746043

  • Microarrays and molecular research: noise discovery? LANCET Ioannidis, J. P. 2005; 365 (9458): 454-455

    View details for Web of Science ID 000226812500005

    View details for PubMedID 15705441

  • Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Mauri, D., Pavlidis, N., Ioannidis, J. P. 2005; 97 (3): 188-194

    Abstract

    Interest in the use of preoperative systemic treatment in the management of breast cancer has increased because such neoadjuvant therapy appears to reduce the extent of local surgery required. We compared the clinical end points of patients with breast cancer treated preoperatively with systemic therapy (neoadjuvant therapy) and of those treated postoperatively with the same regimen (adjuvant therapy) in a meta-analysis of randomized trials.We evaluated nine randomized studies, including a total of 3946 patients with breast cancer, that compared neoadjuvant therapy with adjuvant therapy regardless of what additional surgery and/or radiation treatment was used. Fixed and random effects methods were used to combine data. Primary outcomes were death, disease progression, distant disease recurrence, and loco-regional disease recurrence. Secondary outcomes were local response and conservative local treatment. All statistical tests were two-sided.We found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (summary risk ratio [RR] = 1.00, 95% confidence interval [CI] = 0.90 to 1.12), disease progression (summary RR = 0.99, 95% CI = 0.91 to 1.07), or distant disease recurrence (summary RR = 0.94, 95% CI = 0.83 to 1.06). However, neoadjuvant therapy was statistically significantly associated with an increased risk of loco-regional disease recurrences (RR = 1.22, 95% CI = 1.04 to 1.43), compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant, than the adjuvant, arm received radiation therapy without surgery (RR = 1.53, 95% CI = 1.11 to 2.10). Across trials, we observed heterogeneity in the rates of complete clinical response (range = 7%-65%; P for heterogeneity of <.001), pathologic response (range = 4%-29%; P for heterogeneity of <.001), and adoption of conservative local treatment (range = 28%-89% in neoadjuvant arms, P for heterogeneity of <.001).Neoadjuvant therapy was apparently equivalent to adjuvant therapy in terms of survival and overall disease progression. Neoadjuvant therapy, compared with adjuvant therapy, was associated with a statistically significant increased risk of loco-regional recurrence when radiotherapy without surgery was adopted.

    View details for Web of Science ID 000226748200009

    View details for PubMedID 15687361

  • Preoperative prediction of long-term survival after coronary artery bypass grafting in patients with low left ventricular ejection fraction JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Derose, J. J., Toumpoulis, I. K., Balaram, S. K., Ioannidis, J. P., Belsley, S., Ashton, R. C., Swistel, D. G., Anagnostopoulos, C. E. 2005; 129 (2): 314-321

    Abstract

    We aimed to develop multivariable models of preoperative risk factors that predict long-term survival after coronary artery bypass grafting in patients with ejection fraction 25% or less.We retrospectively evaluated 544 consecutive patients with ejection fraction 25% or less who underwent coronary artery bypass grafting from 1992 to 2002 at a single institution. Long-term survival data (mean follow-up 4.1 years) were obtained from the National Death Index. Multivariable Cox regression analysis was performed to construct a predictive score for long-term mortality. A split-sample approach was also used building a model on a training group (n = 360); this model was then tested on a separate validation group (n = 184).From the entire database, the predictive score was calculated according to the following equation: 0.430(if past congestive heart failure) + 0.049(age in years) + 0.507(if peripheral vascular disease) + 0.580(if emergency operation) + 0.366(if chronic obstructive pulmonary disease). The 5-year survivals of the predictive score quartiles were 82.3%, 78.2%, 65.5%, and 45.5% (P < .0001). The model based on the training group had four independent predictors for long-term mortality (the same as the listed equation except for past congestive heart failure). The 5-year survival rates of the quartiles were 90.1%, 75.4%, 64.3%, and 49.2% in the training group (P < .0001) and 77.4%, 71.2%, 65.8%, and 45.5% in the validation group (P = .0001).Coronary artery bypass grafting in patients with severe ischemic cardiomyopathy achieves satisfactory midterm and long-term survival in selected patients. This new score, which is based on long-term data from a large number of patients, may aid clinicians in selecting therapeutic interventions for patients with ischemic cardiomyopathy.

    View details for DOI 10.1016/j.jtcvs.2004.05.022

    View details for Web of Science ID 000226734700012

    View details for PubMedID 15678041

  • Anemia treatment and decline of renal function - Reply KIDNEY INTERNATIONAL Gouva, C., Nikolopoulos, P., Ioannidis, J. P., Siamopoulos, K. C. 2005; 67 (2): 779-780

    View details for Web of Science ID 000226420600050

  • Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery - The statins for risk reduction in surgery (StaRRS) Study JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY O'Neil-Callahan, K., Katsimaglis, G., Tepper, M. R., Ryan, J., Mosby, C., Ioannidis, J. P., Danias, P. G. 2005; 45 (3): 336-342

    Abstract

    We sought to assess whether statins may decrease cardiac complications in patients undergoing noncardiac vascular surgery.Cardiovascular complications account for considerable morbidity in patients undergoing noncardiac surgery. Statins decrease cardiac morbidity and mortality in patients with coronary disease, and the beneficial treatment effect is seen early, before any measurable increase in coronary artery diameter.A retrospective study recorded patient characteristics, past medical history, and admission medications on all patients undergoing carotid endarterectomy, aortic surgery, or lower extremity revascularization over a two-year period (January 1999 to December 2000) at a tertiary referral center. Recorded perioperative complication outcomes included death, myocardial infarction, ischemia, congestive heart failure, and ventricular tachyarrhythmias occurring during the index hospitalization. Univariate and multivariate logistic regressions identified predictors of perioperative cardiac complications and medications that might confer a protective effect.Complications occurred in 157 of 1,163 eligible hospitalizations and were significantly fewer in patients receiving statins (9.9%) than in those not receiving statins (16.5%, p = 0.001). The difference was mostly accounted by myocardial ischemia and congestive heart failure. After adjusting for other significant predictors of perioperative complications (age, gender, type of surgery, emergent surgery, left ventricular dysfunction, and diabetes mellitus), statins still conferred a highly significant protective effect (odds ratio 0.52, p = 0.001). The protective effect was similar across diverse patient subgroups and persisted after accounting for the likelihood of patients to have hypercholesterolemia by considering their propensity to use statins.Use of statins was highly protective against perioperative cardiac complications in patients undergoing vascular surgery in this retrospective study.

    View details for DOI 10.1016/j.jacc.2004.10.048

    View details for Web of Science ID 000226673400002

    View details for PubMedID 15680709

  • Heterogeneity testing in meta-analysis of genome searches GENETIC EPIDEMIOLOGY Zintzaras, E., Ioannidis, J. P. 2005; 28 (2): 123-137

    Abstract

    Genome searches for identifying susceptibility loci for the same complex disease often give inconclusive or inconsistent results. Genome Search Meta-analysis (GSMA) is an established non-parametric method to identify genetic regions that rank high on average in terms of linkage statistics (e.g., lod scores) across studies. Meta-analysis typically aims not only to obtain average estimates, but also to quantify heterogeneity. However, heterogeneity testing between studies included in GSMA has not been developed yet. Heterogeneity may be produced by differences in study designs, study populations, and chance, and the extent of heterogeneity might influence the conclusions of a meta-analysis. Here, we propose and explore metrics that indicate the extent of heterogeneity for specific loci in GSMA based on Monte Carlo permutation tests. We have also developed software that performs both the GSMA and the heterogeneity testing. To illustrate the concept, the proposed methodology was applied to published data from meta-analyses of rheumatoid arthritis (4 scans) and schizophrenia (20 scans). In the first meta-analysis, we identified 11 bins with statistically low heterogeneity and 8 with statistically high heterogeneity. The respective numbers were 9 and 6 for the schizophrenia meta-analysis. For rheumatoid arthritis, bins 6.2 (the HLA region that is a well-documented susceptibility locus for the disease) and 16.3 (16q12.2-q23.1) had both high average ranks and low between-study heterogeneity. For schizophrenia, this was seen for bin 3.2 (3p25.3-p22.1) and heterogeneity was still significantly low after adjusting for its high average rank. Concordance was high between the proposed metrics and between weighted and unweighted analyses. Data from genome searches should be synthesized and interpreted considering both average ranks and heterogeneity between studies.

    View details for Web of Science ID 000226568200003

    View details for PubMedID 15593093

  • Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility: a meta-analysis HUMAN GENETICS Kavvoura, F. K., Ioannidis, J. P. 2005; 116 (3): 192-199

    Abstract

    A meta-analysis assessed whether the Ala45Thr polymorphism of the neurogenic differentiation 1 (NEUROD1) gene is associated with increased risk of diabetes mellitus type 1 (T1D) or type 2 (T2D). Fourteen case-control studies were analyzed, including genotype data on 3,057 patients with diabetes (T1D n=1,213, T2D n=1,844) and 2,446 controls. Overall and race-specific summary odds ratios (ORs) were obtained with fixed and random effects models. The Thr allele did not significantly increase the overall risk for T1D (OR 1.27 [0.94-1.71], P=0.12) or T2D (OR 1.07 [0.90-1.28], P=0.46). The Thr allele conferred increased susceptibility in subjects of Asian racial descent to T1D (OR 1.88 [1.10-3.21], P=0.020), but not to T2D (OR 1.08 [0.74-1.56], P=0.70). There was no association in subjects of European descent (OR 0.97 [0.76-1.23], P=0.80 for T1D; OR 1.03 [0.88-1.21], P=0.68 for T2D). Larger studies seemed to show more conservative estimates for the association with T1D (P=0.083). The Ala45Thr polymorphism of the NEUROD1 gene has no effect on susceptibility to T2D. It may however be a risk factor for susceptibility to T1D, in particular for subjects of Asian descent, although bias cannot be totally excluded.

    View details for DOI 10.1007/s00439-004-1224-5

    View details for Web of Science ID 000226556800009

    View details for PubMedID 15592940

  • Mortality in systemic sclerosis: an international meta-analysis of individual patient data AMERICAN JOURNAL OF MEDICINE Ioannidis, J. P., Vlachoyiannopoulos, P. G., Haidich, A. B., Medsger, T. A., Lucas, M., Michet, C. J., Kuwana, M., Yasuoka, H., van den Hoogen, F., Boome, L. T., van Laar, J. M., Verbeet, N. L., Matucci-Cerinic, M., Georgountzos, A., Moutsopoulos, H. M. 2005; 118 (1): 2-10

    Abstract

    Studies on mortality associated with systemic sclerosis have been limited by small sample sizes. We aimed to obtain large-scale evidence on survival outcomes and predictors for this disease.We performed a meta-analysis of individual patient data from cohorts recruited from seven medical centers in the United States, Europe, and Japan, using standardized definitions for disease subtype and organ system involvement. The primary outcome was all-cause mortality. Standardized mortality ratios and predictors of mortality were estimated. The main analysis was based only on patients enrolled at each center within 6 months of diagnosis (incident cases).Among 1645 incident cases, 578 deaths occurred over 11,521 person-years of follow-up. Standardized mortality ratios varied by cohort (1.5 to 7.2). In multivariate analyses that adjusted for age and sex, renal (hazard ratio [HR] = 1.9; 95% confidence interval [CI]: 1.4 to 2.5), cardiac (HR = 2.8; 95% CI: 2.1 to 3.8), and pulmonary (HR = 1.6; 95% CI: 1.3 to 2.2) involvement, and anti-topoisomerase I antibodies (HR = 1.3; 95% CI: 1.0 to 1.6), increased mortality risk. Renal, cardiac, and pulmonary involvement tended to occur together (P <0.001). For patients without adverse predictors for 3 years after enrollment, the subsequent risk of death was not significantly different from that for the general population in three cohorts, but was significantly increased in three cohorts that comprised mostly referred patients. Analyses that included all cases in each center (n = 3311; total follow-up: 19,990 person-years) yielded largely similar results.Systemic sclerosis confers a high mortality risk, but there is considerable heterogeneity across settings. Internal organ involvement and anti-topoisomerase I antibodies are important determinants of mortality.

    View details for DOI 10.1016/j.amjmed.2004.04.031

    View details for Web of Science ID 000226359700002

    View details for PubMedID 15639201

  • Nuchal translucency and fetal cardiac defects: A pooled analysis of major fetal echocardiography centers AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Makrydimas, G., Sotiriadis, A., Huggon, I. C., Simpson, J., Sharland, G., Carvalho, J. S., Daubeney, P. E., Ioannidis, J. P. 2005; 192 (1): 89-95

    Abstract

    Increased fetal nuchal translucency is associated with increased risk for congenital heart defects. In the present study, we aimed to investigate whether fetal nuchal translucency distribution differs among different types of congenital heart defects and whether it can lead to an earlier diagnosis.Four fetal echocardiography units provided data on fetuses with a congenital heart defect diagnosis in whom nuchal translucency thickness had been measured in the first trimester. Nuchal translucency data were compared per chromosomal status and type of congenital heart defect. Data on gestational age at diagnosis were also analyzed.Six hundred thirty-seven cases of congenital heart defect with known karyotype and exact nuchal translucency measurements were analyzed. Nuchal translucency was > or =3.5 mm in 22.9% of chromosomally normal fetuses (n = 397) and 58.8% of chromosomally abnormal cases (n = 240). Among fetuses with normal karyotype, the proportion of cases of congenital heart defect with increased nuchal translucency was similar in each of the subtypes of congenital heart defect (P = .96). Mean gestational age at diagnosis of congenital heart defect in fetuses with normal karyotype was 22.1 weeks with nuchal translucency of <3.5 mm and 16.1 weeks with nuchal translucency of > or =3.5 mm.Finding nuchal translucency of > or =3.5 mm may lead to an earlier diagnosis of all major types of congenital heart defects.

    View details for DOI 10.1016/j.ajog.2004.06.081

    View details for Web of Science ID 000226760400015

    View details for PubMedID 15672008

  • Benzodiazepines for alcohol withdrawal COCHRANE DATABASE OF SYSTEMATIC REVIEWS Ntais, C., Pakos, E., Kyzas, P., Ioannidis, J. P. 2005

    Abstract

    Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of benzodiazepines' use in the treatment of alcohol withdrawal symptoms.To evaluate the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal.We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions. We also screened references of retrieved articles.All randomized controlled trials examining the effectiveness and safety of a benzodiazepine in comparison with a placebo or other pharmacological intervention or other benzodiazepine were considered.Two reviewers independently assessed trial quality and extracted data.Fifty-seven trials, with a total of 4,051 people were included. Despite the considerable number of randomized controlled trials, there was a very large variety of outcomes and of different rating scales and relatively limited quantitative synthesis of data was feasible. Benzodiazepines offered a large benefit against alcohol withdrawal seizures compared to placebo (relative risk [RR] 0.16; 95% confidence interval [CI] 0.04 to 0.69; p = 0.01). Benzodiazepines had similar success rates as other drugs (RR 1.02; 95% CI 0.92 to 1.12) or anticonvulsants in particular (RR 1.00; 95% CI 0.87 to 1.16) and offered a significant benefit for seizure control against non-anticonvulsants (RR 0.23; 95% CI 0.07 to 0.75; p = 0.02), but not against anticonvulsants (RR 1.99; 95% CI 0.46 to 8.65). Changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment were similar with benzodiazepines versus other drugs, although some small studies showed isolated significant differences for other, less commonly, used scales. Data on other comparisons were very limited, thus making quantitative synthesis for various outcomes not very informative.Benzodiazepines are effective against alcohol withdrawal symptoms, in particular seizures, when compared to placebo. It is not possible to draw definite conclusions about the relative effectiveness and safety of benzodiazepines against other drugs in alcohol withdrawal, because of the large heterogeneity of the trials both in interventions and assessment of outcomes but the available data do not show prominent differences between benzodiazepines and other drugs in success rates.

    View details for DOI 10.1002/14651858.CD005063.pub2

    View details for Web of Science ID 000232202500071

    View details for PubMedID 16034964

  • Anticonvulsants for alcohol withdrawal COCHRANE DATABASE OF SYSTEMATIC REVIEWS Polycarpou, A., Papanikolau, P., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2005

    Abstract

    Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of anticonvulsants' use in the treatment of alcohol withdrawal symptoms.To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal.We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004); MEDLINE (1966 to October 2004); EMBASE (1988 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions and references of articles.All randomized controlled trials examining the effectiveness, safety and overall risk-benefit of an anticonvulsant in comparison with a placebo or other pharmacological treatment or another anticonvulsant were considered.The authors independently assessed trial quality extracted data.Forty-eight studies, involving 3610 people were included. Despite the considerable number of randomized controlled trials, there was a variety of outcomes and of different rating scales that led to a limited quantitative synthesis of data. For the anticonvulsant versus placebo comparison, therapeutic success tended to be more common among the anticonvulsant-treated patients (relative risk (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.91), and anticonvulsant tended to show a protective benefit against seizures (RR 0.57; 95% CI 0.27 to 1.19), but no effect reached formal statistical significance. For the anticonvulsant versus other drug comparison, CIWA-Ar score showed non-significant differences for the anticonvulsants compared to the other drugs at the end of treatment (weighted mean difference (WMD) -0.73; 95% CI -1.76 to 0.31). For the subgroup analysis of carbamazepine versus benzodiazepine, a statistically significant protective effect was found for the anticonvulsant (WMD -1.04; 95% CI -1.89 to -0.20), p = 0.02), but this was based on only 260 randomized participants. There was a non-significant decreased incidence of seizures (RR 0.50; 95% CI 0.18 to 1.34) favouring the patients that were treated with anticonvulsants than other drugs, and side-effects tended to be less common in the anticonvulsant-group (RR 0.56; 95% CI 0.31 to 1.02).It is not possible to draw definite conclusions about the effectiveness and safety of anticonvulsants in alcohol withdrawal, because of the heterogeneity of the trials both in interventions and the assessment of outcomes. The extremely small mortality rate in all these studies is reassuring, but data on other safety outcomes are sparse and fragmented.

    View details for DOI 10.1002/14651858.CD00564.pub2

    View details for Web of Science ID 000232202500072

    View details for PubMedID 16034965

  • Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: A meta-analysis CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ntais, C., Polycarpou, A., Ioannidis, J. P. 2005; 14 (1): 176-181

    Abstract

    The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.

    View details for Web of Science ID 000226534000024

    View details for PubMedID 15668493

  • The Decameron of poor research BRITISH MEDICAL JOURNAL Berger, V. W., Ioannidis, J. P. 2004; 329 (7480): 1436-1440

    View details for Web of Science ID 000225965800020

    View details for PubMedID 15604177

  • 'Racial' differences in genetic effects for complex diseases NATURE GENETICS Ioannidis, J. P., Ntzani, E. E., Trikalinos, T. A. 2004; 36 (12): 1312-1318

    Abstract

    'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases influenced by a large number of genes. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.

    View details for DOI 10.1038/ng1474

    View details for Web of Science ID 000225354100020

    View details for PubMedID 15543147

  • Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: A metaanalysis AMERICAN JOURNAL OF GASTROENTEROLOGY Economou, M., Trikalinos, T. A., Loizou, K. T., Tsianos, E. V., Ioannidis, J. P. 2004; 99 (12): 2393-2404

    Abstract

    Three variants of the CARD15/NOD2 gene (SNP8, SNP12, and SNP13) have been associated with Crohn's disease (CD). We assessed the impact of NOD2 variants on the CD risk across diverse populations and examined possible associations with disease phenotype.We performed a metaanalysis searching MEDLINE and EMBASE (last search 05/2004) and contacting field experts.Forty-two eligible studies contributed data on 206 comparisons. No variants were detected in Asians. In non-Jewish descent Caucasians carriage of SNP8, SNP12, or SNP13 had an odds ratio (OR) for CD of 2.20 (95% CI: 1.84-2.62), 2.99 (95% CI: 2.38-3.74), and 4.09 (95% CI: 3.23-5.18), respectively. For Jewish descent patients the corresponding ORs were 1.74, 1.93, and 2.45, respectively. The OR in carriers of at least two alleles was 17.1 (95% CI: 10.7-27.2). Large studies tended to yield more conservative estimates than smaller studies, so publication or other bias cannot be excluded. Among CD patients, carrying at least one high-risk variant increased slightly the risk for familial disease (OR = 1.49, (95% CI: 1.18-1.87)), modestly the risk of stenosing CD (OR = 1.94, (95% CI: 1.61-2.34)), and more prominently the risk of small bowel involvement (OR = 2.53, (95% CI: 2.01-3.16)).SNP8, SNP12, and SNP13 have differential effects on CD risk, with SNP13 having the strongest genetic effect. These NOD2 variants are also significant risk factors for CD phenotype, in particular ileal location.

    View details for DOI 10.1111/j.1572-0241.2004.40304.x

    View details for Web of Science ID 000225627500020

    View details for PubMedID 15571588

  • Better reporting of harms in randomized trials: An extension of the CONSORT statement ANNALS OF INTERNAL MEDICINE Ioannidis, J. P., Evans, S. J., Gotzsche, P. C., O'Neill, R. T., Altman, D. G., Schulz, K., Moher, D. 2004; 141 (10): 781-788

    Abstract

    In response to overwhelming evidence and the consequences of poor-quality reporting of randomized, controlled trials (RCTs), many medical journals and editorial groups have now endorsed the CONSORT (Consolidated Standards of Reporting Trials) statement, a 22-item checklist and flow diagram. Because CONSORT primarily aimed at improving the quality of reporting of efficacy, only 1 checklist item specifically addressed the reporting of safety. Considerable evidence suggests that reporting of harms-related data from RCTs also needs improvement. Members of the CONSORT Group, including journal editors and scientists, met in Montebello, Quebec, Canada, in May 2003 to address this problem. The result is the following document: the standard CONSORT checklist with 10 new recommendations about reporting harms-related issues, accompanying explanation, and examples to highlight specific aspects of proper reporting. We hope that this document, in conjunction with other CONSORT-related materials (http://www.consort-statement.org), will help authors improve their reporting of harms-related data from RCTs. Better reporting will help readers critically appraise and interpret trial results. Journals can support this goal by revising Instructions to Authors so that they refer authors to this document.

    View details for Web of Science ID 000225206900005

    View details for PubMedID 15545678

  • Limited benefit of antiretrovial resistance testing in treatment-experienced patients: a meta-analysis AIDS Panidou, E. T., Trikalinos, T. A., Ioannidis, J. P. 2004; 18 (16): 2153-2161

    Abstract

    To estimate the effectiveness of resistance assessments based on viral sequencing (genotypic antiretroviral resistance testing, GART), phenotypic antiretroviral resistance testing (PART) or virtual PART (vPART) in the management of treatment-experienced HIV-1-infected patients.Meta-analysis of randomized controlled trials comparing treatments aided by GART, PART and vPART, and controls.The meta-analysis synthesized data on the proportion of patients with undetectable plasma viral load, the decrease in viral load, and the increase in CD4 cell count at 3 and 6 months after randomization.Ten trials were analyzed (total 2258 participants). Compared with controls, at 3 and 6 months GART increased the proportion of patients with viral load below detection by 11% [95% confidence interval (CI), 6-16], and 10% (95% CI, 5-16), respectively. The difference in viral load change was 0.27 log10 copies/ml (95% CI, 0.11-0.43) and 0.21 log10 copies/ml (95% CI, 0.09-0.34), respectively. However, no improvement was observed in the CD4 cell count at either time point: the difference in CD4 cell count -5.7 x 10(6) cells/l (95% CI, -18.8 to 7.3) and 1.2 x 10(6) cells/l (95% CI, -15.0 to 17.4), respectively, at 3 and 6 months. For PART, there was no clear evidence for any benefit versus no testing (three trials). vPART conferred a small benefit in indirect comparisons versus no testing.Evidence for benefit of antiretroviral resistance testing is sparse and limited to small short-term improvements of virologic response, mostly with GART and less with vPART. Current guidelines widely recommending the use of antiretroviral resistance testing in clinical practice are not commensurate with the available evidence.

    View details for Web of Science ID 000224964700007

    View details for PubMedID 15577648

  • Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Ralston, S. H., Bennett, S. T., Brandi, M. L., Grinberg, D., Karassa, F. B., Langdahl, B., van Meurs, J. B., Mosekilde, L., Scollen, S., Albagha, O. M., Bustamante, M., Carey, A. H., Dunning, A. M., Enjuanes, A., Van Leeuwen, J. P., Mavilia, C., Masi, L., McGuigan, F. E., Nogues, X., Pols, H. A., Reid, D. M., Schuit, S. C., Sherlock, R. E., Uitterlinden, A. G. 2004; 292 (17): 2105-2114

    Abstract

    Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results.To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI [dbSNP: rs9340799] and PvuII [dbSNP: rs2234693] and promoter TA repeats microsatellite) and haplotypes thereof are associated with BMD and fractures.Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers.BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype.No between-center heterogeneity was observed for any outcome in any genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically significant effect on BMD in adjusted or unadjusted analyses, and estimated differences between genetic contrasts were 0.01 g/cm2 or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% CI, 0.71-0.93]; P = .002) and vertebral fractures by 35% (odds ratio, 0.65 [95% CI, 0.49-0.87]; P = .003). Effects on fractures were independent of BMD and unaltered in adjusted analyses. No significant effects on fracture risk were seen for PvuII and TA repeats.ESR1 is a susceptibility gene for fractures, and XbaI determines fracture risk by mechanisms independent of BMD. Our study demonstrates the value of adequately powered studies with standardized genotyping and clinical outcomes in defining effects of common genetic variants on complex diseases.

    View details for Web of Science ID 000224921900023

    View details for PubMedID 15523071

  • Diagnostic performance of coronary magnetic resonance anglography as compared against conventional x-ray angiography - A meta-analysis JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Danias, P. G., Roussakis, A., Ioannidis, J. P. 2004; 44 (9): 1867-1876

    Abstract

    This study was designed to define the current role of coronary magnetic resonance angiography (CMRA) for the diagnosis of coronary artery disease (CAD).Coronary magnetic resonance angiography has been proposed as a promising noninvasive method for diagnosis of CAD, but individual studies evaluating its clinical value have been of limited sample size.We identified all studies (MEDLINE and EMBASE) that evaluated CAD by both CMRA and conventional angiography in >/=10 subjects during the period 1991 to January 2004. We recorded true and false positive and true and false negative CMRA assessments for detection of CAD using X-ray angiography as the reference standard. Analysis was done at segment, vessel, and subject level.We analyzed 39 studies (41 separate comparisons). Across 25 studies (27 comparisons) with data on 4,620 segments (993 subjects), sensitivity and specificity for detection of CAD were 73% and 86%, respectively. Vessel-level analyses (16 studies, 2,041 vessels) showed sensitivity 75% and specificity 85%. Subject-level analyses (13 studies, 607 subjects) showed sensitivity 88% and specificity 56%. At the segment level, sensitivity was 69% to 79% for all but the left circumflex (61%) coronary artery; specificity was 82% to 91%. There was considerable between-study heterogeneity, but weighted summary receiver-operating characteristic curves agreed with these estimates. There were no major differences between subgroups based on technical or population characteristics, year of publication, reported blinding, or sample size.In evaluable segments of the native coronary arteries, CMRA has moderately high sensitivity for detecting significant proximal stenoses and may have value for exclusion of significant multivessel CAD in selected subjects considered for diagnostic catheterization.

    View details for DOI 10.1016/j.jacc.2004.07.051

    View details for Web of Science ID 000224782100017

    View details for PubMedID 15519021

  • Treatment options for acute sinusitis in children CURRENT ALLERGY AND ASTHMA REPORTS Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2004; 4 (6): 471-477

    Abstract

    Much controversy exists regarding the best diagnostic method for acute sinusitis, the efficacy of antibiotics, the best choice of antibiotics, the most appropriate duration of therapy, and the efficacy of ancillary measures and nasal corticosteroids. The therapeutic goal is to identify those children who are more likely to have bacterial sinusitis and unlikely to resolve spontaneously, who may require treatment with antibiotics. The inaccuracy of clinical signs and symptoms complicates further the management of these children. Acute sinusitis is expected to resolve spontaneously in most cases, including many cases of bacterial sinusitis. Antibiotics are needed only for a minority of non-self-resolving infections. Based on current resistance considerations, approximately 80% of bacterial infections are expected to respond to standard doses of amoxicillin. High-dose amoxicillin, amoxicillin/clavulanate, or other b-lactam antibiotics should be considered for children at high risk for carrying resistant organisms. Evidence for the effectiveness of ancillary measures is limited.

    View details for Web of Science ID 000230808900008

    View details for PubMedID 15462714

  • Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time JOURNAL OF CLINICAL EPIDEMIOLOGY Trikalinos, T. A., Churchill, R., Ferri, M., Leucht, S., Tuunainen, A., Wahlbeck, K., Ioannidis, J. P. 2004; 57 (11): 1124-1130

    Abstract

    Meta-analyses of randomized trials may incorporate new evidence, and estimated treatment effects changeover time. We evaluated whether the certainty and estimates of efficacy and tolerability of mental health interventions change over time, as more trials appear on the same topics.One hundred meta-analyses (1,024 trial entries; 99,303 participants) with an outcome of death, relapse, failure or dropout and with five or more trials published in three or more different years were examined with cumulative meta-analysis and recursive cumulative meta-analysis.Eight meta-analyses reached formal statistical significance (P < .05) at some point, but lost this significance eventually when more trials were published; typically large effect sizes in early trials were dissipated with further evidence. With 500 randomized subjects,95% of the time, subsequent changes in odds ratio might be up to 1.5-fold. For death, relapse, and failure outcomes, a decrease in effect size was somewhat more common than an increase, when more data became available (157 vs. 125, P = .06). This was most clear for comparisons of pharmacotherapies versus placebo (79 vs. 51, P = .009).Evidence based on a small number of randomized subjects should be interpreted cautiously. Early treatment efficacy of pharmacotherapies is occasionally overestimated.

    View details for DOI 10.1016/j.jclinepi.2004.02.018

    View details for Web of Science ID 000225672800003

    View details for PubMedID 15612138

  • Radiotherapy vs. nonsteroidal anti-inflammatory drugs for the prevention of heterotopic ossification after major hip procedures: A meta-analysis of randomized trials INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pakos, E. E., Ioannidis, J. P. 2004; 60 (3): 888-895

    Abstract

    To evaluate the efficacy of radiotherapy (RT) vs. nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of heterotopic ossification (HO) after major hip procedures.We conducted a meta-analysis of 7 randomized studies (n = 1143) comparing RT with NSAIDs. Data were combined across studies using fixed and random effects models. We conducted separate analyses for clinically significant HO (Brooker Grade 3 and 4) and for any HO (any Brooker grade).Overall RT tended to be more effective than NSAIDs in preventing Brooker 3 or 4 HO (risk ratio, 0.42; 95% confidence interval [CI], 0.18-0.97) or any HO (risk ratio, 0.75; 95% CI, 0.37-1.71), but with significant between-study heterogeneity for the second analysis. The overall absolute risk difference for Brooker 3 or 4 HO was small (-1.18%; 95% CI, -2.45% to 0.09%). Subgroup analyses showed that early preoperative RT (16-20 hours before surgery) and acetylsalicylic acid were less effective. For postoperative RT, there was a significant dose-response relationship (p = 0.008): 6 Gy of RT was equally effective as NSAIDs, whereas increasing radiation doses were more effective.Although absolute differences may be small, postoperative RT is on average more effective than NSAIDs in preventing HO after major hip procedures, and its efficacy is dose dependent.

    View details for DOI 10.1016/j.ijrobp.2003.11.015

    View details for Web of Science ID 000224350900023

    View details for PubMedID 15465207

  • Availability of large-scale evidence on specific harms from systematic reviews of randomized trials AMERICAN JOURNAL OF MEDICINE Papanikolaou, P. N., Ioannidis, J. P. 2004; 117 (8): 582-589

    Abstract

    To assess how frequently systematic reviews of randomized controlled trials convey large-scale evidence on specific, well-defined adverse events.We searched the Cochrane Database of Systematic Reviews for reviews containing quantitative data on specific, well-defined harms for at least 4000 randomized subjects, the minimum sample required for adequate power to detect an adverse event due to an intervention in 1% of subjects. Main outcome measures included the number of reviews with eligible large-scale data on adverse events, the number of ineligible reviews, and the magnitude of recorded harms (absolute risk, relative risk) based on large-scale evidence.Of 1727 reviews, 138 included evidence on > or =4000 subjects. Only 25 (18%) had eligible data on adverse events, while 77 had no harms data, and 36 had data on harms that were nonspecific or pertained to <4000 subjects. Of 66 specific adverse events for which there were adequate data in the 25 eligible reviews, 25 showed statistically significant differences between comparison arms; most pertained to serious or severe adverse events and absolute risk differences <4%. In 29% (9/31) of a sample of large trials in reviews with poor reporting of harms, specific harms were presented adequately in the trial reports but were not included in the systematic reviews.Systematic reviews can convey useful large-scale information on adverse events. Acknowledging the importance and difficulties of studying harms, reporting of adverse effects must be improved in both randomized trials and systematic reviews.

    View details for DOI 10.1016/j.amjmed.2004.04.026

    View details for Web of Science ID 000224439300007

    View details for PubMedID 15465507

  • Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma: A meta-analysis CLINICAL CANCER RESEARCH Pakos, E. E., Kyzas, P. A., Ioannidis, J. P. 2004; 10 (18): 6208-6214

    Abstract

    Various studies examining the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. The purpose of the current study was to evaluate the relation of TP53 status with response to chemotherapy and/or clinical outcome in osteosarcoma.We conducted a meta-analysis of 16 studies (n=499 patients) that evaluated the correlation between TP53 status and histologic response to chemotherapy and 2-year survival. Data were synthesized in summary receiver operating characteristic curves and with summary likelihood ratios (LRs) and risk ratios.The quantitative synthesis showed that TP53 status is not a prognostic factor for the response to chemotherapy. The positive LR was 1.21 (95% confidence interval, 0.86-1.71), and the negative LR was 0.91 (95% confidence interval, 0.77-1.07). There was no significant between-study heterogeneity. TP53-positive status tended to be associated with a worse 2-year survival, but the overall results were not formally statistically significant. The association was formally significant in studies that clearly stated that measurements were blinded to outcomes (risk ratio, 2.05; 95% confidence interval, 1.23-3.44), and in studies using reverse transcription-PCR for evaluating TP53 alterations (risk ratio, 1.76; 95% confidence interval, 1.07-2.91).TP53 status is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas TP53 gene alterations may be associated with decreased survival.

    View details for Web of Science ID 000224080200031

    View details for PubMedID 15448009

  • Safety reporting in randomized trials of mental health interventions AMERICAN JOURNAL OF PSYCHIATRY Papanikolaou, P. N., Churchill, R., Wahlbeck, K., Ioannidis, J. P. 2004; 161 (9): 1692-1697

    Abstract

    The authors aimed to evaluate the adequacy of the reporting of safety information in publications of randomized trials of mental-health-related interventions.The authors randomly selected 200 entries from the PsiTri registry of mental-health-related controlled trials. This yielded 142 randomized trials that were analyzed for adequacy and relative emphasis of their content on safety issues. They examined drug trials as well as trials of other types of interventions.Across the 142 eligible trials, 103 involved drugs. Twenty-five of the 142 trials had at least 100 randomly chosen subjects and at least 50 subjects in a study arm. Among drug trials, only 21.4% had adequate reporting of clinical adverse events, and only 16.5% had adequate reporting of laboratory-determined toxicity, while 32.0% reported both the numbers and the reasons for withdrawals due to toxicity in each arm. On average, drug trials devoted 1/10 of a page in their results sections to safety, and 58.3% devoted more space to the names and affiliations of authors than to safety. None of the trials of nondrug interventions had adequate or even partially adequate reporting of either clinical adverse events or laboratory-determined toxicity. In multivariate modeling, long-term trials and trials conducted in the United States devoted even less space to safety, while schizophrenia trials devoted more space to safety than did trials in other areas.Safety reporting is largely neglected across trials of mental-health-related interventions, thus hindering the assessment of risk-benefit ratios for rational decision making in mental health care.

    View details for Web of Science ID 000223800600024

    View details for PubMedID 15337661

  • Establishment of genetic associations for complex diseases is independent of early study findings EUROPEAN JOURNAL OF HUMAN GENETICS Trikalinos, T. A., Ntzani, E. E., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2004; 12 (9): 762-769

    Abstract

    Numerous genetic association studies for complex diseases are performed. Investigators place emphasis on formal statistical significance (P-values < 0.05), but the predictive ability of early statistically significant ('positive') findings is unclear. We scrutinized 55 cumulative meta-analyses of genetic associations (579 studies), in order to assess whether having statistical significance in the earliest (first) published study or in at least half among several (> or =3) early-published studies, or high statistical significance in early studies had any predictive ability for establishing or refuting the presence of the genetic association in subsequent research. In 35 associations, a first study was 'positive' and in 15 associations more than half of the early-published reports were 'positive'. The average publication rate of subsequent studies increased 1.71-fold with a 'positive' first report. When compared against the summary results of subsequent research, sensitivity and specificity were 0.65 and 0.38 for the first reports, and 0.40 and 0.73, respectively, when at least three early studies were considered. First studies also had poor predictive ability, when we considered the estimated attributable fraction and coverage of the 95% confidence interval thereof or higher levels of statistical significance. We conclude that although 'positive' findings in the very first reports provide strong incentive for conducting more studies on a putative genetic epidemiological association, the statistical significance or even the magnitude of the effect of early studies cannot adequately predict eventual establishment of an association. Conversely, many genuine epidemiological associations would be missed, if research were abandoned after early underpowered 'negative' studies.

    View details for DOI 10.1038/sj.ejhg.5201227

    View details for Web of Science ID 000223403900011

    View details for PubMedID 15213707

  • Cyclophosphamide in systemic sclerosis: Light and shadows CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Vlachoyiannopoulos, P. G., Ioannidis, J. P. 2004; 22 (5): 551-552

    View details for Web of Science ID 000223975100001

    View details for PubMedID 15485005

  • Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis JOURNAL OF HYPERTENSION Kosmas, I. P., Tatsioni, A., Ioannidis, J. P. 2004; 22 (9): 1655-1662

    Abstract

    To evaluate whether the C677T polymorphism of the methylenetetrahydofolate reductase (MTHFR) gene is consistently associated with hypertension in pregnancy.Meta-analysis of studies comparing women with and without hypertension in pregnancy for the C677T MTHFR polymorphism.Studies were identified with MEDLINE and EMBASE searches complemented with perusal of bibliographies of retrieved articles and communication with investigators. Between-study heterogeneity was estimated and data were combined with random effects models. Sensitivity analyses examined the effect of population and disease characteristics. Bias diagnostics evaluated the evolution of the postulated genetic effect over time and the potential for publication bias.Across 23 comparisons (3169 hypertensive women, 3044 controls), having the T allele (TT or CT) increased the odds of hypertensive disease of pregnancy by 1.21-fold (95% confidence interval, 1.01-1.44), but there was large between-study heterogeneity (P = 0.003). The results were similar and heterogeneity persisted when sensitivity analyses were limited to studies of Caucasian populations, or those of patients with significant proteinuria. While patients with diastolic hypertension > or = 110 mmHg showed an odds ratio of 1.41 (95% confidence interval, 1.03-1.73), no association was seen in patients with less severe diastolic hypertension (odds ratio, 1.00; 95% confidence interval, 0.61-1.65). Early published studies tended to show stronger associations than the subsequent studies.While bias cannot be excluded, the meta-analysis suggests that the T allele may increase the risk of severe diastolic hypertension during pregnancy.

    View details for Web of Science ID 000223557100004

    View details for PubMedID 15311088

  • Treating anemia early in renal failure patients slows the decline of renal function: A randomized controlled trial KIDNEY INTERNATIONAL Gouva, C., Nikolopoulos, P., Ioannidis, J. P., Siamopoulos, K. C. 2004; 66 (2): 753-760

    Abstract

    Erythropoietin is known to improve outcomes in patients with anemia from chronic renal disease. However, there is uncertainty about the optimal timing of initiation of erythropoietin treatment in predialysis patients with non-severe anemia.We conducted a randomized controlled trial of early versus deferred initiation of erythropoietin in nondiabetic predialysis patients with serum creatinine 2 to 6 mg/dL and hemoglobin 9 to 11.6 g/dL. The early treatment arm was immediately started on 50 U/kg/wk of erythropoietin alpha with appropriate titration aiming for hemoglobin of > or =13 g/dL. The deferred treatment arm would start erythropoietin only when hemoglobin decreased to <9 g/dL. The primary end point was a composite of doubling of creatinine, renal replacement, or death.Eighty-eight patients were randomized (early treatment N= 45, deferred treatment N= 43) and followed for a median of 22.5 months. During follow-up, 13 versus 23 patients reached the primary end point in the two arms, respectively (log-rank P= 0.0078). The relative hazard for reaching an end point was 0.42 (P= 0.012). Adjusting for baseline serum creatinine, the adjusted relative hazard was 0.37 (P= 0.004), while the risk increased 2.23-fold (P < 0.001) per 1 mg/dL higher creatinine at baseline. The benefit was similar regardless of the baseline hemoglobin and proteinuria. No patients had any severe adverse events.Early initiation of erythropoietin in predialysis patients with non-severe anemia significantly slows the progression of renal disease and delays the initiation of renal replacement therapy.

    View details for Web of Science ID 000222578400039

    View details for PubMedID 15253730

  • Clinical trials in Sub-Saharan Africa and established standards of care - A systematic review of HIV, tuberculosis, and malaria trials JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kent, D. M., Mwamburi, D. M., Bennish, M. L., Kupelnick, B., Ioannidis, J. P. 2004; 292 (2): 237-242

    Abstract

    The minimum standard of care required for participants in clinical trials conducted in resource-poor settings is a matter of controversy; international documents offer contradictory guidance.To determine whether recently published trials conducted in sub-Saharan Africa met standards of care consistent with best current clinical standards for human immunodeficiency virus (HIV) treatment, tuberculosis treatment, and malaria prevention.Trials published during or after January 1998 that were indexed at the time of the MEDLINE and Cochrane Controlled Trials Register Search (November 20, 2003).All randomized clinical trials that were conducted in sub-Saharan Africa in 3 clinical domains: HIV disease, tuberculosis treatment, and malaria prophylaxis.To establish criteria for best current standards of care, evidence from the literature and published guidelines accepted for well-resourced settings were analyzed; the actual care offered in the trial was then compared with these standards.A total of 128 eligible articles described data from 73 different randomized clinical trials. Only 12 trials (16%) provided care that met guidelines to both intervention and control patients. Only 1 of the 34 trials that enrolled patients with HIV disease provided antiretroviral treatment that conformed to guidelines. Conversely, all tuberculosis treatment trials (n = 13, including 3 for HIV-infected patients) provided tuberculosis therapy that conformed to guidelines. Twenty-one (72%) of 29 malaria prophylaxis trials tested interventions that met guidelines, but only 3 (10%) used any active prophylactic intervention in the control group. Of the 59 trials (81%) that reported on the process of ethical review, all were reviewed by a host African institution and 64% were additionally reviewed by an institution in a developed country.Rates of adherence to established clinical guidelines of care in randomized clinical trials of HIV treatment, tuberculosis treatment, and malaria prophylaxis varied considerably between disease categories. In determining clinical standards for trials in sub-Saharan Africa, researchers and ethics committees appear to take the local level of care into account.

    View details for Web of Science ID 000222579300029

    View details for PubMedID 15249573

  • Extended-interval aminoglycoside administration for children: A meta-analysis PEDIATRICS Contopoulos-Ioannidis, D. G., Giotis, N. D., Baliatsa, D. V., Ioannidis, J. P. 2004; 114 (1): E111-E118

    Abstract

    There has been a long-standing debate regarding whether aminoglycosides should be administered on a multiple daily dosing (MDD) or once-daily dosing (ODD) schedule. Several unique characteristics of the aminoglycosides make ODD an attractive and possibly superior alternative to MDD. These include concentration-dependent bactericidal activity; postantibiotic effect, which allows continued efficacy even when serum concentrations fall below expected minimum inhibitory concentrations; decreased risk of adaptive resistance; and diminished accumulation in renal tubules and inner ear.To assess the relative efficacy and toxicity of ODD, compared with MDD, of aminoglycosides among pediatric patients.Randomized, controlled trials among children, evaluating the relative efficacy and toxicity of ODD versus MDD of aminoglycosides, with similar total daily doses in the compared arms, were selected.PubMed (1966-2003) and Embase (1982-2003) databases, the Cochrane Controlled Trials Registry (2003), and references of eligible studies and pediatric review articles were searched.Study population characteristics and outcome data were extracted independently in duplicate, and consensus was reached on all items. The following outcome data were considered: (1) clinical or microbiologic failure, as defined in each study; (2) clinical failure; (3) microbiologic failure; (4) primary nephrotoxicity, ie, any rise in serum creatinine or decrease in creatinine clearance with thresholds as defined in each study; (5) secondary nephrotoxicity, ie, urinary excretion of proteins or phospholipids; and (6) ototoxicity based on pure tone audiometry, brainstem auditory evoked responses, or otoacoustic emissions for neonates and infants, vestibular testing, clinical impression, or any other method. All of the efficacy and toxicity outcomes were evaluated at the end of therapy.Identification of eligible studies and study characteristics: 24 eligible studies published between 1991 and 2003 were identified. Aminoglycosides were used in different clinical settings (neonatal intensive care unit: 6 studies; cystic fibrosis: 3 studies; cancer: 5 studies; urinary tract infections: 4 studies; diverse infectious indications: 5 studies; pediatric intensive care unit: 1 study). Aminoglycosides used included amikacin (9 studies), gentamicin (11 studies), tobramycin (2 studies), netilmicin (2 studies), and tobramycin or netilmicin (1 study).There was no significant difference between ODD and MDD in the clinical failure rate, microbiologic failure rate, and combined clinical or microbiologic failure rates, but trends favored ODD consistently. There was no between-study heterogeneity for any outcome. Efficacy analysis of all trials indicating either clinical or microbiologic failures demonstrated pooled failure rates of 4.6% (23 of 501 cases) in the ODD arms and 6.9% (34 of 494 cases) in the MDD arms. The fixed-effects risk ratio was 0.71 (95% confidence interval [CI]: 0.45-1.11). A statistically significant benefit was seen with ODD over MDD in trials using amikacin, whereas no statistical significance was seen in trials using other antibiotics. The pooled clinical failure rates were 6.7% (22 of 330 cases) in the ODD arms and 10.4% (34 of 327 cases) in the MDD arms. The fixed-effects risk ratio was 0.67 (95% CI: 0.42-1.07). The pooled microbiologic failure rates were 1.8% (5 of 283 cases) with ODD and 4.0% (11 of 275 cases) with MDD. The fixed-effects risk ratio was 0.51 (95% CI: 0.22-1.18). NEPHROTOXICITY: There was no significant difference between ODD and MDD in the primary nephrotoxicity outcomes. Secondary nephrotoxicity outcomes were significantly better with ODD. The pooled primary nephrotoxicity rates were 1.6% (15 of 955 cases) in the ODD arms and 1.6% (15 of 923 cases) in the MDD arms. The fixed-effects risk ratio was 0.97 (95% CI: 0.55-1.69). The pooled secondary nephrotoxicity rates were 4.4% (3 of 69 cases) in the ODD arms and 15.9% (11 of 69 cases) in the MDD arms, suggesting a statistically significant superiority of ODD. The fixed-effects risk ratio was 0.33 (95% CI: 0.12-0.89). Results were consistent across types of clinical settings and aminoglycosides. OTOTOXICITY: There was no significant difference between ODD and MDD in the primary ototoxicity outcomes. The pooled ototoxicity rates for studies that provided auditory testing results were 2.3% (10 of 436 cases) in the ODD arms and 2.0% (8 of 406 cases) in the MDD arms. The fixed-effects risk ratio was 1.06 (95% CI: 0.51-2.19). In studies that provided clinical vestibular function testing results, no toxicity was documented among 209 patients given ODD and 206 patients given MDD. Studies noting only the clinical impression of hearing impairment also failed to identify any toxicity (ODD: 114 cases; MDD: 114 cases). SUBGROUP AND BIAS ANALYSES: We detected no statistically significant differences between ODD and MDD in any of the examined subgroups (neonatal intensive care unit, cystic fibrosis, cancer, or urinary tract infection), with respect to combined clinical or microbiologic failure outcomes, primary nephrotoxicity outcomes, or ototoxicity (based on auditory testing), when sufficient data were available. Moreover, there was no significant relationship between the effect size (risk ratio) and the trial size for any of the outcomes. DATA INTERPRETATION: Clinical failures were uncommon in the pediatric trials, regardless of the regimen used. If anything, fewer clinical failures tended to occur with ODD. Moreover, we observed a trend toward decreased bacteriologic failures. One meta-analysis of adult data suggested that ODD might reduce nephrotoxicity, whereas other meta-analyses showed nonsignificant trends or no difference in nephrotoxicity outcomes. In our meta-analysis, we were not able to show any reduction in the risk of primary nephrotoxicity outcomes with ODD. However, the event rate was much lower among children, compared with adults, and the secondary nephrotoxicity outcomes favored ODD. Finally, although the 2 regimens seemed equivalent with respect to ototoxicity, reporting on ototoxicity outcomes was incomplete. Reassuringly, even in the trials that performed auditory testing, the rates of ototoxicity in the MDD arms were very low. These results were consistent with meta-analyses of adult data, which showed no difference in ototoxicity rates between ODD and MDD.Although single trials have been small, the available randomized evidence supports the general adoption of ODD of aminoglycosides in pediatric clinical practice. This approach minimizes cost, simplifies administration, and provides similar or even potentially improved efficacy and safety, compared with MDD of these drugs.

    View details for Web of Science ID 000222439200017

    View details for PubMedID 15231982

  • Randomized trials of neurosurgical interventions: A systematic appraisal NEUROSURGERY Vranos, G., Tatsioni, A., Polyzoidis, K., Ioannidis, J. P. 2004; 55 (1): 18-25

    Abstract

    To systematically appraise the study design and quality of reporting of randomized controlled trials (RCTs) on neurosurgical procedures and to identify potential defects and biases.Randomized controlled trials with at least five patients comparing any neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, EMBASE, and the Cochrane Library. We analyzed study design, quality of reporting, and trial results.The median sample size in the 108 eligible reports was 68 patients. Ninety-nine trials (91.7%) reported inclusion and exclusion criteria, 55 (50.9%) mentioned the randomization mode, and 87 (80.6%) adequately described withdrawals, but only 31 (28.7%) described allocation concealment, only 23 (21.3%) gave power calculations, and only 20 (18.5%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 46 reports (42.6%), and no difference between the compared procedures was found in 60 trials (55.6%). Trials with a larger sample size were more likely to report withdrawals (P = 0.02) and power calculations (P = 0.006). Only 14 trials (13.6%) were double-blind, and this was less frequent in longer trials (P = 0.02). Among quality criteria, only the reporting of randomization mode improved significantly over time (P = 0.015).Several aspects of the design and reporting of randomized controlled trials on neurosurgical procedures can be improved. Larger, adequately powered, and accurately reported trials are needed.

    View details for DOI 10.1227/01.NEU.0000126873.00845.A7

    View details for Web of Science ID 000226183900013

    View details for PubMedID 15214970

  • Global estimates of high-level brain drain and deficit FASEB JOURNAL Ioannidis, J. P. 2004; 18 (9): 936-939

    Abstract

    Brain drain, the international migration of scientists in search of better opportunities, has been a long-standing concern, but quantitative measurements are uncommon and limited to specific countries or disciplines. We need to understand brain drain at a global level and estimate the extent to which scientists born in countries with low opportunities never realize their potential. Data on 1523 of the most highly cited scientists for 1981-1999 are analyzed. Overall, 31.9% of these scientists did not reside in the country where they were born (range 18.1-54.6% across 21 different scientific fields). There was great variability across developed countries in the proportions of foreign-born resident scientists and emigrating scientists. Countries without a critical mass of native scientists lost most scientists to migration. This loss occurred in both developed and developing countries. Adjusting for population and using the U.S. as reference, the number of highly cited native-born scientists was at least 75% of the expected number in only 8 countries other than the U.S. It is estimated that approximately 94% of the expected top scientists worldwide have not been able to materialize themselves due to various adverse conditions. Scientific deficit is only likely to help perpetuate these adverse conditions.

    View details for DOI 10.1096/fj.03-1394lfe

    View details for Web of Science ID 000222327500010

    View details for PubMedID 15173104

  • The value of meta-analysis in rheumatology research. Autoimmunity reviews Ioannidis, J. P. 2004; 3: S57-9

    View details for PubMedID 15309799

  • The role of Fc gamma RIIA and IIIA polymorphisms in autoimmune diseases BIOMEDICINE & PHARMACOTHERAPY Karassa, F. B., Trikalinos, T. A., Ioannidis, J. P. 2004; 58 (5): 286-291

    Abstract

    Our knowledge about the role of human Fc receptors for IgG (FcgammaR) has increased considerably within the last several years. These receptors vary in their affinity for IgG, their preferences for IgG subclasses, the cell type-specific expression patterns, and the intracellular signals that they elicit. Additional FcgammaR heterogeneity is introduced by the presence of well characterized genetic polymorphisms. Allelic variants of FcgammaR genes may influence phagocyte biologic activity, providing a basis for inherited predisposition to disease. Recent evidence suggests that certain FcgammaR alleles are genetic risk factors for systemic autoimmune diseases and the development of major manifestations of these diseases. The FcgammaRIIA-R/H131 polymorphism is an important determinant of predisposition to systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). FcgammaRIIA-R131, the low-binding IgG2 allele, seems to confer risk for APS under a recessive model, whereas its effect on SLE susceptibility probably has a dose-response character. The population-attributable fraction of lupus cases due to the R131 allele is 13% and for APS cases is at least 10%, in subjects of European descent. The FcgammaRIIIA-V/F158 polymorphism has a significant impact on renal involvement in lupus patients. The proportion of nephritis cases that could be attributed to the low-binding IgG1 and IgG3 F158 allele is approximately 10-14%. These genetic associations have been well documented in meta-analyses including a large number of studies. Besides the epidemiologic and pathophysiologic interest, this knowledge may be of use in the future in designing novel therapeutic interventions.

    View details for DOI 10.1016/j.biopha.2004.04.004

    View details for Web of Science ID 000222418500004

    View details for PubMedID 15194164

  • The Gini coefficient as a measure for understanding accrual inequalities in multicenter clinical studies JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A. B., Ioannidis, J. P. 2004; 57 (4): 341-348

    Abstract

    Clinical sites participating in multicenter trials may have unequal performance in recruiting subjects. We propose using the Gini coefficient as a quantitative measure of site accrual inequalities.We evaluated the relationship of this metric to other study characteristics across 166 clinical studies (27,865 subjects) conducted by the AIDS Clinical Trials Group between 1986 and 1999.Overall there was a modest recruitment inequality among clinical centers (mean Gini=0.33). In multivariate modeling, site accrual inequalities were higher when there was more protracted enrollment, and a larger number of sites and were lower in antiretroviral studies than other studies. In long-term studies, the site accrual inequality increased significantly over time (P=0.004). In efficacy trials, a higher Gini coefficient was associated with higher likelihood of the study results being statistically significant (P=0.010).The Gini coefficient may be easily and routinely incorporated in the description of the characteristics of a clinical study and may provide insights about its enrollment pattern.

    View details for DOI 10.1016/j.jclinepi.2003.09.011

    View details for Web of Science ID 000221772500004

    View details for PubMedID 15135834

  • UCHL1 is a Parkinson's disease susceptibility gene ANNALS OF NEUROLOGY Maraganore, D. M., Lesnick, T. G., Elbaz, A., Chartier-Harlin, M. C., Gasser, T., Kruger, R., Hattori, N., Mellick, G. D., Quattrone, A., Satoh, J., Toda, T., Wang, J., Ioannidis, J. P., de Andrade, M., Rocca, W. A. 2004; 55 (4): 512-521

    Abstract

    The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.

    View details for DOI 10.1002/ana.20017

    View details for Web of Science ID 000220437200008

    View details for PubMedID 15048890

  • Meta-analysis of the association of the cathepsin D Ala224Val gene polymorphism with the risk of Alzheimer's disease: A HuGE gene-disease association review AMERICAN JOURNAL OF EPIDEMIOLOGY Ntais, C., Polycarpou, A., Ioannidis, J. P. 2004; 159 (6): 527-536

    Abstract

    A C-to-T polymorphism in exon 2 of the cathepsin D gene encoding cathepsin D (CTSD) has been implicated as a risk factor for Alzheimer's disease. The authors performed a meta-analysis of 14 studies (16 comparisons) with CTSD genotyping (3,174 Alzheimer's disease cases and 3,298 controls). Overall, the random effects odds ratio for the T versus the C allele was 1.17 (95% confidence interval (CI): 0.95, 1.44), with some between-study heterogeneity (p < 0.01). There was significant between-study heterogeneity but no evidence of a significant association when the first hypothesis-generating study was excluded from the calculations (odds ratio (OR) = 1.11, 95% CI: 0.91, 1.35; p = 0.29). The summary odds ratio for T carriers versus T noncarriers was similar in subjects carrying or not carrying an apolipoprotein E epsilon4 allele (APOE*4). The increased susceptibility to Alzheimer's disease conferred by APOE*4 carriage tended to be more prominent in the presence of the T allele (random effects OR = 6.07, 95% CI: 4.19, 8.79, and OR = 4.09, 95% CI: 3.15, 5.31, in T carriers and noncarriers, respectively). The meta-analysis shows that the CTSD polymorphism is not a major risk factor for Alzheimer's disease, although a small effect or an enhancement of the APOE*4 effect cannot be excluded.

    View details for Web of Science ID 000220180600001

    View details for PubMedID 15003956

  • Maternal viral load and rate of disease progression among vertically HIV-1-infected children: an international meta-analysis AIDS Ioannidis, J. P., Tatsioni, A., Abrams, E. J., Bulterys, M., COOMBS, R. W., Goedert, J. J., Korber, B. T., Mayaux, M. J., Mofenson, L. M., Moye, J., Newell, M. L., Shapiro, D. E., Teglas, J. P., Thompson, B., Wiener, J. 2004; 18 (1): 99-108

    Abstract

    To evaluate whether maternal human immunodeficiency virus type 1 (HIV-1) RNA levels in the serum/plasma of mothers at or close to the time of delivery affects the rate of disease progression among vertically HIV-1-infected children and whether it correlates with other parameters affecting infant disease progression.International meta-analysis of eight studies with 574 HIV-1 infected infants with available maternal HIV-1 RNA measurements at or close to delivery and clinical follow-up. The primary outcome was disease progression (stage C disease or death, n = 178). Cohort-stratified Cox models were used.Higher maternal HIV-1 RNA level at or close to delivery significantly increased disease progression risk [hazard ratio (HR), 1.25; 95% confidence interval (CI), 1.04-1.52 per 1 log10 increase; P = 0.02) with a borderline effect on mortality (HR, 1.26; 95% CI, 0.96-1.65; P = 0.10]. The association with disease progression risk was strong in the first 6 months of life (HR, 1.77; 95% CI, 1.28-2.45; P = 0.001), but not subsequently (HR, 1.03; 95% CI, 0.81-1.30). Maternal HIV-1 RNA, early infant HIV-1 RNA (at 30-200 days after birth) and infant CD4 were independent predictors of disease progression in the first 6 months. Maternal HIV-1 RNA at or close to delivery correlated with early infant HIV-1 RNA (r = 0.26, P < 0.001). Effects were independent of maternal and infant treatment.Higher maternal HIV-1 RNA at or close to delivery strongly predicts disease progression for HIV-1-infected infants, especially in their first 6 months of life and correlates with the early peak of viremia in the infected child.

    View details for DOI 10.1097/01.aids.0000088200.77946.42

    View details for Web of Science ID 000189101600012

    View details for PubMedID 15090835

  • Materializing research promises: opportunities, priorities and conflicts in translational medicine. Journal of translational medicine Ioannidis, J. P. 2004; 2 (1): 5

    Abstract

    There is considerable evidence that the translation rate of major basic science promises to clinical applications has been inefficient and disappointing. The deficiencies of translational science have often been proposed as an explanation for this failure. An alternative explanation is that until recently basic science advances have made oversimplified assumptions that have not matched the true etiological complexity of most common diseases; while clinical science has suffered from poor research practices, overt biases and conflicts of interest. The advent of molecular medicine and the recasting of clinical science along the principles of evidence-based medicine provide a better environment where translational research may now materialize its goals. At the same time, priority issues need to be addressed in order to exploit the new opportunities. Translational research should focus on diseases with global impact, if true progress is to be made against human suffering. The health outcomes of interest for translational efforts need to be carefully defined and a balance must be struck between the subjective needs of healthcare consumers and objective health outcomes. Development of more simple, practical and safer interventions may be as important a target for translational research as the development of cures for diseases where no effective interventions are available at all. Moreover, while the role of the industry is catalytic in translating research advances to licensed interventions, academic independence needs to be sustained and strengthened at a global level. Conflicts of interest may stifle translational research efforts internationally. The profit motive is unlikely to be sufficient alone to advance biomedical research towards genuine progress.

    View details for DOI 10.1186/1479-5876-2-5

    View details for PubMedID 14754464

  • Evidence report on the treatment of pain in cancer patients. Journal of the National Cancer Institute. Monographs Carr, D. B., Goudas, L. C., Balk, E. M., Bloch, R., Ioannidis, J. P., Lau, J. 2004: 23-31

    Abstract

    Pain associated with cancer is of widespread concern. We conducted a systematic review to evaluate the best available evidence on the efficacy of treatments of cancer-related pain. The sources used were MEDLINE, CancerLit, and the Cochrane Library from 1966 through April 2001, as well as bibliographies of meta-analyses and review articles. We selected randomized controlled trials (RCTs) reporting on cancer pain treatment. We recorded the study characteristics, patient and disease characteristics, treatment comparisons, outcome measures, and results. The methodological quality, applicability, and magnitude of treatment effect for each study were graded. We screened 24 822 titles and selected 213 RCTs to address specific questions. RCTs of cancer pain control often enroll few subjects, have low methodological quality, offer little detail about pain characteristics and mechanisms, and involve heterogeneous interventions and outcomes. Nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, selected adjuvant medications, bisphosphonates, radionuclides, external radiation, palliative chemotherapy, and neurolytic celiac plexus block are each efficacious in relieving cancer pain. However, the retrieved RCTs indicate no difference in the analgesic efficacies of NSAIDs versus other NSAIDs, NSAIDs plus opioids versus NSAIDs alone, or NSAIDs versus opioids. Studies of adjuvant medications and behavioral therapies are too few and varied to synthesize. RCTs of the analgesic effects of corticosteroids were not retrieved in our review, although we did conduct supplemental evidence reviews concerning pain control in oral mucositis, acute herpes zoster, or postherpetic neuralgia. RCTs confirm the efficacy of diverse interventions in relieving cancer pain. The optimal initial and subsequent sequence of choices among analgesic drug types cannot be inferred from the retrieved RCTs. Patient preferences, the relative efficacy of different routes of drug administration, the side effects of analgesics, and the relation of pain control to quality of life have not been studied comprehensively. The quantity and quality of scientific evidence on cancer pain relief compare unfavorably with evidence related to treatment of other high-impact conditions, including cancer itself. One contributor to this gap is the heterogeneity of outcomes instruments employed: of 218 retrieved trials, there were 125 distinct pain outcomes assessed. In the current era of patient-centered care, improving the quality and combinability of trials on cancer pain relief should be a high research priority.

    View details for PubMedID 15263038

  • Diagnosis of sensorineural hearing loss with neural networks versus logistic regression modeling of distortion product otoacoustic emissions AUDIOLOGY AND NEURO-OTOLOGY Ziavra, N., Kastanioudakis, I., Trikalinos, T. A., Skevas, A., Ioannidis, J. P. 2004; 9 (2): 81-87

    Abstract

    We investigated whether modeling with artificial neural networks or logistic regression of distortion product otoacoustic emissions (DPOAE), across diverse frequencies, may achieve an accurate diagnosis of sensorineural hearing loss (SNHL) of cochlear origin. 256 ears (90 with SNHL and 166 with normal hearing) were evaluated with pure-tone audiometry, impedance audiometry, speech audiometry and DPOAE. Ears were split into training (n = 176) and validation (n = 80) sets. Input variables included gender, age, examination time, DPOAE intensity at F(2) frequencies 593, 937, 1906, 3812 and 6031 Hz, and respective values corrected for noise levels. In the validation data set, an average network had an area under the receiver operating characteristic curve (AUC) of 0.86 (accuracy 84%). Logistic regressions including all these variables or those selected by backward elimination had AUC values of 0.91 and 0.92, respectively (accuracy 85% both). Eleven of 12 trained networks had better specificity than the backward elimination logistic regression, and the backward elimination logistic regression had a better sensitivity than 11 of the 12 networks. Both modeling approaches correctly identified all ears with sudden hearing loss, congenital hearing loss, head trauma, nuclear jaundice and ototoxicity, and 2-3 of 5 ears with acoustic trauma, but missed 1-3 of 3 ears with Ménière's disease and 4-6 of 8 ears with abnormal pure-tone thresholds on audiometry which had no accompanying findings. For SNHL exceeding 45 dB HL on a pure-tone threshold, sensitivity was 83% (15/18) by neural networks and 84 or 94% (16/18 or 17/18) by logistic regression. Both neural-network-based analysis and logistic regression modeling of the DPOAE pattern across a range of frequencies offer promising approaches for the objective diagnosis of moderate and severe SNHL.

    View details for DOI 10.1159/000075999

    View details for Web of Science ID 000189170300004

    View details for PubMedID 14981356

  • Physical examination LANCET Ioannidis, J. P. 2003; 362 (9400): 2023-2023

    View details for Web of Science ID 000187210700033

    View details for PubMedID 14683669

  • HIV: prevention of opportunistic infections. Clinical evidence Ioannidis, J., Wilkinson, D. 2003: 809-830

    View details for PubMedID 15555123

  • Vitamin D receptor gene polymorphisms and risk of prostate cancer: A meta-analysis CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ntais, C., Polycarpou, A., Ioannidis, J. P. 2003; 12 (12): 1395-1402

    Abstract

    Several polymorphisms in the vitamin D receptor (VDR) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 14 studies (17 comparisons) with TaqI genotyping (1870 prostate cancer cases; 2843 controls), 6 studies (8 comparisons) with poly(A) repeat genotyping (540 cases; 870 controls), 5 studies with BsmI genotyping (987 cases; 1504 controls), and 3 studies with FokI genotyping (514 cases; 545 controls). The random-effects odds ratio (OR) for the t versus T allele was 0.95 [95% confidence interval (CI), 0.86-1.05]. There was no suggestion of an overall effect either in recessive or dominant modeling, and the comparison of t/t versus T/T also showed no differential prostate cancer susceptibility (OR, 0.88; 95% CI, 0.70-1.10). No effect of t was seen in subjects of European descent (nine comparisons; OR, 0.97; 95% CI, 0.87-1.08), Asian descent (five comparisons; OR, 0.88; 95% CI, 0.66-1.17), or African descent (three comparisons; OR, 0.94; 95% CI, 0.41-2.17). There was no between-study heterogeneity in any of these analyses. Overall, the random effects OR was 0.94 (95% CI, 0.75-1.18; no between-study heterogeneity) for the S versus L allele, 0.92 (95% CI, 0.63-1.35; P < 0.01 for heterogeneity) for the B versus b allele, and 1.03 (95% CI, 0.86-1.23; no between-study heterogeneity) for the f versus F allele. The meta-analysis shows that these four polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.

    View details for Web of Science ID 000187575900002

    View details for PubMedID 14693728

  • Isolated intraparotid Kaposi sarcoma in human immunodeficiency virus type 1 infection MAYO CLINIC PROCEEDINGS Rizos, E., Drosos, A. A., Ioannidis, J. P. 2003; 78 (12): 1561-1563

    Abstract

    Isolated Kaposi sarcoma (KS) of the parotid gland is an uncommon but distinct entity in patients with human immunodeficiency virus type 1 (HIV-1). A 30-year-old white homosexual man in whom HIV-1 had been diagnosed 2 years previously developed right parotid gland enlargement in the absence of constitutional symptoms. He had been taking zidovudine, lamivudine, and indinavir; his CD4 cell count was 0.297 x 10(9)/L, and HIV-1 RNA load was 47 copies/mL. After surgical excision of the parotid gland, biopsy findings disclosed KS of an intraparotid lymph node. A literature review revealed 6 other men with HIV-1 and isolated parotid KS. To our knowledge, our patient is the first to have received triple antiretroviral therapy with excellent immunological and virological response and parotid gland enlargement that might reflect immune reconstitution. Even in the absence of skin or other lesions, KS should be considered in the differential diagnosis of parotid gland enlargement in patients with HIV-1, even in those who are responding to highly active antiretroviral treatment.

    View details for Web of Science ID 000186873000015

    View details for PubMedID 14661687

  • Modelling of escalating outpatient antibiotic expenditures JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY Zintzaras, E., Ioannidis, J. P. 2003; 52 (6): 1001-1004

    Abstract

    To model the relative role of old and newly introduced antibiotics in shaping increased antibiotic use.Grouped data covering nationwide consumption and expenditure for out-of-hospital antibiotics in Greece (1990-1999) were used. The antibiotic formulations were categorized into 'common old formulations', 'old formulations with intermittent sales', 'recast formulations' and 'new substances'. The effect of each category was investigated based on index and pricing analyses.We estimated a 143% net increase in out-of-hospital antibiotic use during 1990-1999. The increase was 59% when all formulations of antibiotic substances available by 1990 were considered. A rapid turnaround of formulations of old substances was noticed with 669 formulations marketed during the decade. Sixteen new antibiotic substances were first introduced after 1990 and by 1999 they accounted for 34.9% of total out-of-hospital antibiotic expenditures. Three new antibiotics (a macrolide and two cephalosporins) accounted for over 90% of this amount. For all three, other less expensive alternatives were available.In the studied setting, out-of-hospital antibiotic use has been expanding in a highly substance-specific and non-rational fashion that is accelerated by the introduction of new drugs.

    View details for DOI 10.1093/jac/dkg464

    View details for Web of Science ID 000187227000020

    View details for PubMedID 14585862

  • Number of published systematic reviews and global burden of disease: database analysis BRITISH MEDICAL JOURNAL Swingler, G. H., Volmink, J., Ioannidis, J. P. 2003; 327 (7423): 1083-1084

    View details for Web of Science ID 000186530400019

    View details for PubMedID 14604930

  • Randomised trials comparing chemotherapy regimens for advanced non-small cell lung cancer: biases and evolution over time EUROPEAN JOURNAL OF CANCER Ioannidis, J. P., Polycarpou, A., Ntais, C., Pavlidis, N. 2003; 39 (16): 2278-2287

    Abstract

    We systematically evaluated the evidence from randomised trials comparing various chemotherapy regimens for advanced non-small cell lung cancer. Across 254 eligible trials (42661 patients), no regimens were compared in >6 studies. Twenty-six trials (10%) found statistically significant differences in survival between the compared arms. Only five reported the randomisation mode, and four reported adequate allocation concealment; nine performed unaccounted interim analyses. Statistical significance was more common in larger (P=0.003), more recent studies (P=0.031), and trials from countries with only one published eligible study (P=0.008). Increased reported median survival was independently associated with platinum and/or taxane and combination regimens, but also with the year of publication, smaller sample size, and larger representation of non-stage IV patients and patients with a better performance status. The proportion of enrolled patients with a performance status of 2 or worse decreased significantly over time (12.9% per decade, P<0.001). Randomised evidence in this field is fragmented and subject to considerable selection biases.

    View details for DOI 10.1016/S0959-8049(03)00571-9

    View details for Web of Science ID 000186452000014

    View details for PubMedID 14556918

  • Evaluation of cluster randomized controlled trials in sub-Saharan Africa AMERICAN JOURNAL OF EPIDEMIOLOGY Isaakidis, P., Ioannidis, J. P. 2003; 158 (9): 921-926

    Abstract

    Cluster randomized controlled trials (CRCTs) are attractive in settings in which individual randomization is difficult or impossible. This issue is common when studying several health problems in developing countries. The authors aimed to assess empirically the extent to which the prerequisite design and analysis aspects of cluster randomization were taken into account and reported properly in CRCTs conducted in sub-Saharan Africa. CRCTs published in the last three decades were evaluated by using a checklist based on the Consolidated Standards of Reporting Trials (CONSORT) statement. The authors identified 51 eligible CRCTs; 40 of them (78%) had been published after 1990. Only 10 (20%) studies took clustering into account in sample size or power calculations, and only 19 (37%) took clustering into account in the analysis. Intracluster correlation coefficients and design effects were reported in only one (2%) and three (6%) trials, respectively. An increasing number of CRCTs are conducted in sub-Saharan Africa, but many are not analyzed and reported properly. The special features stemming from cluster randomization need to be addressed in the design, analysis, and reporting of these studies.

    View details for DOI 10.1093/aje/kwg232

    View details for Web of Science ID 000186321900011

    View details for PubMedID 14585770

  • Predictive ability of DNA microarrays for cancer outcomes and correlates: an empirical assessment LANCET Ntzani, E. E., Ioannidis, J. P. 2003; 362 (9394): 1439-1444

    Abstract

    DNA microarrays are being used for many applications, including the prediction of cancer outcomes by simultaneous analysis of the expression of thousands of genes. We systematically assessed the predictive performance of this method for major clinical outcomes (death, metastasis, recurrence, response to therapy) and the correlation of gene profiling with other clinicopathological correlates of malignant disorders.Eligible reports retrieved from MEDLINE (1995 to April, 2003) were assessed for features of study design, reported predictive performance, and consideration of other prognostic factors. We searched for study variables that increased the chances that a significant association with a clinical outcome or correlate would be found.84 eligible studies were identified, of which 30 addressed major clinical outcomes. A median of 25 (IQR 15-45) patients with cancer were included. Among the studies of major clinical outcomes, nine did cross-validation but it was complete in only two of them; six studies used independent validation of supervised predictive models. Smaller studies showed better sensitivity and specificity for clinical outcomes than larger studies. Only 11 studies addressing major clinical outcomes did subgroup or adjusted analyses for other prognostic factors. Across all 84 studies, significant associations were 3.5 (95% CI 1.5-8.0) times more likely per doubling of sample size and 9.7 (2.0-47.0) times more likely per ten-fold increase in microarray probes.DNA microarrays addressing cancer outcomes show variable prognostic performance. Larger studies with appropriate clinical design, adjustment for known predictors, and proper validation are essential for this highly promising technology.

    View details for Web of Science ID 000186356600008

    View details for PubMedID 14602436

  • Mother-to-child transmission of HIV: developing integration of healthcare programmes with clinical, social and basic research studies - Report of the International Workshop held at Chobe Marina Lodge, Kasane, Botswana, 21-25 January 2003 ACTA PAEDIATRICA Menu, E., Scarlatti, G., Barre-Sinoussi, F., Gray, G., Bollinger, B., Ioannidis, J. P., Miotti, P., Osborne, C. 2003; 92 (11): 1343-1348

    Abstract

    Considerable efforts are still needed in the public health sector, as well as in clinical, social and basic research, to improve programmes for HIV-1 MTCT (mother-to-child transmission) prevention and care. Advantage should be taken of the remarkable amount of expertise and resources that have accumulated over the past few years to accelerate the process of integration. Future initiatives should include integrating specialists and people with diverse backgrounds and targeting their scientific and programmatic ideas to address real-world problems in the area of MTCT of HIV-1.

    View details for DOI 10.1080/08035250310006025

    View details for Web of Science ID 000186522300019

    View details for PubMedID 14696857

  • Screening performance of first-trimester nuchal translucency for major cardiac defects: A meta-analysis AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Makrydimas, G., Sotiriadis, A., Ioannidis, J. P. 2003; 189 (5): 1330-1335

    Abstract

    The purpose of this study was to evaluate the screening performance of increased first-trimester nuchal translucency for the detection of major congenital heart defects.A meta-analysis based on MEDLINE and EMBASE searches (up to June 2002) that assessed the diagnostic performance of increased nuchal translucency for congenital heart defect detection. Weighted sensitivity and specificity estimates (random effects) and summary receiver-operating characteristic curves were obtained.Eight independent studies with 58,492 pregnant women were analyzed. There was significant heterogeneity among the studies. Nuchal translucency above the 99th percentile had a sensitivity of 31% and specificity of 98.7% (random effects calculations), with a positive likelihood ratio of 24. Summary receiver-operating characteristic estimates were consistent with these values. The ability of nuchal translucency measurements above this threshold to detect cardiac malformations varied nonsignificantly (P=.64) for different congenital heart defects types (sensitivity range, 25%-55%).Nuchal translucency screening is a modestly efficient strategy for congenital heart defect detection; the use of the 99th percentile threshold may capture approximately 30% of congenital heart defects.

    View details for DOI 10.1067/S0002-9378(03)00645-8

    View details for Web of Science ID 000186979500022

    View details for PubMedID 14634564

  • Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ioannidis, J. P., Karvouni, E., Katritsis, D. G. 2003; 42 (8): 1406-1411

    Abstract

    The aim of this study was to assess whether small creatine kinase-MB isoenzyme (CK-MB) elevations after percutaneous coronary intervention (PCI) affect the subsequent mortality risk.Several studies have evaluated the relationship of CK-MB levels after PCI with the subsequent risk of death. While there is consensus that elevations exceeding 5 times the upper limit of normal increase mortality significantly, there is uncertainty about the exact clinical impact of smaller CK-MB elevations.We performed a meta-analysis of seven studies with CK-MB measurements and survival outcomes on 23230 subjects who underwent PCI. Data were combined with random effects models.Mean follow-up was 6 to 34 months per study. By random effects, 19% (95% confidence interval [CI], 16% to 23%) had one- to five-fold CK-MB elevations, while only 6% (95% CI, 5% to 9%) had >5-fold elevations. Compared with subjects with normal CK-MB, there was a dose-response relationship with relative risks for death being 1.5 (95% CI, 1.2 to 1.8, no between-study heterogeneity) with one- to three-fold CK-MB elevations, 1.8 (95% CI, 1.4 to 2.4, no between-study heterogeneity) with three- to five-fold CK-MB elevations, and 3.1 (95% CI, 2.3 to 4.2, borderline between-study heterogeneity) with over five-fold CK-MB elevations (p < 0.001 for all).Any increase in CK-MB after PCI is associated with a small, but statistically and clinically significant, increase in the subsequent risk of death.

    View details for DOI 10.1016/S0735-1097(03)01044-1

    View details for Web of Science ID 000185860800012

    View details for PubMedID 14563583

  • HIV lipodystrophy case definition using artificial neural network modelling ANTIVIRAL THERAPY Ioannidis, J. P., Trikalinos, T. A., Law, M., Carr, A. 2003; 8 (5): 435-441

    Abstract

    A case definition of HIV lipodystrophy has recently been developed from a combination of clinical, metabolic and imaging/body composition variables using logistic regression methods. We aimed to evaluate whether artificial neural networks could improve the diagnostic accuracy.The database of the case-control Lipodystrophy Case Definition Study was split into 504 subjects (265 with and 239 without lipodystrophy) used for training and 284 independent subjects (152 with and 132 without lipodystrophy) used for validation. Back-propagation neural networks with one or two middle layers were trained and validated. Results were compared against logistic regression models using the same information.Neural networks using clinical variables only (41 items) achieved consistently superior performance than logistic regression in terms of specificity, overall accuracy and area under the ROC curve. Their average sensitivity and specificity were 72.4 and 71.2%, as compared with 73.0 and 62.9% for logistic regression, respectively (area under the ROC curve, 0.784 vs 0.748). The discriminating performance of the neural networks was largely unaffected when built excluding 13 parameters that patients may not have readily available. The average sensitivity and specificity of the neural networks remained the same when metabolic variables were also considered (total 60 items) without a clear advantage against logistic regression (overall accuracy 71.8%). The performance of networks considering also body composition variables was similar to that of logistic regression (overall accuracy 78.5% for both).Neural networks may offer a means to improve the discriminating performance for HIV lipodystrophy, when only clinical data are available and a rapid approximate diagnostic decision is needed. In this context, information on metabolic parameters is apparently not helpful in improving the diagnosis of HIV lipodystrophy, unless imaging and body composition studies are also obtained.

    View details for Web of Science ID 000231266700010

    View details for PubMedID 14640391

  • Pharmacogenetics and association studies in schizophrenia DRUG DEVELOPMENT RESEARCH Ntzani, E. E., Ioannidis, J. P. 2003; 60 (2): 152-163

    View details for DOI 10.1002/ddr.10294

    View details for Web of Science ID 000185694900009

  • The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma - A meta-analysis CANCER Pakos, E. E., Ioannidis, J. P. 2003; 98 (3): 581-589

    Abstract

    There is controversy regarding whether P-glycoprotein (Pgp) may be a prognostic factor for the response to chemotherapy and clinical disease progression in patients with osteosarcoma.The authors conducted a meta-analysis of 14 studies (n = 631 patients) that evaluated the correlation between Pgp and histologic response to chemotherapy and clinical disease progression (death, metastasis, or recurrence). Data were synthesized in receiver operating characteristic curves and with fixed-effects and random-effects likelihood ratios and risk ratios.Pgp had no discriminating ability for identifying poor responders versus good responders to chemotherapy: The positive likelihood ratio was 1.15 (95% confidence interval [95% CI], 0.93-1.43), and the negative likelihood ratio was 0.88 (95% CI, 0.65-1.18; random-effects calculations). There was some between-study heterogeneity, but no study showed strong discriminating ability. Conversely, Pgp positivity increased the risk of disease progression 1.92-fold (95% CI, 1.18-3.13; random-effects calculations) with some between-study heterogeneity that disappeared when only studies that employed immunohistochemistry were considered (risk ratio, 2.23; 95% CI, 1.37-3.64). The results were robust in various sensitivity analyses, although smaller studies tended to show stronger associations with the risk of disease progression compared with larger studies (P = 0.03).The available evidence showed conclusively that Pgp was not associated with the histologic response of patients with osteosarcoma to combination chemotherapy regimens. Conversely, Pgp positivity, as determined by immunohistochemistry, was a strong correlate of more rapid disease progression, although there was heterogeneity across the performed studies that, to some extent, may have reflected bias, differential measurements of Pgp, or confounding with other risk factors.

    View details for DOI 10.1002/cnr.11546

    View details for Web of Science ID 000184246000017

    View details for PubMedID 12879476

  • Effects of CCR5-Delta 32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis AIDS Ioannidis, J. P., Contopoulos-Ioannidis, D. G., Rosenberg, P. S., Goedert, J. J., De Rossi, A., Espanol, T., Frenkel, L., Mayaux, M. J., Newell, M. L., Pahwa, S. G., Rousseau, C., Scarlatti, G., Sei, S., Sen, L., O'Brien, T. R. 2003; 17 (11): 1631-1638

    Abstract

    Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis.Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated.There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed.The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.

    View details for DOI 10.1097/01.aids.0000060411.18106.0f

    View details for Web of Science ID 000184661800007

    View details for PubMedID 12853745

  • Association of Leiden mutation in Factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis JOURNAL OF HYPERTENSION Kosmas, I. P., Tatsioni, A., Ioannidis, J. P. 2003; 21 (7): 1221-1228

    Abstract

    To evaluate whether the V Leiden mutation is consistently associated with hypertension in pregnancy across populations of pregnant women.Meta-analysis of studies comparing women with and without hypertension in pregnancy for the V Leiden mutation.Studies were identified with MEDLINE and EMBASE searches complemented with perusal of bibliographies of retrieved articles and communication with investigators. Data were evaluated with random effects models and between-study heterogeneity was estimated. Sensitivity analyses examined the effect of population and study characteristics. Bias diagnostics evaluated the evolution of the postulated effect over time and the potential for publication bias. RESULTS Across 19 studies (2742 hypertensive women, 2403 controls), V Leiden mutation increased the odds of hypertensive disease of pregnancy by 2.25-fold [95% confidence interval (CI), 1.50-3.38], but there was large between-study heterogeneity (P = 0.002). The results were similar and heterogeneity persisted when sensitivity analyses were limited to studies with Caucasians, proteinuria, diastolic hypertension threshold > 110 mmHg, specified selection of cases, and matching. While studies published up to 2000 showed an odds ratio of 3.16 (95% CI, 2.04-4.92), no association was seen in studies published in 2001-2002 (odds ratio 0.97; 95% CI, 0.61-1.54). There was also evidence of potential publication bias: the five largest studies showed no association (odds ratio 1.21; 95% CI, 0.84-1.74).Although modest effects of V Leiden mutation on the risk of hypertension in pregnancy cannot be excluded, the association observed in early and small studies may be typical of bias, in particular time-lag bias and publication bias.

    View details for DOI 10.1097/01.hjh.0000059025.82022.ff

    View details for Web of Science ID 000184278000002

    View details for PubMedID 12817161

  • SRD5A2 gene polymorphisms and the risk of prostate cancer: A meta-analysis CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ntais, C., Polycarpou, A., Ioannidis, J. P. 2003; 12 (7): 618-624

    Abstract

    Several polymorphisms in the 5alpha-reductase type 2 (SRD5A2) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 9 studies (12 comparisons) with V89L genotyping (2558 prostate cancer cases and 3349 controls), 7 studies (8 comparisons) with A49T genotyping (1594 cases and 2137 controls), and 4 studies with TA repeat genotyping (1109 cases and 1378 controls). The random effects odds ratio (OR) for the L versus V allele was 1.02 [95% confidence interval (CI), 0.94-1.11]. There was no suggestion of an overall effect either in recessive or dominant modeling, and comparison of L/L versus V/V also showed no differential prostate cancer susceptibility (OR, 1.03; 95% CI, 0.83-1.28). The random effects OR for the T versus A allele was 1.56 (95% CI, 0.93-2.62). However, excluding the first published study there was no evidence for any effect (OR, 1.08; 95% CI, 0.72-1.61). Moreover, the T allele had a low prevalence (0%, 1%, and 2% in Asian, African and European controls, respectively). The random effects OR for longer versus short TA alleles was 0.88 (95% CI, 0.74-1.05). Longer TA allele homozygotes were nonsignificantly under-represented among prostate cancer cases (OR, 0.53; 95% CI, 0.26-1.06). We exclude a role for the V89L polymorphism in conferring susceptibility to prostate cancer. The A49T and TA repeat polymorphisms may have a modest effect on prostate cancer susceptibility, but bias and chance findings cannot be excluded; any genuine genetic effects would account only for a small proportion of prostate cancer in the population.

    View details for Web of Science ID 000184311700005

    View details for PubMedID 12869400

  • Suitable monitoring approaches to antiretroviral therapy in resource-poor settings: Setting the research agenda CLINICAL INFECTIOUS DISEASES Kent, D. M., McGrath, D., Ioannidis, J. P., Bennish, M. L. 2003; 37: S13-S24

    Abstract

    The delivery of antiretroviral therapy in the developing world requires guidelines for the appropriate monitoring of therapy, including monitoring for treatment effectiveness and treatment failure, drug toxicities, adherence to therapy, and the emergence of resistant organisms. Guidelines developed in wealthy industrialized countries, which rely heavily on laboratory tests often unavailable in the developing world, may not be feasible or appropriate for resource-limited settings. Even if the standard of care routinely delivered in industrialized settings cannot be replicated, antiretroviral treatment programs with less-intense monitoring have the potential to reduce morbidity and mortality from human immunodeficiency virus. Research to identify monitoring strategies that provide the greatest benefit to those living with human immunodeficiency virus in resource-limited settings and that use the available technologies and resources needs to be conducted within a conceptual and ethical framework that takes into account differences between rich and poor countries.

    View details for Web of Science ID 000183826900003

    View details for PubMedID 12822128

  • Role of the Fc gamma receptor IIA polymorphism in the antiphospholipid syndrome - an international meta-analysis ARTHRITIS AND RHEUMATISM Karassa, F. B., Bijl, M., Davies, K. A., Kallenberg, C. G., Khamashta, M. A., Manger, K., Michel, M., Piette, J. C., Salmon, J. E., Song, Y. W., Tsuchiya, N., Yoo, D. H., Ioannidis, J. P. 2003; 48 (7): 1930-1938

    Abstract

    To assess the impact of the FcgammaRIIA-R/H131 polymorphism on the risk for antiphospholipid syndrome (APS), both primary and secondary to systemic lupus erythematosus (SLE).This international meta-analysis combined data from 9 research teams. FcgammaRIIA-R/H131 genotypes were determined in 481 APS cases (206 with primary APS), 1,420 SLE controls, and 1,655 disease-free controls. Data were combined using fixed-effects and random-effects models.Compared with disease-free controls, the RR genotype was enriched in the entire group of APS cases (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.28-2.14); this was driven mostly by patients with secondary APS (OR 1.95, 95% CI 1.45-2.63). The excess of RR homozygotes but not heterozygotes among APS patients suggested a recessive mode of inheritance, rather than the additive model seen for SLE susceptibility, where RR conferred greatest risk, and RH intermediate risk, for SLE. This probably reflected the additional influence of another opposing genetic effect of HH homozygosity on APS predisposition (OR 0.72 for RH versus HH, 95% CI 0.55-0.96). Among SLE patients, those with APS were more frequently HH homozygotes than heterozygotes (OR 0.56 for RH versus HH, 95% CI 0.39-0.81). HH homozygosity also tended to predominate in primary APS compared with secondary APS (OR 0.50 for RR versus HH, 95% CI 0.25-0.99 by fixed-effects model). There was no significant between-study heterogeneity for any of these effects.The FcgammaRIIA-R/H131 polymorphism is an important determinant of predisposition to APS, with different influences on SLE and APS susceptibility per se.

    View details for DOI 10.1002/art.11059

    View details for Web of Science ID 000184067700021

    View details for PubMedID 12847687

  • HIV: opportunistic infections. Clinical evidence Ioannidis, J., Wilkinson, D. 2003: 795-816

    View details for PubMedID 15366175

  • Levels of absolute survival benefit for systemic therapies of advanced cancer: a call for standards EUROPEAN JOURNAL OF CANCER Ioannidis, J. P., Pavlidis, N. 2003; 39 (9): 1194-1198

    Abstract

    Research on systemic interventions in patients with advanced stage malignancies should be systematised with an emphasis on the absolute gain in survival for the median patient. Such information is most meaningful with relatively large-scale evidence. Here, we summarise the survival impact of 36 interventions compared against other interventions or no treatment for advanced stage malignancies in meta-analyses of individual patient data or in selected recent (2000-2002) randomised trials with >300 randomised subjects. Although 16 interventions showed a formally statistically significant survival benefit against the comparator arm, this exceeded 3 months in only 7 cases. We propose a standardised categorisation of the median survival prolongation in trials and meta-analyses. Level 0: no proven survival benefit; level I: 0-3 months; level II: >3-6 months; level III: >6-24 months; and level IV: more than 24 months. These standardised levels may be incorporated into clinical practice guidelines for individual care and policy-making.

    View details for DOI 10.1016/S0959-8049(03)00119-9

    View details for Web of Science ID 000183427600013

    View details for PubMedID 12763206

  • F-18-FDG PET for the diagnosis and grading of soft-tissue sarcoma: A meta-analysis JOURNAL OF NUCLEAR MEDICINE Ioannidis, J. P., Lau, J. 2003; 44 (5): 717-724

    Abstract

    PET using (18)F-FDG is increasingly used for the diagnosis and grading of tumors. Several studies have been performed that evaluate the diagnostic and grading performance of (18)F-FDG PET for soft-tissue sarcoma, but each study has had a limited sample size. Therefore, we undertook a comprehensive meta-analysis of the evidence.Relevant studies were identified from MEDLINE and EMBASE. Diagnostic and grading performance were evaluated for qualitative visualization; standard uptake value (SUV, cutoffs of 2.0 and 3.0); and metabolic rate of glucose (MRG, cutoff of 6.0 micro mol/100 g/min). Quantitative data synthesis included independent weighting of sensitivity and specificity, construction of summary receiver operating characteristic curves, and pooled analyses.The meta-analysis included 15 studies with 441 soft-tissue lesions (227 malignant, 214 benign). For diagnosis of malignant versus benign lesions, typical pairs of sensitivity and specificity estimates from the summary receiver operating characteristic curves were 92% and 73% for qualitative visualization; 87% and 79% for SUV 2.0; 70% and 87% for SUV 3.0; and 74% and 73% for MRG 6.0. Diagnostic performance was similar for primary and recurrent lesions. By qualitative interpretation, (18)F-FDG was positive in all intermediate/high-grade tumors (95% confidence interval [CI], 97.3%-100%), 74.4% (95% CI, 58.6%-85.9%) of low-grade tumors, and 39.3% (95% CI, 29.1%-50.3%) of benign lesions (including 11 of 12 inflammatory lesions). Using an SUV cutoff of 2.0, respective rates were 89.4% (95% CI, 79.4%-95.6%), 33.1% (95% CI, 15.6%-55.3%), and 19.1% (95% CI, 10.6%-30.5%). Limited data on comparisons with MRI and CT showed no differences against (18)F-FDG PET in diagnosing recurrent and metastatic disease.(18)F-FDG PET has very good discriminating ability in the evaluation of both primary and recurrent soft-tissue lesions. (18)F-FDG PET may be helpful in tumor grading but offers inadequate discrimination between low-grade tumors and benign lesions.

    View details for Web of Science ID 000182724000014

    View details for PubMedID 12732672

  • Design, quality, and bias in randomized controlled trials of systemic lupus erythematosus JOURNAL OF RHEUMATOLOGY Karassa, F. B., Tatsioni, A., Ioannidis, J. P. 2003; 30 (5): 979-984

    Abstract

    To appraise systematically the study design and quality of reporting of randomized controlled trials (RCT) on systemic lupus erythematosus (SLE) and to identify potential defects and biases.RCT with at least 5 patients with SLE were retrieved from MEDLINE, EMBASE, and the Cochrane Library. We analyzed study design, quality of reporting, and trial results.Ninety-four trial reports (37 on lupus nephritis) were eligible with 2,257 SLE patients (n = 795 in lupus nephritis trials). Median sample size was 28 patients. Fifty-one trials (54.3%) were double blind, but only 31 (33.0%) mentioned the randomization mode, only 19 (20.2%) described allocation concealment, and only 7 (7.5%) were adequately powered. Sixty-three trials (67%) described adequately reasons for withdrawals. Nephritis trials had on average longer followup (p = 0.001) and were less likely to be double blind (p < 0.001), to describe reasons for withdrawals [both overall (p = 0.008) and per arm (p = 0.009)] and to involve a comparison against placebo or no treatment (p < 0.001). Larger trials scored higher on several quality characteristics. Significant efficacy or trend for efficacy was claimed in 72 reports (76.6%) and this was even more common in trials published in 1999-2002 (89.5%). Significant efficacy was found more frequently in trials that clearly specified withdrawals per arm (p = 0.001) and outcomes (p = 0.001) and used intention-to-treat analyses (p = 0.03). Besides outcome specification, no other quality variables seemed to improve significantly over time.Several aspects of the design and reporting of RCT on SLE can be improved. Larger, adequately powered, and accurately reported trials are needed.

    View details for Web of Science ID 000182639000016

    View details for PubMedID 12734892

  • Late-starter sites in randomized controlled trials JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A. B., Ioannidis, J. P. 2003; 56 (5): 408-415

    Abstract

    In a cohort of 14 randomized controlled trials conducted by the Adult AIDS Clinical Trials Group between 1986 and 1999 with a target sample size of >400 (total enrollment 15,531 patients), we evaluated whether "late-starter" sites can make a meaningful contribution to eventual trial accrual. The sites that started recruiting within 5 months from the time the first patient entered the trial were eventually responsible for over 90% of the total enrollment in 11 of the 14 trials. Across the 14 trials, some sites were consistently among the first to start enrollment, whereas others were routinely among the last. The late-starter sites are unlikely to make important contributions to eventual trial enrollment in large clinical trials conducted by groups with a fixed number of sites. Protracting administrative efforts to add more sites many months after a multicenter trial has started may not be useful to trial accrual.

    View details for DOI 10.1016/S0895-4356(03)00032-5

    View details for Web of Science ID 000183589200002

    View details for PubMedID 12812813

  • Diagnostic performance of intracardiac echogenic foci for Down syndrome: A meta-analysis OBSTETRICS AND GYNECOLOGY Sotiriadis, A., Makrydimas, G., Ioannidis, J. P. 2003; 101 (5): 1009-1016

    Abstract

    To synthesize the accumulated data on the diagnostic performance of intracardiac echogenic foci for Down syndrome, a meta-analysis was performed.We conducted MEDLINE and EMBASE searches (1985 to August 2002) using the key words "intracardiac (echogenic) focus/foci," "golfballs," "trisomy 21," and "Down syndrome." Bibliographies of retrieved articles were also screened, and experts were contacted. Both single and multiple intracardiac echogenic foci qualified, regardless of cardiac location. Eligible studies included and described both chromosomally normal and abnormal fetuses; the fetal karyotype was unknown at the time of sonographic examination; and chromosomal status was confirmed by karyotype or postnatal clinical examination.Sensitivity and specificity were recorded for intracardiac echogenic foci in a "combined" setting (regardless of the presence of other sonographic markers) and "isolated" setting (in the absence of other markers). Weighted estimates and summary receiver operating characteristic curves were calculated. Across 11 studies (51,831 pregnancies, 333 Down syndrome cases), random effects sensitivity and specificity were 26% (95% confidence interval 19, 34) and 95.8% (95% confidence interval 92.2, 97.8), respectively, with a positive likelihood ratio of 6.2 ("combined" setting, likelihood ratio 7.0; "isolated" setting, likelihood ratio 5.4). Summary receiver operating characteristic curves were also consistent with these values. With a 0.8% risk of amniocentesis-induced fetal loss, one fetus is lost per Down case detected when the background Down risk is 1:770.Intracardiac echogenic foci increase the risk of Down syndrome five- to seven-fold. This information should be considered in the decision making for amniocentesis in conjunction with the woman's background risk.

    View details for DOI 10.1016/S0029-7844(03)00168-6

    View details for Web of Science ID 000182531500031

    View details for PubMedID 12738165

  • Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study RHEUMATOLOGY Vlachoyiannopoulos, P. G., Kanellopoulos, P. G., Ioannidis, J. P., Tektonidou, M. G., Mastorakou, I., Moutsopoulos, H. M. 2003; 42 (5): 645-651

    Abstract

    To evaluate whether premenopausal women with antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE) have increased prevalence of atherosclerosis after adjustment has been made for known cardiovascular risk factors.We evaluated premenopausal women with APS in comparison with age-matched groups of patients with SLE [positive or negative for anticardiolipin (aCL) antibodies] or rheumatoid arthritis (RA), and healthy subjects. Thirty-three subjects in each group were assessed for cardiovascular risk factors, including a detailed lipid profile. Ultrasonography of carotid and femoral arteries assessed the intima-media thickness (IMT) and the presence of atherosclerotic plaque.Atherosclerotic plaques were detected in 5, 2, 4, 1 and 1 subject in the five groups respectively. APS patients had significantly more affected vessels than RA patients and healthy controls (P=0.042 and P=0.016, respectively), but not compared with SLE patients. No consistent differences in IMT, traditional cardiovascular risk factors or lipid parameters were detected among the five groups. The odds for atherosclerosis independently increased 1.19-fold per year of increasing age [95% confidence interval (CI) 1.08-1.31; P=0.001), 1.019-fold per 1 mg/dl increase in low-density lipoprotein (LDL) (95% CI 1.003-1.036; P=0.020), 1.035-fold per additional 1 g of methylprednisolone equivalent cumulative corticosteroid dose (95% CI, 0.996-1.074; P=0.074), and 4.35-fold in the presence of APS or SLE (95% CI 0.75-25.2; P=0.10). Neither aCL nor anti-beta(2)GPI antibodies were associated with atherosclerosis.Premenopausal APS and SLE women have an increased prevalence of carotid and femoral plaque that is not accounted for by other predictors of atherosclerosis, including age, lipid parameters and cumulative steroid dose.

    View details for DOI 10.1093/rheumatology/keg182

    View details for Web of Science ID 000182634400007

    View details for PubMedID 12709540

  • Translation of highly promising basic science research into clinical applications AMERICAN JOURNAL OF MEDICINE Contopoulos-Ioannidis, D. G., Ntzani, E. E., Ioannidis, J. P. 2003; 114 (6): 477-484

    Abstract

    To evaluate the predictors of and time taken for the translation of highly promising basic research into clinical experimentation and use.We identified 101 articles, published between 1979 and 1983 in six major basic science journals, which clearly stated that the technology studied had novel therapeutic or preventive promises. Each case was evaluated for whether the promising finding resulted in relevant randomized controlled trials and clinical use. Main outcomes included the time to published trials, time to published trials with favorable results ("positive" trials), and licensed clinical use.By October 2002, 27 of the promising technologies had resulted in at least one published randomized trial, 19 of which had led to the publication of at least one positive randomized trial. Five basic science findings are currently licensed for clinical use, but only has been used extensively for the licensed indications. Promising technologies that did not lead to a published human study within 10 to 12 years were unlikely to be tested in humans subsequently. Some form of industry involvement in the basic science publication was the strongest predictor of clinical experimentation, accelerating the process by about eightfold (95% confidence interval: 3 to 19) when an author had industry affiliations.Even the most promising findings of basic research take a long time to translate into clinical experimentation, and adoption in clinical practice is rare.

    View details for DOI 10.1016/S0002-9343(03)00013-5

    View details for Web of Science ID 000182551900007

    View details for PubMedID 12731504

  • Awareness of the side effects of possessed medications in a community setting EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY Papanikolaou, P. N., Ioannidis, J. P. 2003; 58 (12): 821-827

    Abstract

    RATIONALE.To evaluate in a community setting the extent of and parameters related with awareness of side effects of medications by health consumers.We performed in-house interviews in an entire community. The population of the community of Chalki, Greece, was surveyed. Detailed information was recorded on all medications possessed by each individual. The main outcome measure was awareness of medication side effects.A total of 1079 medications were recorded among 279 subjects. Among 180 subjects for whom direct information was available, and who possessed at least one medication only 47 (26%) were aware of the side effects of at least one of their medications. Side effects awareness was more frequent in subjects who had experienced some adverse event themselves (76%), in those with completed university education (67%), ex-smokers (46%), housewives (45%), and never married adults (41%) and was less frequent in more permanent island residents (odds ratio 0.76 per 10% of lifetime spent in the island) and economic immigrants (0%). Side effects awareness existed for only 8% of the possessed medications and was more frequent when an adverse event had been experienced (54%), for medications not provided locally initially (28%), and for medications for joint and musculoskeletal problems (15%). Awareness rates were unrelated to availability of prescription, specialist involvement, or follow-up by a physician concerning the specific medication.Awareness of side effects was infrequent in this community setting and was determined mostly by live experiences of adverse events and social parameters. There is a need to improve the dissemination of adequate safety information among consumers in the ambulatory use of pharmaceuticals.

    View details for DOI 10.1007/s00228-003-0570-x

    View details for Web of Science ID 000183105300007

    View details for PubMedID 12698309

  • Genetic associations: false or true? TRENDS IN MOLECULAR MEDICINE Ioannidis, J. P. 2003; 9 (4): 135-138

    Abstract

    Genetic association studies for multigenetic diseases are like fishing for the truth in a sea of trillions of candidate analyses. Red herrings are unavoidably common, and bias might cause serious misconceptions. However, a sizeable proportion of identified genetic associations are probably true. Meta-analysis, a rigorous, comprehensive, quantitative synthesis of all the available data, might help us to separate the true from the false.

    View details for DOI 10.1016/S1471-4914(03)00030-3

    View details for Web of Science ID 000182911700002

    View details for PubMedID 12727138

  • The Fc gamma RIIIA-F158 allele is a risk factor for the development of lupus nephritis: A meta-analysis KIDNEY INTERNATIONAL Karassa, F. B., Trikalinos, T. A., Ioannidis, J. P. 2003; 63 (4): 1475-1482

    Abstract

    The Fc gamma RIIIA-V/F158 polymorphism affects immunoglobulins (Ig)G1- and IgG3-binding capacity and may modulate the expression of renal disease in patients with systemic lupus erythematosus (SLE). We aimed to determine whether this polymorphism confers risk for the development of lupus nephritis and SLE in general.A meta-analysis was performed based on the Medline and Embase databases (last update, August 2002), perusal of abstracts from major meetings (1999 to 2001), assessment of bibliographies of pertinent articles, and additional data gathered after contact with primary investigators.A total of 16 comparisons from 11 studies involving V/F158 genotyping of 1154 patients with lupus nephritis, 1261 SLE patients without nephritis, and 1455 disease-free controls were included. Comparison of lupus nephritis patients with non-nephritis SLE subjects revealed a significant overrepresentation of the low-binding F158 allele among patients who developed renal disease [odds ratio (OR) 1.20, 95% confidence interval (95% CI) 1.06 to 1.36, P = 0.003)], without significant between-study heterogeneity. FF homozygotes had the highest risk of renal disease as compared to VV homozygotes (OR 1.47, 95% CI 1.11 to 1.93, P = 0.006). It was uncertain whether the F158 allele influenced susceptibility to SLE per se (OR 1.19, 95% CI 0.99 to 1.43, P = 0.063 for SLE patients without nephritis versus disease-free controls; 0.01 < P < 0.10 for heterogeneity) and the observed trend for an association was driven mostly by the smaller studies (P = 0.058 for publication bias). No such bias was detected for analyses on susceptibility to lupus nephritis.The Fc gamma RIIIA-V/F158 polymorphism has a significant impact on the development of lupus nephritis.

    View details for Web of Science ID 000181485000031

    View details for PubMedID 12631364

  • An objective case definition of lipodystrophy in HIV-infected adults: a case-control study LANCET Carr, A., Emery, S., Law, I., Puls, R., Lundgren, J. D., Powderly, W. G., Carr, B., Cooper, D. A., Grinspoon, S., Ioannidis, J., Lewis, R., Law, M., Lichtenstein, K., Murray, J., Pizzuti, D., Rozenbaum, W., Schambelan, M., Moore, A., Miller, J. 2003; 361 (9359): 726-735

    Abstract

    Lipodystrophy (peripheral lipoatrophy, central fat accumulation, and lipomatosis) is a common and disfiguring problem in adult patients with HIV-1 infection on antiretrovirals. However, an objective, validated definition of the disorder does not exist. We aimed to develop an objective, sensitive, specific, and broadly applicable case definition of HIV lipodystrophy.In a case-control study, 1081 consecutive, HIV-infected, adult outpatients (261 [15%] women) without active AIDS were recruited from 32 sites worldwide. We classed patients with at least one moderate or severe subjective lipodystrophic feature, identified by lipodystrophy-specific physical examination and patient questionnaire, and apparent to both doctor and patient as cases (n=417). We classed patients with no such feature as controls (n=371), and patients without a clear diagnosis as non-assigned. We used objective clinical, metabolic, and body composition measurements to construct a logistic regression model with a subset of randomly selected cases and controls. The model was validated in the remaining patients.A model including age, sex, duration of HIV infection, HIV disease stage, waist to hip ratio, anion gap, serum HDL cholesterol concentration, trunk to peripheral fat ratio, percentage leg fat, and intra-abdominal to extra-abdominal fat ratio had 79% (95% CI 70-85) sensitivity and 80% (95% CI 71-87) specificity for diagnosis of lipodystrophy. Models that incorporated only clinical, or only clinical and metabolic variables had lower sensitivity and specificity than the inclusive model. Models for lipoatrophy, fat accumulation, and lipomatosis could not be developed since pure phenotypes occurred in fewer than 10% of patients with clinical diagnoses of these disorders.Our objective case definition of HIV-associated lipodystrophy should improve assessment of lipodystrophy prevalence, risk factors, and pathogenesis; prevention and treatment approaches; and assist in diagnosis.

    View details for Web of Science ID 000181232000007

    View details for PubMedID 12620736

  • Genetic associations in large versus small studies: an empirical assessment LANCET Ioannidis, J. P., Trikalinos, T. A., Ntzani, E. E., Contopoulos-Ioannidis, D. G. 2003; 361 (9357): 567-571

    Abstract

    Advances in human genetics could help us to assess prognosis on an individual basis and to optimise the management of complex diseases. However, different studies on the same genetic association sometimes have discrepant results. Our aim was to assess how often large studies arrive at different conclusions than smaller studies, and whether this situation arises more frequently when findings of first published studies disagree with those of subsequent research.We examined the results of 55 meta-analyses (579 study comparisons) of genetic associations and tested whether the magnitude of the genetic effect differs in large versus smaller studies.We noted significant between-study heterogeneity in 26 (47%) meta-analyses. The magnitude of the genetic effect differed significantly in large versus smaller studies in ten (18%), 20 (36%), and 21 (38%) meta-analyses with tests of rank correlation, regression on SE, and regression on inverse of variance, respectively. The largest studies generally yielded more conservative results than the complete meta-analyses, which included all studies (p=0.005). In 14 (26%) meta-analyses the proposed association was significantly stronger in the first studies than in subsequent research. Only in nine (16%) meta-analyses was the genetic association significant and replicated without hints of heterogeneity or bias. There was little concordance in first versus subsequent discrepancies, and large versus small discrepancies.Genuine heterogeneity and bias could affect the results of genetic association studies. Genetic risk factors for complex diseases should be assessed cautiously and, if possible, using large scale evidence.

    View details for Web of Science ID 000181033400010

    View details for PubMedID 12598142

  • Effects of CCR5-Delta 32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection AIDS Mulherin, S. A., O'Brien, T. R., Ioannidis, J. P., Goedert, J. J., Buchbinder, S. P., Coutinho, R. A., Jamieson, B. D., Meyer, L., Michael, N. L., Pantaleo, G., Rizzardi, G. P., Schuitemaker, H., Sheppard, H. W., Theodorou, I. D., Vlahov, D., Rosenberg, P. S. 2003; 17 (3): 377-387

    Abstract

    To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression.Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia.We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion.Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter.The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.

    View details for DOI 10.1097/01.aids.0000050783.28043.3e

    View details for Web of Science ID 000181434800012

    View details for PubMedID 12556692

  • Evaluation of the association of autoantibodies with mortality in the very elderly: a cohort study RHEUMATOLOGY Ioannidis, J. P., Katsifis, G. E., Stavropoulos, E. D., Manoussakis, M. N., Moutsopoulos, H. M. 2003; 42 (2): 357-361

    Abstract

    To evaluate whether autoantibodies in the absence of rheumatic diseases increase the risk of mortality among very elderly subjects who are otherwise in good functional condition.Autoantibodies were measured in 1987 in 156 elderly nursing home residents (median age 84 yr) who were followed subsequently over 14.6 yr.Eleven subjects had anticardiolipin antibodies, 30 had rheumatoid factor and 19 had antibodies to single-stranded DNA (ssDNA). Other autoantibodies were more rare. During follow-up, 144 subjects died. Adjusting for age as a time-dependent covariate, the hazard ratio for death was 0.71 [95% confidence interval (CI) 0.38-1.32] for anticardiolipin antibodies, 0.93 (95% CI 0.60-1.41) for rheumatoid factor, 1.08 (95% CI 0.65-1.79) for antibodies to ssDNA, and 0.99 (95% CI, 0.70-1.41) for any autoantibody. Hazard ratios were similar when adjusted also for sex and clinical conditions.Our results exclude the possibility that the autoantibodies evaluated increase substantially the risk of death among very elderly subjects in good functional condition.

    View details for DOI 10.1093/rheumatology/keg096

    View details for Web of Science ID 000181378100026

    View details for PubMedID 12595636

  • Is vitamin C superior to diltiazem for radial artery vasodilation in patients awaiting coronary artery bypass grafting? JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Drossos, G. E., Toumpoulis, I. K., Katritsis, D. G., Ioannidis, J. P., Kontogiorgi, P., Svarna, E., Anagnostopoulos, C. E. 2003; 125 (2): 330-335

    Abstract

    We aimed to measure the vasodilating effects of vitamin C on the radial arteries of healthy subjects and to assess whether vitamin C is superior in this regard to diltiazem, a commonly used vasodilator in coronary artery bypass using radial conduits.In a case-control study (study 1) oral single-dose vitamin C (2 g) was given to 15 healthy nonsmokers and 15 matched otherwise healthy smokers. In a randomized double-blind study (study 2) oral single-dose vitamin C (2 g, n = 15) and diltiazem (180 mg, n = 15) were compared in preoperative patients with coronary artery disease. We examined the dilation of the radial artery with high-resolution ultrasonography and measurement of the lumen surface and color Doppler images of the nondominant radial artery just before and 2 hours after drug administration.In study 1 both smokers and nonsmokers showed a significant increase in the lumen surface at 2 hours compared with at baseline (P <.001 and P =.013, respectively). The increase was larger in smokers (median, 37.5% vs 14.3%; P =.004). In study 2 both groups showed statistically significant increases in the lumen surface at 2 hours compared with at baseline (P <.001 and P =.008 for vitamin C and diltiazem, respectively). Vitamin C achieved a larger increase than diltiazem (median, 33.3% vs 18.2%; P =.016). In multivariate modeling the increase in lumen surface was independently predicted by use of vitamin C over diltiazem (+21.2%, P =.007), diabetes mellitus (+14.5%, P =.085), increased cholesterol (+26.2%, P =.001), and smoking history (+20.8%, P =.017).Vitamin C is a potent acute vasodilator in both smokers and nonsmokers and is superior to diltiazem in preoperative coronary patients who need protection from vasospasm of the radial conduit.

    View details for DOI 10.1067/mtc.2003.3

    View details for Web of Science ID 000181100800015

    View details for PubMedID 12579102

  • Nail pigmentation and fatigue in a 39-year-old woman CLINICAL INFECTIOUS DISEASES Mackowiak, P. A. 2003; 36 (3): 348-?

    View details for Web of Science ID 000180546700015

    View details for PubMedID 12539085

  • Association of the CYP17 gene polymorphism with the risk of prostate cancer: A meta-analysis CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ntais, C., Polycarpou, A., Ioannidis, J. P. 2003; 12 (2): 120-126

    Abstract

    A T-to-C polymorphism in the 5' promoter region of the CYP17 gene that encodes the cytochrome P450c17alpha has been implicated as a risk factor for prostate cancer, but individual studies have been inconclusive or controversial. Therefore we performed a meta-analysis of 10 studies (12 comparisons) with CYP17 genotyping on 2404 patients with prostate cancer and 2755 controls. Overall, the random effects odds ratio (OR) for the A2 (C) versus A1 (T) allele was 1.08 [95% confidence interval (CI), 0.95-1.22], with some between-study heterogeneity (P = 0.04). There was no suggestion of an overall effect either in recessive or dominant modeling of A2 effects, and the comparison of A2/A2 versus A1/A1 also showed no differential susceptibility to prostate cancer (OR, 1.15; 95% CI, 0.91-1.46). No effect of A2 was seen in subjects of European descent (7 comparisons, OR, 1.04; 95% CI, 0.92-1.18, no significant between-study heterogeneity) or Asian descent (2 comparisons, OR, 1.06; 95% CI, 0.66-1.71; P = 0.02 for heterogeneity), whereas A2 increased susceptibility to prostate cancer in subjects of African descent (3 comparisons, OR, 1.56; 95% CI, 1.07-2.28; no between-study heterogeneity). Smaller studies unilaterally showed more prominent genetic effects for A2 than larger studies (P = 0.038). The meta-analysis suggests that the CYP17 polymorphism is unlikely to increase considerably the risk of sporadic prostate cancer on a wide population basis, especially in subjects of European descent. Previously reported associations may reflect publication bias, although it is also possible that the polymorphism may be important in subjects of African descent.

    View details for Web of Science ID 000180918800007

    View details for PubMedID 12582021

  • Acute sinusitis in children: current treatment strategies. Paediatric drugs Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Lau, J. 2003; 5 (2): 71-80

    Abstract

    Acute sinusitis is a very common infection in childhood, but its management remains a controversial issue. Antibacterials may be effective in selected children, but direct evidence is limited. One randomized, placebo-controlled trial has shown that amoxicillin or amoxicillin/clavulanate are better than placebo for children with symptoms of nasal discharge and cough that are persistent (over 10 days) and not improving. However, another placebo-controlled trial of the same agents did not demonstrate any benefit from antibacterials in a patient population selected with a clinical diagnosis of sinusitis of moderate severity, based on a composite clinical symptom score. A systematic assessment of cure rates with various antibacterials shows no consistent differences between classes. Evidence on the use of ancillary measures and nasal corticosteroids is also limited. The only randomized, placebo-controlled trial of antihistamines and decongestants has shown no incremental benefit when given in addition to amoxicillin. Another placebo-controlled randomized trial showed some transient symptomatic improvement with the use of nasal corticosteroids. No randomized trials exist on the use of antral lavage in children with acute sinusitis. The current rates of antimicrobial resistance among commonly implicated pathogens should be considered in therapeutic decisions. However, there is no evidence from well-designed trials on specifically how to manage children at high risk of carrying resistant organisms. The inaccuracy of clinical signs and symptoms in documenting the diagnosis further complicates therapeutic decisions. Nevertheless, radiographic assessment does not meaningfully improve the accuracy of the diagnosis for uncomplicated cases, and it is not cost effective. In the absence of definitive evidence, treatment with amoxicillin 45 mg/kg/day in two divided doses may be used in selected patients with symptoms that are persistent and not improving. High doses (90 mg/kg in two divided doses) may also be considered, and amoxicillin/clavulanate may be a more appropriate choice when there is high risk of resistant pathogens, e.g. in a child attending a childcare center, or recent use of antibacterials. However, a considerable proportion of children, especially those with mild or improving symptoms, may not have to be treated at all.

    View details for PubMedID 12529160

  • Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Karvouni, E., Katritsis, D. G., Ioannidis, J. P. 2003; 41 (1): 26-32

    Abstract

    We sought to evaluate the impact of intravenous antagonists of the platelet IIb/IIIa receptor on the survival of patients undergoing percutaneous coronary interventions (PCIs).Several trials have shown that intravenous antagonists of the platelet glycoprotein (GP) IIb/IIIa receptor reduce the incidence of myocardial infarction (MI) and composite cardiac outcomes (death, MI, or revascularization) in patients undergoing PCI. However, individual studies have not had adequate power to examine differences in mortality.We performed a meta-analysis of 19 randomized, placebo-controlled trials (20 comparisons, n = 20,137). Death was the primary outcome. Secondary outcomes included MI, composite cardiac outcomes, and major bleeding.Mortality was significantly reduced at 30 days (risk ratio [RR] 0.69 [95% confidence interval [CI] 0.53 to 0.90]), at six months (RR 0.79 [95% CI 0.64 to 0.97]), and including longer follow-up (RR 0.79 [95% CI 0.66 to 0.94]), with no significant between-study heterogeneity. The relative risk reduction was largely similar in trials of patients with or without acute myocardial infarction (AMI), in trials continuing or discontinuing heparin after the procedure, and in trials using stents or another PCI as the intended primary procedure. Myocardial infarction and composite outcomes were significantly reduced (p < 0.001 for all) at 30 days and six months. Major bleeding was significantly increased only in trials where heparin infusion was continued after the procedure (RR 1.70 [95% CI 1.36 to 2.14]), although there was no excess bleeding when heparin was discontinued (RR 1.02 [95% CI 0.85 to 1.24]).In patients undergoing PCI, GP IIb/IIIa receptor antagonists confer a significant and sustained decrease (20% to 30%) in the risk of death.

    View details for Web of Science ID 000180175600005

    View details for PubMedID 12570940

  • Effect of CCR5-Delta 32 heterozygosity on the risk of perinatal HIV-1 infection: A meta-analysis JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Contopoulos-Ioannidis, D. G., O'Brien, T. R., Goedert, J. J., Rosenberg, P. S., Ioannidis, J. P. 2003; 32 (1): 70-76

    Abstract

    Several studies have investigated whether heterozygosity for a 32-basepair deletion in the CC chemokine receptor 5 gene (CCR5-Delta32 ) affects susceptibility to perinatal HIV-1 infection, but results have been inconclusive. We performed a meta-analysis of published data from 11 studies of HIV-1 perinatally exposed children who were genotyped for the CCR5-Delta32 polymorphism. The crude overall HIV-1 infection rates, by simple data pooling, were 20% (one of five) amongCCR5-Delta32 homozygote children, 39% (131 of 335) among CCR5-Delta32 heterozygote children, and 40% (1408 of 3526) among wild-type CCR5 homozygote children. Compared with wild-type homozygotes, the random effects risk ratio for heterozygotes was 1.04 (95% confidence interval [CI], 0.92-1.17) among all children (N = 3861) and 1.03 (95% CI, 0.90-1.17) among those of European descent (n = 2890). Results were similar when adjusted for the available data on the CCR2-641 polymorphism (n = 1542). The meta-analysis clarifies that perinatal infection is not significantly altered by heterozygosity for CCR5-Delta32 in the child.

    View details for Web of Science ID 000180407600010

    View details for PubMedID 12514416

  • Important drug safety information on the Internet - Assessing its accuracy and reliability DRUG SAFETY Tatsioni, A., Gerasi, E., Charitidou, E., Simou, N., Mavreas, V., Ioannidis, J. P. 2003; 26 (7): 519-527

    Abstract

    The Internet is becoming increasingly important as a source of health-related information, but the accuracy and reliability of information presented on the world wide web is debated.We aimed to assess whether important, recent drug safety information is accurately reflected on Internet sites.We evaluated whether major warnings issued by the US FDA between October 1, 2000 and September 30, 2001 on severe and life-threatening drug toxicity were mentioned 4-16 months later in the top ten web pages identified for these drugs by each of seven different search engines. We examined predictors of precise mention of the FDA warnings using logistic regressions.Twenty major safety warnings on 21 drugs (including three withdrawals) were eligible for the study. Among 519 different pertinent web pages retrieved (16-32 for each drug), precise mention of the safety issue was made in only 165 (31.8%). Best rates of precise mention were seen in web sites sponsored by attorneys (79.4%), in physician-oriented web pages (65.5%) and for withdrawn drugs (57.9%). In addition to these factors, better coverage of the FDA warnings was independently seen when no other adverse effects from the same organ system was mentioned (p < 0.001), while coverage was worse when there was no date on the site and web page (p = 0.020), and when the site owner could not be classified or was unknown (p = 0.014).Important safety warnings are inadequately covered in the majority of web pages. This deficiency creates a source of potentially harmful misinformation for health consumers.

    View details for Web of Science ID 000183232200006

    View details for PubMedID 12735787

  • Clinicopathologic predictors of death and ESRD in patients with pauci-immune necrotizing glomerulonephritis AMERICAN JOURNAL OF KIDNEY DISEASES Kapitsinou, P. P., Ioannidis, J. P., Boletis, J. N., Sotsiou, F., Nakopoulou, L., Daphnis, E., Moutsopoulos, H. M. 2003; 41 (1): 29-37

    Abstract

    Pauci-immune necrotizing glomerulonephritis (PING) occurs in various settings and has a very variable prognosis. We investigated whether clinicopathologic findings at the time of renal biopsy may predict major disease outcomes.We evaluated 72 consecutive patients with biopsy-documented PING. Kaplan-Meier curves and Cox models assessed event rates and risk factors for death, end-stage renal disease (ESRD), and death or new ESRD (after the renal biopsy).During a follow-up of 305 person-years, 11 patients died, 13 patients developed ESRD, and 16 patients died or developed new ESRD. Among patients first seen within 3 months of renal biopsy (incident cases), the 5-year mortality rate was 20%, whereas the death or new ESRD rate was 34%. In univariate analyses, older age, lower creatinine clearance, erythrocyte sedimentation rate, and percentages of abnormal glomeruli, glomeruli with fibrous crescents, and glomeruli with global sclerosis were significant predictors of mortality, whereas antineutrophil cytoplasmic autoantibodies with cytoplasmic staining conferred borderline protection. For ESRD, significant predictors included a greater creatinine level, lower hematocrit, interstitial fibrosis, tubular necrosis, greater C-reactive protein level, and percentages of abnormal glomeruli, glomeruli with extracapillary proliferation, cellular crescents, and global glomerulosclerosis. For death or new ESRD, predictors were fairly similar. Adjusting for baseline creatinine level, the risk for ESRD increased 1.78-fold (95% confidence interval [CI], 1.23 to 2.58) per each 10% increase in global sclerosis and 1.47-fold (95% CI, 1.05 to 2.07) per each 10% increase in glomeruli with cellular crescents.Global glomerulosclerosis and crescents in a renal biopsy are strong predictors of the long-term outcome of PING.

    View details for DOI 10.1053/ajkd.2003.50013

    View details for Web of Science ID 000180161100004

    View details for PubMedID 12500219

  • Allocation concealment in clinical trials - Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Balk, E. M., Bonis, P. A., Lau, J., Ioannidis, J. P. 2002; 288 (19): 2408-2409

    View details for Web of Science ID 000179292300020

  • Association of Polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: A meta-analysis JOURNAL OF BONE AND MINERAL RESEARCH Ioannidis, J. P., Stavrou, I., Trikalinos, T. A., Zois, C., Brandi, M. L., Gennari, L., Albagha, O., Ralston, S. H., Tsatsoulis, A. 2002; 17 (11): 2048-2060

    Abstract

    The contribution of genetic polymorphisms to bone mineral density (BMD) and fracture risk in women is a controversial topic. We evaluated the effect of the XbaI and PvuII polymorphisms of the estrogen receptor a to BMD and fracture risk in a meta-analysis, including published data and additional information from investigators. Five thousand eight hundred thirty-four women from 30 study groups were analyzed with fixed and random effects models. The PvuII polymorphism was not associated with BMD at any skeletal site examined and 95% CIs exclude effects over 0.015 g/cm2 for both the femoral neck and the lumbar spine. Conversely, XX homozygotes (women carrying two copies of the gene variant without an XbaI restriction site) consistently had higher BMD than other subjects. The magnitude of the effect was similar in the femoral neck and lumbar spine (0.014 g/cm2 [95% CI, 0.003-0.025] and 0.015 g/cm2 [95% CI, 0.000-0.030], respectively; no between-study heterogeneity for either). Total body BMD was also significantly higher in XX homozygotes (by 0.039 g/cm2 and 0.029 g/cm2 compared with Xx and xx, respectively). Available data on fractures suggested a protective effect for XX (odds ratio [OR], 0.66 [95% CI, 0.47-0.93] among 1591 women), but not PP (OR, 0.93 [95% CI, 0.72-1.18] among 2,229 women). In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk.

    View details for Web of Science ID 000178779700018

    View details for PubMedID 12412813

  • Predictors of sustained amenorrhea from pulsed intravenous cyclophosphamide in premenopausal women with systemic lupus erythematosus JOURNAL OF RHEUMATOLOGY Ioannidis, J. P., Katsifis, G. E., Tzioufas, A. G., Moutsopoulos, H. M. 2002; 29 (10): 2129-2135

    Abstract

    To identify predictors of intravenous cyclophosphamide (IC) induced sustained amenorrhea, especially in young premenopausal women with systemic lupus erythematosus (SLE).The cumulative dose resulting in sustained amenorrhea in 50 and 90% of the treated women (D50 and D90) and predictors of sustained amenorrhea at various ages were determined with Kaplan-Meier plots and Cox regressions in a consecutively enrolled cohort of 67 premenopausal women with SLE who received a pulsed IC regimen (monthly doses of 0.75-1.00 g/m2) for nephritis (n = 59) or other indications (n = 8).Twenty-one of 67 women developed sustained amenorrhea of > 12 months' duration. Age was the strongest determinant of this adverse event. For women in the upper age tertile (>or= 32 years old), D50 was 8 g/m2 and D90 was 12 g/m2, and no strong protective or predisposing factors were identified. Conversely, only 5 of 44 women

    View details for Web of Science ID 000178374000017

    View details for PubMedID 12375322

  • Azithromycin is effective in patients with chronic bronchitis - Reply JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Lau, J. 2002; 50 (3): 434-434

    View details for DOI 10.1093/jac/dkf120

    View details for Web of Science ID 000177999000021

  • Conduction delay within the coronary sinus in humans: Implications for atrial arrhythmias JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Katritsis, D., Ioannidis, J. P., Giazitzoglou, E., Korovesis, S., Anagnostopoulos, C. E., Camm, A. J. 2002; 13 (9): 859-862

    Abstract

    Striated myocardial connections between the venous wall of the coronary sinus (CS) and the left atrium have been described in humans. This aim of this study was to investigate the conduction properties and potential arrhythmogenicity of CS and left atrial myocardial connections in patients with and patients without paroxysmal atrial fibrillation (PAF).Thirty-eight patients with PAF, 52 patients with other arrhythmias, and 44 patients without arrhythmia underwent catheter mapping of the CS from the distal superoposterior part to the ostium. Catheterization of the superoposterior CS was feasible in 21, 32, and 25 subjects in the three groups, respectively (P = 0.82). Discrete double potentials or fractionated electrograms were recorded during proximal CS or right atrial pacing in 14 (66.7%), 11 (34.4%), and 5 (20.0%) patients, respectively (P = 0.004). In 29 patients, double or fractionated potentials were recorded at the distal superoposterior CS, in 3 at the mid-CS, and in 4 at the ostium. Spontaneous or induced atrial ectopy and/or tachyarrhythmias were recorded in 18 (85.7%), 12 (37.5%), and 2 (8.0%) patients in the three groups, respectively (P < 0.001) and originated from the CS in 6, 3, and 0 patients, respectively (P = 0.010).Recording of double potentials is possible within the CS, particularly at its distal superoposterior part, near the left superior pulmonary vein. Their prevalence is higher in patients with PAF than in subjects with other or no arrhythmias, and their presence denotes possible sources or substrate for atrial arrhythmia.

    View details for Web of Science ID 000178250500004

    View details for PubMedID 12380921

  • Commentary: Meta-analysis of individual participants' data in genetic epidemiology AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Rosenberg, P. S., Goedert, J. J., O'Brien, T. R. 2002; 156 (3): 204-210

    Abstract

    The authors summarize their experience in the conduct of meta-analysis of individual participants' data (MIPD) with time-to-event analyses in the field of genetic epidemiology. The MIPD offers many advantages compared with a meta-analysis of the published literature. These include standardization of case definitions, outcomes, and covariates; inclusion of updated information; the ability to fully test the assumptions of time-to-event models; better control of confounding; standardization of analyses of genetic loci that are in linkage disequilibrium; evaluation of alternative genetic models and multiple genes; consistent treatment of subpopulations; assessment of sampling bias; and the establishment of an international collaboration with the capability to prospectively update the meta-analyses and synthesize new information on multiple genetic loci and outcomes. The disadvantages of a MIPD compared with a meta-analysis of the published literature are that a much greater commitment of time and resources is required to collect primary data and to coordinate a large collaborative project. An MIPD may collect additional, unpublished data, but it is possible that not all published data may be contributed at the individual level. For questions that justify the required intensive effort, the MIPD method is a useful tool to help clarify the role of candidate genes in complex human diseases.

    View details for DOI 10.1093/aje/kwf031

    View details for Web of Science ID 000177055400002

    View details for PubMedID 12142254

  • Association between maternal and infant class I and IIHLA alleles and of their concordance with the risk of perinatal HIV type I transmissions 9th Conference on Retroviruses and Opportunistic Infections Polycarpou, A., Ntais, C., Korber, B. T., Elrich, H. A., Winchester, R., Krogstad, P., Wolinsky, S., Rostron, T., Rowland-Jones, S. L., Ammann, A. J., Ioannidis, J. P. MARY ANN LIEBERT INC. 2002: 741–46

    Abstract

    We aimed to investigate the influence of class I and class II HLA specificities and of the concordance between maternal and infant HLA on vertical HIV-1 transmission. HLA typing of samples from mothers and infants enrolled in the Ariel study, a perinatal HIV-1 transmission cohort including 203 mother-infant pairs, was performed by serological and molecular methods. HLA effects were evaluated alone and by multivariate modeling considering also other known predictors of perinatal HIV-1 transmission (maternal viral load, antiretroviral therapy, duration of rupture of membranes, and histological chorioamnionitis). Modest associations were seen with specific HLA markers (increased risk with infant B67 and B58 and maternal DR1; decreased risk with maternal B12), but these were not statistically significant after adjusting for multiple comparisons. Mother-infant concordance at any class I locus was a strong predictor of transmission (odds ratio [OR], 4.16; p = 0.028). Transmission was not associated with class II concordance. Class I HLA concordance retained its importance after adjusting for maternal viral load, antiretroviral therapy, duration of rupture of membranes or histological chorioamnionitis. In multivariate modeling, only class I concordance (OR, 3.59; p = 0.069) and chorioamnionitis (OR, 3.79; p = 0.030) were retained as independent predictors of transmission. HLA alleles, and in particular the class I concordance between maternal and neonatal HLA, may regulate the risk of perinatal HIV-1 transmission.

    View details for Web of Science ID 000177038600001

    View details for PubMedID 12167265

  • Risk of myelotoxicity with intravenous cyclophosphamide in patients with systemic lupus erythematosus RHEUMATOLOGY Katsifis, G. E., Tzioufas, A. G., Vlachoyiannopoulos, P. G., Voulgarelis, M., Moutsopoulos, H. M., Ioannidis, J. P. 2002; 41 (7): 780-786

    Abstract

    To determine the incidence of serious myelotoxicity from intravenous cyclophosphamide (IC) in systemic lupus erythematosus (SLE).In a retrospective study, white blood cell (WBC) counts with differential and platelet counts were determined in 92 SLE patients (96 courses) given 1623 doses of IC.Only one patient developed a total leucocyte count <1000/mm3, one developed a neutrophil count <500/mm3, two had a lymphocyte count <100/mm3 and no patients had platelet counts <50000/mm3 during follow-up. The risk of a neutrophil count <500/mm3 was 0.06 per 100 visits [95% confidence interval (CI) 0.00-0.34]. Two patients discontinued IC due to neutropenia [rate of 0.12 per 100 doses (95% CI 0.01-0.44)]. No clinical consequences were recorded in conjunction with low blood cell counts. In multivariate models, both the cumulative number of IC doses and European Consensus Lupus Activity Measurement (ECLAM) score affected neutrophil and lymphocyte counts adversely. For neutrophils, lowering the ECLAM score by 1 point counteracted four additional doses of IC after adjusting for steroid dose.IC and SLE disease activity have independent effects in lowering white blood cell counts, but serious myelotoxicity of IC is uncommon.

    View details for Web of Science ID 000176783900011

    View details for PubMedID 12096228

  • Electrocardiogram-gated single-photon emission computed tomography versus cardiac magnetic resonance imaging for the assessment of left ventricular volumes and ejection fraction - A meta-analysis JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ioannidis, J. P., Trikalinos, T. A., Danias, P. G. 2002; 39 (12): 2059-2068

    Abstract

    The purpose of this study was to evaluate the accuracy of electrocardiogram (ECG)-gated single-photon emission computed tomography (SPECT) for assessment of left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) compared with the gold standard of cardiac magnetic resonance imaging (MRI).Several comparisons of ECG-gated SPECT with cardiac MRI have been performed for evaluation of LV volumes and EF, but each has considered few subjects, thus leaving uncertainty about the frequency of discrepancies between the two methods.We performed a meta-analysis of data on 164 subjects from nine studies comparing ECG-gated SPECT versus cardiac MRI. Data were pooled in correlation and regression analyses relating ECG-gated SPECT and cardiac MRI measurements. The frequency of discrepancies of at least 30 ml in EDV, 20 ml in ESV and 5% or 10% in EF and concordance for EF < or =40% versus >40% were determined.There was an overall excellent correlation between ECG-gated SPECT and cardiac MRI for EDV (r = 0.89), ESV (r = 0.92) and EF (r = 0.87). However, rates of discrepancies for individual subjects were considerable (37% [95% confidence interval [CI], 26% to 50%] for at least 30 ml in EDV; 35% [95% CI, 23% to 49%] for at least 20 ml in ESV; 52% [95% CI, 37% to 63%] for at least 5% in EF; and 23% [95% CI, 11% to 42%] for at least 10% in EF). The misclassification rate for the 40% EF cutoff was 11%.Electrocardiogram-gated SPECT measurements of EDV, ESV and EF show high correlation with cardiac MRI measurements, but substantial errors may occur in individual patients. Electrocardiogram-gated SPECT offers useful functional information, but cardiac MRI should be used when accurate measurement is required.

    View details for Web of Science ID 000176266900026

    View details for PubMedID 12084609

  • Correlation of quality measures with estimates of treatment effect in meta-analyses of randomized controlled trials JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Balk, E. M., Bonis, P. A., MOSKOWITZ, H., Schmid, C. H., Ioannidis, J. P., Wang, C. C., Lau, J. 2002; 287 (22): 2973-2982

    Abstract

    Specific features of trial quality may be associated with exaggeration or shrinking of the observed treatment effect in randomized studies. Therefore, assessment of trial quality is often used in meta-analysis. However, the degree to which specific quality measures are associated with treatment effects has not been well established across a broad range of clinical areas.To determine if quality measures are associated with treatment effect size in randomized controlled trials (RCTs).Quality measures from published quality assessment scales were evaluated in RCTs included in meta-analyses from 4 medical areas (cardiovascular disease, infectious disease, pediatrics, and surgery). Included meta-analyses incorporated at least 6 RCTs, examined dichotomous outcomes, and demonstrated significant between-study heterogeneity in the odds ratio (OR) scale.Relative ORs comparing overall treatment effect (summary OR) of high vs low-quality studies, as determined by each quality measure, with relative ORs less than 1 indicating larger treatment effect in low-quality studies.Twenty-four quality measures were analyzed for 276 RCTs from 26 meta-analyses. Relative ORs of high vs low-quality studies for these quality measures ranged from 0.83 to 1.26; none was statistically significantly associated with treatment effect. The proportion of studies fulfilling specific quality measures varied widely in the 4 medical areas. In analyses limited to specific medical areas, placebo control, multicenter studies, study country, caregiver blinding, and statistical methods were significantly associated with treatment effect on 7 occasions. These relative ORs ranged from 0.40 to 1.74. However, the directions of these associations were not consistent.Individual quality measures are not reliably associated with the strength of treatment effect across studies and medical areas. Although use of specific quality measures may be appropriate in specific well-defined areas in which there is pertinent evidence, findings of associations with treatment effect cannot be generalized to all clinical areas or meta-analyses.

    View details for Web of Science ID 000176128300027

    View details for PubMedID 12052127

  • Shared epitopes and rheumatoid arthritis: Disease associations in Greece and meta-analysis of Mediterranean European populations SEMINARS IN ARTHRITIS AND RHEUMATISM Ioannidis, J. P., Tarassi, K., Papadopoulos, I. A., Voulgari, P. V., Boki, K. A., Papasteriades, C. A., Drosos, A. A. 2002; 31 (6): 361-370

    Abstract

    To assess the strength of the associations between HLA shared epitopes (SE) and rheumatoid arthritis (RA) susceptibility, articular disease severity, and extra-articular features in Mediterranean European populations.One hundred and seventy-four Greek RA patients and 103 controls were evaluated. Data were then included in a meta-analysis of 9 studies of Mediterranean European populations (959 RA patients and 1,405 controls).In our study population, SE alleles were significantly more common in RA patients than in controls (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.4-4.3). Larsen radiologic score was predicted by SE and disease duration. SE did not increase the risk of any extra-articular manifestation. The meta-analysis showed a pooled OR of 3.7 (95% CI, 2.6-5.2) for susceptibility to RA conferred by SE (OR, 3.4 v 3.9 in Greek v non-Greek populations).SE determine articular destruction without increasing the risk of extra-articular manifestations. The immunogenetic associations of RA susceptibility are consistent, but their strength may depend on the SE prevalence in different ethnic groups.

    View details for DOI 10.1053/sarh.2002.31725

    View details for Web of Science ID 000176587500002

    View details for PubMedID 12077708

  • Standardized retrieval of side effects data for meta-analysis of safety outcomes - A feasibility study in acute sinusitis JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Chew, P., Lau, J. 2002; 55 (6): 619-626

    Abstract

    Accurate and complete safety data are indispensable for the proper evaluation of the benefit-to-harm ratio of medical interventions. We evaluated whether a systematic review and meta-analysis of standardized safety data is feasible by requesting information on side effects directly from the investigators of all 38 antibiotic trials on acute sinusitis published in the last decade. We requested standardized information on gastrointestinal toxicity outcomes, including hospitalizations, discontinuations, and days with nausea/vomiting, diarrhea, or both. Responses were received only for 16 trials (42%), and safety data were contributed only for 9 trials (24%). In some trials, safety data had not been collected, had been lost, or had been transferred to other companies. The odds of data retrieval was higher in general medical journals (P =.024) and independently improved with an increase in sample size (P =.064). The available information suggested side effects may equal or exceed in severity the marginal treatment benefits. Interpretation of safety data was further complicated by heterogeneity or lack of information of use of concomitant drugs, mode of collection of safety information, use of blinding, and other study design parameters. Availability of standardized information for performing meta-analysis of safety data may be limited. Standardized reporting, prospective collection, and long-term availability of safety information should be improved.

    View details for Web of Science ID 000175958600010

    View details for PubMedID 12063104

  • Role of the Fc gamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis - A meta-analysis ARTHRITIS AND RHEUMATISM Karassa, F. B., Trikalinos, T. A., Ioannidis, J. P. 2002; 46 (6): 1563-1571

    Abstract

    To assess the impact of the Fcgamma receptor type IIa (FcgammaRIIa)-R/H131 polymorphism on the risk for systemic lupus erythematosus (SLE) and development of lupus nephritis.A meta-analysis was performed based on the Medline and Embase databases (last retrieval August 2001), assessment of bibliographies of pertinent articles, and additional data gathered after contact with primary investigators.A total of 25 comparisons from 17 studies involving R/H131 genotyping of 1,405 patients with lupus nephritis, 1,709 SLE patients without nephritis, and 2,580 non-SLE controls were included. No association between RR genotype and risk of lupus nephritis relative to both other genotypes (odds ratio [OR] 1.05, 95% confidence interval [95% CI] 0.88-1.27) was demonstrated in the total meta-analysis or in any racial subgroup. The RR genotype was more frequent in SLE patients as a whole (OR 1.30, 95% CI 1.10-1.52) and in SLE patients without nephritis (OR 1.27, 95% CI 1.04-1.55) compared with disease-free controls. A potential dose-response relation between the R131 allele and the risk of SLE was also identified, with an OR of 1.23 for RR versus RH (95% CI 1.03-1.46). The OR was 1.55 for RR versus HH (95% CI 1.21-1.98). There was no significant heterogeneity between racial subgroups. The population-attributable fractions of SLE cases due to the FcgammaRIIa-R131 allele were 13%, 40%, and 24% in subjects of European, African, and Asian descent, respectively.The FcgammaRIIa-R/H131 polymorphism represents a significant risk factor for SLE but has no clear effect on susceptibility for lupus nephritis.

    View details for DOI 10.1002/art.10306

    View details for Web of Science ID 000176199200018

    View details for PubMedID 12115187

  • Citation of randomized evidence in support of guidelines of therapeutic and preventive interventions JOURNAL OF CLINICAL EPIDEMIOLOGY Giannakakis, I. A., Haidich, A. B., Contopoulos-Ioannidis, D. G., Papanikolaou, G. N., Baltogianni, M. S., Ioannidis, J. P. 2002; 55 (6): 545-555

    Abstract

    Guideline statements may be supported by evidence obtained from various study designs, but randomized trials are usually considered most important for making recommendations about therapeutic and preventive interventions. This study evaluated the extent to which randomized trials are cited in guidelines published in major journals. The references of 191 guidelines of therapeutic and/or preventive interventions published in Annals of Internal Medicine, BMJ, JAMA, Lancet, NEJM and Pediatrics in 1979, 1984, 1989, 1994, and 1999, were analyzed. The percentage of guidelines not citing any randomized controlled trials (RCTs) decreased gradually from 95% in 1979 to 53% in 1999. Among 4,853 references of the guidelines, there were 393 RCTs (8.1% of total), 19 systematic reviews (0.4%), and 23 meta-analyses of RCTs (0.5%). Among 19 guidelines published in 1999 or 1994 with <2 RCTs cited, in eight cases additional pertinent RCTs were identified that had not been cited by the guideline. There is a clear increase in the use of randomized evidence by guidelines over time. However, several guidelines in major journals still cite few or no RCTs.

    View details for Web of Science ID 000175958600002

    View details for PubMedID 12063096

  • Opportunistic infections and HIV. Clinical evidence Ioannidis, J., Wilkinson, D. 2002: 717-737

    View details for PubMedID 12230699

  • Association of polymorphisms of the estrogen receptor alpha gene with the age of menarche HUMAN REPRODUCTION Stavrou, I., Zois, C., Ioannidis, J. P., Tsatsoulis, A. 2002; 17 (4): 1101-1105

    Abstract

    The age of menarche may be subject to hereditary influences, but the specific genetic determinants are largely unknown. We evaluated whether the XbaI and PvuII polymorphisms of the estrogen receptor alpha gene are associated with the age of menarche.We performed genotyping for XbaI and PvuII in a cohort of 145 adolescent females from a closed community in North-Western Greece.There was strong linkage disequilibrium between the two polymorphisms. Menarche occurred later in girls with the XX genotype than in girls with the Xx or xx genotype (mean +/- SD: 13.36 +/- 1.24 versus 12.80 +/- 1.14 and 12.75 +/- 1.35 years respectively; P = 0.017). Menarche also tended to occur later in PP homozygotes than in Pp and pp subjects, but the difference was not significant (mean +/- SD: 13.09 +/- 1.29 versus 12.80 +/- 1.19 and 12.85 +/- 1.33 years respectively). The strongest effect was seen when the PX haplotype was considered [mean +/- SD: 13.43 +/- 1.18 years for homozygotes versus 12.76 +/- 1.25 years in heterozygotes and in subjects without the PX allele, P = 0.006].We document that the XbaI polymorphism, and possibly PvuII, may be genetic determinants of the age of menarche.

    View details for Web of Science ID 000175118500044

    View details for PubMedID 11925413

  • Protein conjugate pneumococcal vaccines. BMJ (Clinical research ed.) Spoulou, V., Gilks, C. F., Ioannidis, J. P. 2002; 324 (7340): 750-751

    View details for PubMedID 11923145

    View details for PubMedCentralID PMC1122694

  • Relation between burden of disease and randomised evidence in sub-Saharan Africa: survey of research BRITISH MEDICAL JOURNAL Isaakidis, P., Swingler, G. H., Pienaar, E., Volmink, J., Ioannidis, J. P. 2002; 324 (7339): 702-705

    Abstract

    To evaluate whether the amount of randomised clinical research on various medical conditions is related to the burden of disease and health needs of the local populations in sub-Saharan Africa.Construction and analysis of comprehensive database of randomised controlled trials in sub-Saharan Africa based on Medline, the Cochrane Controlled Trials Register, and several African databases.Sub-Saharan Africa.Number of trials and randomised subjects for each category of disease in the global burden of disease taxonomy; ratios of disability adjusted life years (DALYs) per amount of randomised evidence.1179 eligible randomised controlled trials were identified. The number of trials published each year increased over time. Almost half of the trials (n=565) had been done in South Africa. There was relatively good correlation between the estimated burden of disease at year 2000 and the number of trials performed (r=0.53, P=0.024) and the number of participants randomised (r=0.68, P=0.002). However,some conditions-for example, injuries (over 20 000 DALYs per patient ever randomised)-were more neglected than others.Despite recent improvements, few clinical trials are done in sub-Saharan Africa. Clinical research in this part of the world should focus more evenly on the major contributors to burden of disease.

    View details for Web of Science ID 000174648200017

    View details for PubMedID 11909786

  • Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjogren's syndrome ARTHRITIS AND RHEUMATISM Ioannidis, J. P., Vassiliou, V. A., Moutsopoulos, H. M. 2002; 46 (3): 741-747

    Abstract

    Primary Sjögren's syndrome (SS) may lead to lymphoproliferative disease (LPD) and death in certain patients. We sought to determine the incidence and predictors of adverse long-term outcomes to achieve a rational predictive classification of the syndrome.Predictive modeling was performed in a cohort of 723 consecutive patients with primary SS (587 newly diagnosed [incident] cases and 136 prevalent cases).During 4,384 person-years of followup, we recorded 39 deaths (7 due to lymphoma) and 38 diagnoses of LPD. The standardized mortality ratio was 1.15 (95% confidence interval [95% CI] 0.86-1.73) compared with the general population of Greece. In incident cases, the probability of LPD was 2.6% at 5 years and 3.9% at 10 years. Mortality rates were significantly higher in patients with low C4 levels at the first study visit (hazard ratio [HR] 4.39, 95% CI 2.18-8.83). LPD was independently predicted by the presence of parotid enlargement (HR 5.21, 95% CI 1.76-15.4), palpable purpura (HR 4.16, 95% CI 1.65-10.5), and low C4 levels (HR 2.40, 95% CI 0.99-5.83) at the first study visit. All patients who eventually developed lymphoma resulting in death during the followup period had either low C4 levels or palpable purpura at the first study visit. Training-validation split-cohort modeling confirmed the predictive importance of low C4 levels and palpable purpura, both of which were present in 20.9% of patients at their first visit.In patients with primary SS, 1 in 5 deaths is attributable to lymphoma. The presence of palpable purpura and low C4 levels at the first visit adequately distinguishes high-risk patients (type I primary SS) from patients with an uncomplicated disease course (type II [low-risk] primary SS).

    View details for DOI 10.1002/art.10221

    View details for Web of Science ID 000174409200021

    View details for PubMedID 11920410

  • Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease JOURNAL OF RHEUMATOLOGY Pakas, I., Ioannidis, J. P., Malagari, K., Skopouli, F. N., Moutsopoulos, H. M., Vlachoyiannopoulos, P. G. 2002; 29 (2): 298-304

    Abstract

    To evaluate the safety and efficacy of monthly intravenous pulses of cyclophosphamide (CP) in combination with low or high doses of prednisolone in patients with systemic sclerosis (SSc) related interstitial lung disease (ILD) with FVC < 70% of predicted.An open label, non-parallel arm study, performed in the rheumatology outpatient clinic of a university hospital. Twenty-eight patients with SSc related ILD were evaluated. Endpoint evaluations included the evolution of high resolution computed tomography, pulmonary function tests, skin involvement and dyspnea over 12 months. Patients were treated with monthly IV CP in combination with prednisolone at low (< 10 mg/day; n = 12) or high doses (1 mg/kg/day for 4 weeks, then reducing the prednisolone by 5 mg/day on alternating days each 2 weeks; n = 16).In the low dose steroid group, no improvement was seen for any endpoint at 6 and 12 months of followup. In the high dose steroid group, at 12 months there was significant improvement in the percentage of "ground glass" parenchymal lung involvement (-5.7%; p = 0.003), as well as in the percentage of predicted FVC (12.4%; p < 0.001), the percentage of predicted DLCO (7.3%; p = 0.029), the percentage of skin involvement (-5.4%; p = 0.01), and the severity of dyspnea (p = 0.012). Substantial improvement was seen as early as 6 months. One patient (low dose group) died from ILD.A combination of IV pulse CP with high doses of prednisolone shows promising efficacy in improving the clinical, physiological, and radiological evolution of SSc related ILD with reversal of the underlying alveolitis.

    View details for Web of Science ID 000173618300016

    View details for PubMedID 11842824

  • Management of clinically inapparent adrenal mass. Evidence report/technology assessment (Summary) Lau, J., Balk, E., Rothberg, M., Ioannidis, J. P., Devine, D., Chew, P., Kupelnick, B., Miller, K. 2002: 1-5

    View details for PubMedID 12945556

  • Design and quality considerations for randomized controlled trials in systemic sclerosis ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Kyriakidi, M., Ioannidis, J. P. 2002; 47 (1): 73-81

    Abstract

    To appraise systematically randomized controlled trials (RCTs) on systemic sclerosis (SSc) in order to determine whether the parameter of study design and its quality may influence the reporting of efficacy for tested interventions.Seventy RCTs were analyzed (1965-2000) in terms of design, patient characteristics, outcomes, and reported results.Median sample size was 28 patients. Fifty-nine trials were double blind, but only 16 mentioned the randomization mode and only 7 described allocation concealment. There was sufficient information on withdrawals in 37 trials. Larger trials with longer followup scored higher on quality characteristics, but had higher withdrawal rates. Only 8 trials had a followup of more than 1 year. Significant efficacy was less likely to be reported in double-blind studies (P = 0.029) and in studies with larger rates of withdrawal (P = 0.032). Specification of the following parameters improved over time: power calculations (P = 0.0003), outcomes (P = 0.001), and sample size per arm (P = 0.011).Several aspects of the quality of design and conduct of SSc RCTs can be improved. Adequately powered trials with longer followup and clear outcomes are needed.

    View details for Web of Science ID 000173803700012

    View details for PubMedID 11932881

  • Improving safety reporting from randomised trials DRUG SAFETY Ioannidis, J. P., Lau, J. 2002; 25 (2): 77-84

    Abstract

    Randomised clinical trials offer a unique opportunity for capturing safety information under a controlled setting that minimises biases in the comparison of different therapeutic options. Nevertheless, empirical evidence across diverse medical fields suggests that the reporting of safety information in clinical trials is largely neglected and receives less attention compared with efficacy outcomes. An analysis of 192 randomised trials has shown that reasons for withdrawals due to toxicity were specified per study arm in only 46% of the trial reports. Adequate reporting of clinical adverse effects and laboratory-determined toxicity occurred in only 39 and 29% of the trials, respectively, even with lenient definitions of what constitutes adequate reporting. The use of standardised scales for adverse effects is a prerequisite for improved reporting on safety in randomised trials. Safety data need to be collected and analysed in a systematic fashion and active surveillance for toxicity during the conduct of a randomised trial is preferable to passive surveillance. Standardised reporting of safety data does not necessarily require extensive space to accomplish. It is essential to provide numerical data per study arm on each type of adverse effect along with a categorisation of the severity of the adverse effects with an emphasis on severe and life-threatening reactions. The severity grading must be referred to well-known standardised scales and new scales need to be carefully defined. Information on withdrawals due to toxicity is also important to report, along with the specific reasons leading to discontinuation. Tabulation of information may be helpful and rare or not previously reported adverse effects should be described in detail. The availability of newer options such as electronic publication, publication of raw databases, large database research, meta-analytic approaches, and prospective registration of clinical trials and of their databases may further improve the safety insights we can gain from randomised clinical trials.

    View details for Web of Science ID 000174615500002

    View details for PubMedID 11888350

  • Discontinuation of Pneumocystis carinii prophylaxis in patients infected with human immunodeficiency virus: A meta-analysis and decision analysis CLINICAL INFECTIOUS DISEASES Trikalinos, T. A., Ioannidis, J. P. 2001; 33 (11): 1901-1909

    Abstract

    We performed a meta-analysis and a decision analysis on the discontinuation of prophylaxis for Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus who had adequate immune recovery while receiving highly active antiretroviral therapy. In the meta-analysis (14 studies with 3584 subjects who had discontinued prophylaxis), 8 cases of PCP occurred during 3449 person-years (0.23 cases per 100 person-years [95% confidence interval, 0.10-0.46]). In the decision analysis, mortality and time spent alive without immunodeficiency in the modeled discontinuation strategy were similar to those in the continuation strategy. For patients who received primary prophylaxis, the discontinuation strategy led to slightly fewer episodes of PCP and fewer toxicity-related prophylaxis withdrawals (e.g., 8.6 vs. 34.5 cases per 100 patients during a 10-year period). Patients on the discontinuation strategy were more likely to be receiving trimethoprim-sulfamethoxazole when they became immunodeficient. Comparative results were similar for patients with prior PCP. Discontinuation of PCP prophylaxis in patients with adequate immune recovery is a useful strategy that should be widely considered.

    View details for Web of Science ID 000171998800016

    View details for PubMedID 11692302

  • Declaring competing interests - Types of competing interests would be of interest BRITISH MEDICAL JOURNAL Papanikolaou, G. N., Ioannidis, J. P. 2001; 323 (7322): 1187-1188

    View details for Web of Science ID 000172346800038

    View details for PubMedID 11794253

  • Effects of CCR5-Delta 32, CCR2-641, and SDF-1 3 ' A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data ANNALS OF INTERNAL MEDICINE Ioannidis, J. P., Rosenberg, P. S., Goedert, J. J., Ashton, L. J., Benfield, T. L., Buchbinder, S. P., Coutinho, R. A., Eugen-Olsen, J., Gallart, T., Katzenstein, T. L., Kostrikis, L. G., Kuipers, H., Louie, L. G., Mallal, S. A., Margolick, J. B., Martinez, O. P., Meyer, L., Michael, N. L., Operskalski, E., Pantaleo, G., Rizzardi, G. P., Schuitemaker, H., Sheppard, H. W., Stewart, G. J., Theodorou, I. D., Ullum, H., Vicenzi, E., Vlahov, D., Wilkinson, D., Workman, C., Zagury, J. F., O'Brien, T. R. 2001; 135 (9): 782-795

    Abstract

    Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results.To examine postulated associations of genetic alleles with HIV-1 disease progression.Meta-analysis of individual-patient data.19 prospective cohort studies and case-control studies from the United States, Europe, and Australia.Patients with HIV-1 infection who were of European or African descent.Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models.Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all).The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.

    View details for Web of Science ID 000172013700003

    View details for PubMedID 11694103

  • Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for lower respiratory tract infections JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Chew, P., Lau, J. 2001; 48 (5): 691-703

    Abstract

    We carried out a meta-analysis of randomized controlled trials of azithromycin compared with other antibiotics in the treatment of lower respiratory tract infections, including acute bronchitis (five comparisons including 1372 patients), acute exacerbations of chronic bronchitis (13 comparisons including 1342 patients) and community-acquired pneumonia (18 comparisons with 1664 patients). For the first two indications, azithromycin did not offer any statistically significant reduction in clinical failures [random effects odds ratios 0.84, 95% confidence interval (CI) 0.54-1.31 and 0.64, 95% CI 0.31-1.32, respectively] and absolute risk differences were small. For community-acquired pneumonia, azithromycin significantly reduced clinical failures by about one-third (random effects odds ratio 0.63, 95% CI 0.41-0.95). The absolute incremental benefit was approximately one clinical failure prevented per 50 treated patients with community-acquired pneumonia. There was no significant heterogeneity for different comparators and for bacterial versus atypical pneumonias. Azithromycin was discontinued because of adverse events in only 23 of 3487 patients (0.7%). Although results should be interpreted cautiously as most trials were open-label and susceptible to bias, the meta-analysis indicates that, compared with antibiotics with traditional pharmacokinetics that require more prolonged courses, azithromycin offers no significant advantage for bronchitis, but may be more effective in community-acquired pneumonia.

    View details for Web of Science ID 000172342800012

    View details for PubMedID 11679558

  • Replication validity of genetic association studies NATURE GENETICS Ioannidis, J. P., Ntzani, E. E., Trikalinos, T. A., Contopoulos-Ioannidis, D. G. 2001; 29 (3): 306-309

    Abstract

    The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.

    View details for Web of Science ID 000171911000017

    View details for PubMedID 11600885

  • Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for upper respiratory tract infections JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY Ioannidis, J. P., Contopoulos-Ioannidis, D. G., Chew, P., Lau, J. 2001; 48 (5): 677-689

    Abstract

    We carried out a meta-analysis of randomized controlled trials comparing 3-5 days of azithromycin with other antibiotics that are typically given in longer courses for the treatment of upper respiratory tract infections. For acute otitis media (19 comparisons including 3421 patients), acute sinusitis (11 comparisons including 1742 patients) and acute pharyngitis (16 comparisons including 2447 patients), azithromycin had similar clinical failure rates to the other antibiotics [random effects odds ratios 1.12, 95% confidence interval (CI) 0.81-1.54; 0.91, 95% CI 0.60-1.39; and 1.07, 95% CI 0.59-1.94, respectively]. The difference in clinical failures was <0.5%, and no 95% CIs exceeded 2.0%. There was no heterogeneity between studies. Subtle differences between comparators could have been due to chance. There were no significant differences in bacteriological outcomes. Azithromycin was discontinued because of adverse events in only 37 of 4870 (0.8%) patients. Short courses of azithromycin are as effective as longer courses of other antibiotics for upper respiratory tract infections. Convenience of dosing should be balanced against the increased cost of this regimen for the treatment of these common infections, where often no antibiotic may be indicated at all.

    View details for Web of Science ID 000172342800011

    View details for PubMedID 11679557

  • Effect of early patient enrollment on the time to completion and publication of randomized controlled trials AMERICAN JOURNAL OF EPIDEMIOLOGY Haidich, A. B., Ioannidis, J. P. 2001; 154 (9): 873-880

    Abstract

    The authors evaluated whether early enrollment affects the significance of the results and the time to completion and publication of randomized controlled trials. Seventy-seven efficacy randomized controlled trials (total enrollment, 28,992 patients) initiated by the Acquired Immunodeficiency Syndrome Clinical Trials Group between 1986 and 1996 were evaluated. After adjustment for target sample size, for each 10-fold increase in the first-month accrual, the odds of a trial reaching statistically significant results increased 2.8-fold (p = 0.040). The relative enrollment during the first month over target sample size (hazard ratio (HR) = 1.40 per 10 percent increase, p = 0.004) and masking (HR = 1.78 for double-blind vs. single or unblinded studies, p = 0.031) were the major predictors of faster completion. Rapid early accrual (HR = 1.09 per 10 additional patients accrued the first month, p = 0.011) and statistical significance in favor of an experimental arm (HR = 2.47, p = 0.004) independently predicted faster publication. Early enrollment is a strong predictor of whether a study will reach formal statistical significance, and it can offer predictive information on the time needed to complete the study and publish its findings. Ongoing unpublished studies and their enrollment rates may need to be considered when interpreting the accumulated evidence.

    View details for Web of Science ID 000171923900011

    View details for PubMedID 11682370

  • Technical report: Evidence for the diagnosis and treatment of acute uncomplicated sinusitis in children: A systematic overview PEDIATRICS Ioannidis, J. P., Lau, J. 2001; 108 (3)

    Abstract

    To evaluate and analyze the existing evidence for the diagnosis and treatment of acute uncomplicated sinusitis in children.A systematic overview and meta-analysis considered all pertinent studies with at least 10 children younger than 18 years with acute symptoms of <30 days and without serious complications.Clinical improvement rates for intervention studies of antibiotics or ancillary measures; concordance of diagnostic tests (expressed as likelihood ratios).Of 1857 citations originally reviewed, we identified 21 qualifying studies, compared with 450 reports on complications of acute sinusitis and 233 nonsystematic reviews of the subject. The qualifying studies included 5 randomized, controlled trials and 8 case series on antibiotic therapy, 3 randomized, controlled trials on ancillary treatments, and 8 studies with information on diagnostic tests (including 3 therapeutic trials). Definitions and inclusion criteria were heterogeneous across studies. The pooled clinical improvement rate with antibiotics was 88% (177/202) in randomized, controlled trials and 92% (318/345) in nonrandomized studies; the improvement rates on no antibiotics were 60% and 80%, respectively. Improvement rates were significantly higher in nonrandomized studies (Mantel-Haenszel odds ratio: 1.79; 95% CI: 1.05-3.04, stratified for use of antibiotics). Data on ancillary measures were sparse and heterogeneous. In studies comparing clinical findings with plain film radiography, the pooled rate of abnormal radiographic findings against a clinical diagnosis of sinusitis was 73% (596/814; range: 55% to 96% between studies). There was poor concordance between clinical criteria, plain radiographs, ultrasonography, computed tomography, and fluid on aspiration in all available paired assessments (all positive likelihood ratios were /=0.2).Good, high-quality evidence for acute uncomplicated sinusitis in children is limited. Diagnostic modalities show poor concordance, and treatment options are based on inadequate data. More evidence is needed for defining the optimal treatment and diagnostic methods for this common condition.

    View details for Web of Science ID 000170781500018

    View details for PubMedID 11533375

  • Meta-analysis of the association between low-affinity Fc gamma receptor gene polymorphisms and hematologic and autoimmune diseases BLOOD Trikalinos, T. A., Karassa, F. B., Ioannidis, J. P. 2001; 98 (5): 1634-1635

    View details for Web of Science ID 000170685000060

    View details for PubMedID 11547773

  • Association of collagen I alpha 1 Sp1 polymorphism with the risk of prevalent fractures: A meta-analysis JOURNAL OF BONE AND MINERAL RESEARCH Efstathiadou, Z., Tsatsoulis, A., Ioannidis, J. P. 2001; 16 (9): 1586-1592

    Abstract

    Several studies have addressed the effect of the Spl polymorphism of the collagen Ialpha 1 (COLIA1) gene on the prevalence of fractures. The results are not in full agreement on whether this polymorphism is associated with fracture risk. To clarify this uncertainty, we performed a meta-analysis including 13 eligible studies with 3641 subjects. The COLIA1 Spl polymorphism showed a dose-response relationship with the prevalence of fractures. The risk was 1.25-fold (95% CI, 1.09-1.45) in Ss heterozygotes versus SS homozygotes, 1.68-fold (95% CI, 1.35-2.10) in ss homozygotes versus SS homozygotes, and 1.35 (95% CI, 1.04-1.75) for ss homozygotes versus Ss heterozygotes by random effects calculations. There was modest heterogeneity for these three effect estimates (p value for heterogeneity, 0.17, 0.16, and 0.08, respectively). The Sp1 polymorphism effects possibly were larger when the analysis was limited to studies considering only vertebral fractures (pooled risk ratios [RR], 1.30, 2.07, and 1.46, respectively). Conversely, the Spl polymorphism effects tended to be smaller in studies with mean patient age > or = 65 years than in studies with younger patients on average, but the differences were not formally significant. We estimated the total average attributable fraction (AF) of fractures due to the s allele in European/U.S. populations as 9.4%. The meta-analysis suggests an important role for the Spl polymorphism in the regulation of fracture risk; however, potential heterogeneity across ethnic groups, age groups, and skeletal sites may be important to clarify in future studies. Very large studies or meta-analyses are required to document subtle genetic differences in fracture risk.

    View details for Web of Science ID 000170599600003

    View details for PubMedID 11547828

  • Patterns of patient enrollment in randomized controlled trials JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A. B., Ioannidis, J. P. 2001; 54 (9): 877-883

    Abstract

    We aimed to describe enrollment patterns in a large cohort of randomized controlled trials (RCTs) and evaluate whether early recruitment predicts the ability of RCTs to reach their target enrollment. We considered all 77 efficacy RCTs initiated by the AIDS Clinical Trials Group between 1986 and 1996 (28,992 patients enrolled until November 1999). Thirteen RCTs (17%) failed to reach half their target recruitment. Enrollment trajectories showed that the initial rate of accrual determined the subsequent rates of enrollment. The target sample size was attained by 7/8, 11/14, 15/35 and 4/20 of trials with very rapid, rapid, moderate and slow enrollment during the first 3 months, respectively (P < 0.001). Enrollment during the first month or two strongly correlated with subsequent accrual (P < 0.001). The patient pool, the eligibility criteria, the attractiveness of a trial and adequacy of the network of clinical sites may influence RCT enrollment. Early enrollment offers strong evidence on the feasibility of a trial and is indicative of its future pace of recruitment.

    View details for Web of Science ID 000170603100003

    View details for PubMedID 11520646

  • Comparison of evidence of treatment effects in randomized and nonrandomized studies JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Haidich, A. B., Pappa, M., Pantazis, N., Kokori, S. I., Tektonidou, M. G., Contopoulos-Ioannidis, D. G., Lau, J. 2001; 286 (7): 821-830

    Abstract

    There is substantial debate about whether the results of nonrandomized studies are consistent with the results of randomized controlled trials on the same topic.To compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between randomized and nonrandomized studies.MEDLINE (1966-March 2000), the Cochrane Library (Issue 3, 2000), and major journals were searched.Forty-five diverse topics were identified for which both randomized trials (n = 240) and nonrandomized studies (n = 168) had been performed and had been considered in meta-analyses of binary outcomes.Data on events per patient in each study arm and design and characteristics of each study considered in each meta-analysis were extracted and synthesized separately for randomized and nonrandomized studies.Very good correlation was observed between the summary odds ratios of randomized and nonrandomized studies (r = 0.75; P<.001); however, nonrandomized studies tended to show larger treatment effects (28 vs 11; P =.009). Between-study heterogeneity was frequent among randomized trials alone (23%) and very frequent among nonrandomized studies alone (41%). The summary results of the 2 types of designs differed beyond chance in 7 cases (16%). Discrepancies beyond chance were less common when only prospective studies were considered (8%). Occasional differences in sample size and timing of publication were also noted between discrepant randomized and nonrandomized studies. In 28 cases (62%), the natural logarithm of the odds ratio differed by at least 50%, and in 15 cases (33%), the odds ratio varied at least 2-fold between nonrandomized studies and randomized trials.Despite good correlation between randomized trials and nonrandomized studies-in particular, prospective studies-discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.

    View details for Web of Science ID 000170429600030

    View details for PubMedID 11497536

  • Bias in uncontrolled therapeutic trials in rheumatology due to selection of populations with extreme characteristics JOURNAL OF RHEUMATOLOGY Ioannidis, J. P., Karassa, F. B. 2001; 28 (8): 1881-1887

    Abstract

    To assess the prevalence of biases from selection of patients with extreme characteristics in recent uncontrolled therapeutic studies in rheumatology.We hand searched 4 major rheumatology journals for uncontrolled trials published in 1997 or 1998 that measured therapeutic efficacy by comparing one or more variables at followup vs at baseline. We evaluated the susceptibility to bias from random measurement error and natural variability for variables used for defining eligibility that overlap with those used for defining outcomes.Twenty-five studies were analyzed. In 22 studies, the eligibility criteria were related to the outcome criteria and defined a patient population with extreme characteristics. Only 3 studies clearly reported that they had performed a baseline measurement separate from the screening (eligibility) measurement. The remaining 19 reports (76%) might be susceptible to bias: in 7, identical variables were used for eligibility criteria and outcomes; 3 used outcome variables that were also used for characterizing eligibility along with other criteria; 2 used specific eligibility variables that were part of composite outcome scores; and 7 selected patients on the basis of vague descriptors of disease severity, while disease severity was also the outcome.Several recent uncontrolled trials of therapeutic interventions in rheumatology are subject to biases stemming from the selection of patients with extreme characteristics. Baseline evaluations separate from the screening measurements should be performed and eligibility criteria and outcomes should be carefully defined.

    View details for Web of Science ID 000170254700024

    View details for PubMedID 11508595

  • Identification and catheter ablation of extracardiac and intracardiac components of ligament of Marshall tissue for treatment of paroxysmal atrial fibrillation JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Katritsis, D., Ioannidis, J. P., Anagnostopoulos, C. E., Sarris, G. E., Giazitzoglou, E., Korovesis, S., Camm, A. J. 2001; 12 (7): 750-758

    Abstract

    The ligament of Marshall is a left atrial neuromuscular bundle with sympathetic innervation that may be a source of atrial fibrillation (AF)-inducing automatic activity.Twenty-four patients with paroxysmal AF (including 18 with adrenergic AF) and 25 with other arrhythmias underwent catheter mapping. In cases of adrenergic AF, radiofrequency ablation was attempted when Marshall potentials were recorded. Patients were followed for 2 months before and 11.2 +/- 4.2 months after the procedure. Catheterization of the distal superoposterior coronary sinus was feasible in 14 patients with AF (10 with adrenergic AF) and 12 patients without AF. A discrete Marshall potential was recorded in 12 patients with AF versus 3 patients without AF (P = 0.004). In 10 patients with adrenergic AF, this potential followed the atrial electrogram during sinus rhythm by 26 +/- 5 msec on left atrial recordings and 24 +/- 4 msec on coronary sinus recordings, and preceded it during atrial ectopy by 29 +/- 5 msec and 26 +/- 5 msec, respectively. It was abolished by epicardial (n = 1), endocardial (n = 4), or combined epicardial and endocardial ablation (n = 5). Seven patients with ablation showed significant reductions in adrenergic AF, whereas no significant change was seen in 8 adrenergic AF patients not undergoing ablation (P = 0.004). No improvement was seen in 3 of 4 patients with only endocardial ablation, whereas all 6 patients with epicardial ablation improved (P = 0.033).Recording of Marshall potential is feasible in patients with paroxysmal AF. Combined epicardial and endocardial catheter ablation of ligament of Marshall tissue may reduce the paroxysms of adrenergic AF.

    View details for Web of Science ID 000169654400004

    View details for PubMedID 11469421

  • Pathways for inappropriate dispensing of antibiotics for rhinosinusitis: A randomized trial CLINICAL INFECTIOUS DISEASES Contopoulos-Ioannidis, D. G., Koliofoti, I. D., Koutroumpa, I. C., Giannakakis, I. A., Ioannidis, J. P. 2001; 33 (1): 76-82

    Abstract

    We evaluated the extent of and factors that determine the inappropriate use of antibiotics that are obtained without a physician's prescription. Ninety-eight Greek pharmacists were visited by actress-researchers who played clients requesting antibiotics without a physician's prescription. Pharmacists were randomly challenged in a scenario that involved simulated cases of acute uncomplicated rhinosinusitis with either low fever (38.5 degrees C) or high fever (40 degrees C). Antibiotics were offered by 34 (69%) of 49 pharmacists who were presented with the high-fever scenario and by 42 (86%) of 49 pharmacists who were presented with the low-fever scenario (risk difference, 16.3%; P = .05). Thirty-two (65%) and 35 (71%) pharmacists in the high- and low-fever study arms, respectively, agreed to sell the actress-researchers broad-spectrum antibiotics. Only 28 (57%) and 17 (35%) pharmacists, respectively, recommended that the patient visit a physician (P = .03). Inappropriate recommendations regarding antibiotic use were very common in the studied setting. Antibiotics were more likely to be offered to persons who did not have a prescription when they were less likely to be clinically indicated.

    View details for Web of Science ID 000169101500019

    View details for PubMedID 11389498

  • C-reactive protein concentrations and angiographic characteristics of coronary lesions CLINICAL CHEMISTRY Katritsis, D., Korovesis, S., Giazitzoglou, E., Parissis, J., Kalivas, P., Webb-Peploe, M. M., Ioannidis, J. P., Haliassos, A. 2001; 47 (5): 882-886

    Abstract

    C-Reactive protein (CRP) is a strong predictor of clinical outcome in coronary artery disease (CAD), and inflammation has been implicated in the process. We aimed to evaluate whether CRP concentrations measured with a new, automated particle-enhanced immunoturbidimetric method for high-sensitivity CRP may be related to specific high-risk angiographic features of coronary lesions.In a cross-sectional study, we examined 103 consecutive patients undergoing cardiac catheterization for suspected CAD. We assessed the association of preprocedural CRP concentrations with clinical presentation (unstable angina) and angiographic features of coronary lesions.Twenty patients had unstable angina. Independent predictors of unstable angina included increased CRP [odds ratio (OR), 2.93 per 10-fold increase in CRP; 95% confidence interval (CI), 1.28-6.69; P = 0.01] and the presence of macroscopic thrombus (OR, 7.08; 95% CI, 1.33-37.8; P = 0.02). Thirty-two culprit lesions had macroscopic thrombus or eccentric/irregular discrete morphology without total occlusion. Increased CRP was the strongest predictor of such features (OR, 2.04 per 10-fold increase in CRP; 95% CI, 1.03-4.04; P = 0.04), and the effect was independent of the presence of unstable angina.Among patients with suspected CAD undergoing coronary angiography, increased CRP is strongly associated with unstable angina and with specific high-risk features of the culprit coronary lesions.

    View details for Web of Science ID 000168383200015

    View details for PubMedID 11325892

  • Accuracy of imaging technologies in the diagnosis of acute cardiac ischemia in the emergency department: A meta-analysis ANNALS OF EMERGENCY MEDICINE Ioannidis, J. P., Salem, D., Chew, P. W., Lau, J. 2001; 37 (5): 471-477

    Abstract

    We sought to quantitatively evaluate the evidence on the diagnostic performance of imaging technologies (including rest and stress echocardiography and technetium-99m sestamibi scanning) for the diagnosis of acute cardiac ischemia and acute myocardial infarction in the emergency department.We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. Both prospective and retrospective studies qualified for the assessment of diagnostic performance. Diagnostic performance was assessed by means of random-effect estimates of test sensitivity, specificity, and the diagnostic odds ratio and was summarized by using summary receiver-operating characteristic curves.Diagnostic accuracy was evaluated in 10 studies of rest echocardiography, 2 studies of dobutamine stress echocardiography, and 6 studies of technetium-99m sestamibi scanning. However, only 3 rest echocardiography and 5 technetium-99m sestamibi studies evaluated patients strictly in the ED setting. Patient populations were often highly selected to represent low- or moderate-risk groups. When limited to ED studies, rest echocardiography showed excellent sensitivity of 93% (95% CI, 81% to 97%) and good specificity of 66% (95% CI, 43% to 83%). The results were similar when all studies were considered, including data from reports of admitted patients and patients sent to the cardiac care unit. There was insufficient literature on stress echocardiography in the ED to properly assess the technology. Technetium-99m sestamibi scanning also showed excellent sensitivity (range, 91.5% to 100%) and good specificity (range, 49.3% to 84.4%) for acute myocardial infarction; for acute cardiac ischemia, the random-effects pooled sensitivity was 89% (95% CI, 73% to 96%), and the pooled specificity was 77% (95% CI, 63% to 87%).For selected low- and moderate-risk patient groups, echocardiography and technetium-99m sestamibi imaging appear to have very good diagnostic performance with a similar sensitivity and specificity profile. More evidence should be accumulated on their performance specifically in the ED setting.

    View details for Web of Science ID 000168495300007

    View details for PubMedID 11326183

  • Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: A meta-analysis 23rd Annual Meeting of the Society-of-General-Internal-Medicine Balk, E. M., Ioannidis, J. P., Salem, D., Chew, P. W., Lau, J. MOSBY-ELSEVIER. 2001: 478–94

    Abstract

    We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of acute cardiac ischemia (ACI), including acute myocardial infarction (AMI) and unstable angina.We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. We examined the diagnostic performance of creatine kinase, creatine kinase-MB, myoglobin, and troponin I and T testing. Diagnostic performance was assessed by using estimates of test sensitivity and specificity and was summarized by summary receiver-operating characteristic curves.Only 4 studies were found that evaluated all patients with ACI; 73 were found that focused only on a diagnosis of AMI. To diagnose ACI, presentation biomarker tests had sensitivities of 16% to 19% and specificities of 96% to 100%; serial biomarker tests had sensitivities of 31% to 45% and specificities of 95% to 98%. Considering only the diagnosis of AMI, presentation biomarker tests had summary sensitivities of 37% to 49% and summary specificities of 87% to 97%; serial biomarker tests had summary sensitivities of 79% to 93% and summary specificities of 85% to 96%. Variation of test sensitivity was best explained by test timing. Longer symptom duration or time between serial tests yielded higher sensitivity.The limited evidence available to evaluate the diagnostic accuracy of biomarkers for ACI suggests that biomarkers have very low sensitivity to diagnose ACI. Thus, biomarkers alone will greatly underdiagnose ACI and will be inadequate to make triage decisions. For AMI diagnosis alone, multiple testing of individual biomarkers over time substantially improves sensitivity, while retaining high specificity, at the expense of additional time. Further high-quality studies are needed on the clinical effect of using biomarkers for patients with ACI in the ED and on optimal timing of serial testing and in combination with other tests.

    View details for Web of Science ID 000168495300008

    View details for PubMedID 11326184

  • Accuracy and clinical effect of out-of-hospital electrocardiography in the diagnosis of acute cardiac ischemia: A meta-analysis ANNALS OF EMERGENCY MEDICINE Ioannidis, J. P., Salem, D., Chew, P. W., Lau, J. 2001; 37 (5): 461-470

    Abstract

    We sought to evaluate quantitatively the evidence on the diagnostic performance of out-of-hospital ECG for the diagnosis of acute cardiac ischemia (ACI) and acute myocardial infarction (AMI) and the clinical effect of out-of-hospital thrombolysis.We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998 on the diagnostic accuracy of out-of-hospital ECG and the clinical effect of out-of-hospital thrombolysis. Both prospective and retrospective studies qualified for the assessment of diagnostic performance. For clinical effect, data from prospective nonrandomized studies were synthesized separately from data from randomized trials. Diagnostic performance was assessed by using estimates of test sensitivity, specificity, and diagnostic odds ratios and was summarized by using summary receiver-operating characteristic curves. Measures of clinical effect included time savings, early ventricular function, early mortality, and long-term survival.Diagnostic accuracy was evaluated in 11 studies with a total of 7,508 patients. Data were available for ACI in 5 studies and for AMI in 8 studies. For ACI, the random-effects pooled sensitivity was 76% (95% CI, 54% to 89%), the specificity was 88% (95% CI, 67% to 96%), and the diagnostic odds ratio was 23 (95% CI, 6.3 to 85). The respective figures for AMI were sensitivity of 68% (95% CI, 59% to 76%), specificity of 97% (95% CI, 89% to 92%), and diagnostic odds ratio of 104 (95% CI, 48 to 224). Both in nonrandomized (n=4, total 1,531 patients) and randomized (n=9, total 6,643 patients) studies, out-of-hospital thrombolysis shortened the time from onset of symptoms to thrombolytic treatment by 40 to 60 minutes. Data on short-term ejection fraction were sparse. Hospital mortality was reduced by 16% (95% CI, 2% to 27%) among randomized trials, and a similar estimate of effect was seen in nonrandomized studies. There was no clear effect on long-term mortality, but data were sparse.Out-of-hospital ECG has excellent diagnostic performance for AMI and very good performance for ACI. Out-of-hospital thrombolysis achieves time savings and improves short-term mortality, but the effect on long-term mortality is unknown.

    View details for DOI 10.1067/mem.2001.114904

    View details for Web of Science ID 000168495300006

    View details for PubMedID 11326182

  • Evidence on interventions to reduce medical errors - An overview and recommendations for future research JOURNAL OF GENERAL INTERNAL MEDICINE Ioannidis, J. P., Lau, J. 2001; 16 (5): 325-334

    Abstract

    To critically review the existing evidence on interventions aimed at reducing errors in health care delivery.Systematic review of randomized trials on behavioral, educational, informational and management interventions relating to medical errors. Pertinent studies were identified from MEDLINE, EMBASE, the Cochrane Clinical Trials Registry, and communications with experts.Both inpatients and outpatients qualified. No age or disease restrictions were set.Outcomes were medical errors, including medication, prescription, and diagnostic errors, and excluding preventive medicine errors and simple ordering of redundant tests.Thirteen randomized studies qualified for evaluation. The trials varied extensively in their patient populations (mean age, 2 weeks to 83 years), study setting, definition of errors, and interventions. Most studies could not afford masking and rigorous allocation concealment. In 9 of 13 studies, error rates in the control arms were very high (10% to 63%), and large treatment benefits from the studied interventions were demonstrated for the main outcome. Interventions were almost always effective in a sample of 24 nonrandomized studies evaluated for comparison. Actual patient harm from serious errors was rarely recorded.Medical errors were very frequent in the studies we identified, arising sometimes in more than half of the cases where there is an opportunity for error. Relatively simple interventions may achieve large reductions in error rates. Evidence on reduction of medical errors needs to be better categorized, replicated, and tested in study designs maximizing protection from bias. Emphasis should be placed on serious errors.

    View details for Web of Science ID 000168978000008

    View details for PubMedID 11359552

  • Diagnosing acute cardiac ischemia in the emergency department: A systematic review of the accuracy and clinical effect of current technologies Annual Meeting of the American-Association-of-Clinical-Chemists Lau, J., Ioannidis, J. P., Balk, E. M., Milch, C., Terrin, N., Chew, P. W., Salem, D. MOSBY-ELSEVIER. 2001: 453–60

    Abstract

    Acute cardiac ischemia (ACI) encompasses the diagnoses of unstable angina pectoris and acute myocardial infarction (AMI). Accurate diagnosis and triage of patients with ACI in the emergency department should increase survival for these patients and reduce unnecessary hospital admissions.We conducted a systematic review of the English-language literature published between 1966 and December 1998 on the accuracy and clinical effect of diagnostic technologies for ACI. We evaluated prospective and retrospective studies of adult patients who presented to the ED with symptoms suggesting ACI. Outcomes were diagnostic performance (test sensitivity and specificity) and measures of clinical effect. Meta-analyses were performed when appropriate. A decision and cost-effectiveness analysis was conducted that investigated various diagnostic strategies used in the diagnosis of ACI in the ED.We screened 6,667 abstracts, reviewed 407 full articles, and included 106 articles articles in the main analysis. Single measurements of biomarkers at presentation to the ED have low sensitivity for AMI, although they have high specificity. Serial measurements greatly increase the sensitivity for AMI while maintaining their excellent specificity. Diagnostic technologies to evaluate ACI in selected populations, such as electrocardiography, sestamibi perfusion imaging, and stress ECG, may have very good to excellent sensitivity; however, they have not been sufficiently studied. The Goldman Chest Pain Protocol has good sensitivity (about 90%) for AMI but has not been shown to result in any differences in hospitalization rate, length of stay, or estimated costs in the single clinical effect study performed. Its applicability to patients with unstable angina pectoris has not been evaluated. The use of an Acute Cardiac Ischemia-Time-Insensitive Predictive Instrument led to the appropriate triage of 97% of patients with ACI presenting to the ED and reduced unnecessary hospitalizations.Many of the current technologies remain underevaluated, especially regarding their clinical effect. The extent to which combinations of tests may provide better accuracy than any single test needs further study.

    View details for Web of Science ID 000168495300005

    View details for PubMedID 11326181

  • Any casualties in the clash of randomised and observational evidence? BMJ (Clinical research ed.) Ioannidis, J. P., Haidich, A. B., Lau, J. 2001; 322 (7291): 879-880

    View details for PubMedID 11302887

    View details for PubMedCentralID PMC1120057

  • How significant is sensorineural hearing loss in primary Sjogren's syndrome? An individually matched case-control study JOURNAL OF RHEUMATOLOGY Boki, K. A., Ioannidis, J. P., Segas, J. V., Maragkoudakis, P. V., Petrou, D., Adamopoulos, G. K., Moutsopoulos, H. M. 2001; 28 (4): 798-801

    Abstract

    We evaluated whether sensorineural loss and vestibular abnormalities are common in patients with primary Sjögren's syndrome (pSS) and whether such abnormalities are clinically significant.In an individually matched case-control design, 48 patients with pSS underwent complete audiovestibular evaluation along with 48 age and sex matched individuals without otologic problems. Differences of > 20 dB between patient and control ears at any frequency tested were considered to be significant.Significant differences in hearing loss were seen at 4,000 Hz (6 vs 0 ears; p = 0.03) and at 8,000 Hz (9 vs 0 ears; p = 0.003). Small differences in hearing acuity were also observed in the lower frequencies, but the absolute mean difference was < 3 dB. A decrease of at least 60 dB in hearing acuity at any frequency up to 4,000 Hz was seen only in 3 elderly pSS patients. Abnormal brainstem auditory evoked responses were recorded in 7 patients and 5 controls, but no patient had retrocochlear lesions identified on magnetic resonance imaging. Four patients in each group had abnormalities on electronystagmography.pSS is associated with sensorineural hearing loss affecting preferentially the high frequencies, but clinically significant defects are not common. There is no evidence of retrocochlear disease or increased vestibular involvement in pSS.

    View details for Web of Science ID 000167808600020

    View details for PubMedID 11327253

  • Comparison of myocardial fractional flow reserve and intravascular ultrasound for the assessment of slotted-tube stents CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Katritsis, D. G., Ioannidis, J. P., Korovesis, S., Giazitzoglou, E., Parissis, J., Kalivas, P., Webb-Peploe, M. M. 2001; 52 (3): 322-326

    Abstract

    Intravascular ultrasound (IVUS) and myocardial fractional flow reserve (FFR) have been reported to provide similar results for assessment of coil stent deployment. Their relative value in slotted-tube stents has not been investigated. Fourteen patients subjected to coronary angioplasty and IVUS-guided elective stenting with a slotted-tube stent underwent IVUS assessment and FFR measurement following stent implantation at inflation pressures of 12 and 18 atm. FFR values (mean +/- SD) preangioplasty, postangioplasty, and poststenting at 12 atm and 18 atm, were 0.58 +/- 0.07, 0.83 +/- 0.05, 0.94 +/- 0.02, and 0.94 +/- 0.02, respectively. After inflation at 12 atm, the area under the receiver operating characteristic (ROC) curve for the concordance of IVUS and FFR measurements was 0.89 (P = 0.02). Six patients had either an abnormal IVUS (n = 2) or FFR < 0.94 (n = 1) or both abnormal IVUS and FFR < 0.94 (n = 3) after the first inflation and had a second inflation at 18 atm. The area under the ROC curve for the concordance between IVUS and FFR final measurements was 0.855 (P = 0.10). Perfect concordance between IVUS and FFR was seen only for FFR values less than 0.91 or larger than 0.94. Overall, IVUS and FFR have substantial concordance with respect to slotted-tube stent deployment. However, FFR values between 0.91 and 0.94 after inflation are difficult to interpret.

    View details for Web of Science ID 000167249000012

    View details for PubMedID 11246245

  • Predictive modeling and heterogeneity of baseline risk in meta-analysis of individual patient data JOURNAL OF CLINICAL EPIDEMIOLOGY Trikalinos, T. A., Ioannidis, J. P. 2001; 54 (3): 245-252

    Abstract

    We developed and evaluated methods for the analysis and interpretation of the baseline risk heterogeneity in meta-analysis of individual patient data (MIPD) based on information on predictive factors. We used data from a typical MIPD of eight clinical trials (1792 patients, 2947 years of follow-up) on the efficacy of high-dose acyclovir in human immunodeficiency virus infection. Cox models with four predictive factors (age, disease state, CD4 cell count and hemoglobin levels) were used to estimate predicted individual hazards both for single trials and for various MIPD modeling methods (simple pooling, adjusted for study, stratified per study, fixed and random effects for predictors). For each study and for each method of MIPD synthesis, we estimated the odds ratio for death in the upper versus the lower quartile of predicted risk (Extreme Quartile Odds Ratio, EQuOR) and the respective rate ratio (Extreme Quartile Rate Ratio, EQuRR). Only the CD4 cell count showed a significantly heterogeneous predictive effect across the eight studies (P =.024). The EQuOR of single studies ranged from 3.5 (little heterogeneity) to 24 (intermediate heterogeneity), substantially lower than the EQuOR of the MIPD (167 to 275, depending on the model used). The EQuRR values ranged from 3.5 to 77 for single studies and from 77 to 116 for the various MIPD models. Predictive modeling can be a major strength of MIPD, when performed and interpreted with standardized approaches. All models consistently show that MIPD may be a study design with extreme heterogeneity of patient baseline risk.

    View details for Web of Science ID 000167162300005

    View details for PubMedID 11223322

  • Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads < 1000 copies/mL JOURNAL OF INFECTIOUS DISEASES Ioannidis, J. P., Abrams, E. J., Ammann, A., Bulterys, M., Goedert, J. J., Gray, L., Korber, B. T., Mayaux, M. J., Mofenson, L. M., Newell, M. L., Shapiro, D. E., Teglas, J. P., WILFERT, C. M. 2001; 183 (4): 539-545

    Abstract

    In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

    View details for Web of Science ID 000166586000003

    View details for PubMedID 11170978

  • Early mortality and morbidity of bilateral versus single internal thoracic artery revascularization: Propensity and risk modeling JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ioannidis, J. P., Galanos, O., Katritsis, D., Connery, C. P., Drossos, G. E., Swistel, D. G., Anagnostopoulos, C. E. 2001; 37 (2): 521-528

    Abstract

    We examined whether bilateral internal thoracic artery (BITA) revascularization is associated with any increased in-hospital mortality and complications compared with single internal thoracic artery (SITA) revascularization.Despite proven long-term benefits, BITA revascularization has been slow to be adopted because of fear of increased early morbidity.We evaluated 1,697 consecutive patients undergoing BITA (n = 867) or SITA (n = 830) revascularization. We used propensity score analyses and adjusted risk models to address differences between arms.There were 20 (2.3%) deaths in the BITA group versus 26 (3.1%) in the SITA group (odds ratio 0.73, p = 0.30). Propensity analysis identified several parameters that affected the decision to use BITA. Adjusting for propensity score and all potential risk factors, the odds ratio for death with BITA versus SITA was practically 1. Bilateral internal thoracic artery revascularization did not increase the number of in-hospital complications with the possible exception of deep sternal wound infections (11 [1.3%] vs. 3 [0.4%], p = 0.057). In multivariate modeling BITA increased the risk of deep sternal wound infections only in emergent cases and in older patients; the excess risk was negligible among 1,206 patients (71.1% of total) who did not have emergent revascularization and were < or =70 years old (risk difference 0.3%, p = 0.74). There was no difference in length of stay after adjustment for propensity factors (mean 11.3 vs. 11.7 days, p = 0.66).Bilateral internal thoracic artery revascularization grafting confers no increased risk for early death and does not prolong hospital stay. The small increase in the risk of deep sternal wound infections does not affect the majority of patients.

    View details for Web of Science ID 000166847200025

    View details for PubMedID 11216973

  • Evolution of treatment effects over time: Empirical insight from recursive cumulative metaanalyses PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ioannidis, J. P., Lau, J. 2001; 98 (3): 831-836

    Abstract

    Evidence on how much medical interventions work may change over time. It is important to determine what fluctuations in the treatment effect reported by randomized trials and their metaanalyses may be expected and whether extreme fluctuations signal future major changes. We applied recursive cumulative metaanalysis of randomized controlled trials to evaluate the relative change in the pooled treatment effect (odds ratio) over time for 60 interventions in two medical fields (pregnancy/perinatal medicine, n = 45 interventions; myocardial infarction, n = 15 interventions). We evaluated the scatter of relative changes for different numbers of total patients in previous trials. Outlier cases were noted with changes greater than 2.5 standard deviations of the expected. With 500 accumulated patients, the pooled odds ratio may change by 0.6- to 1.7-fold in the immediate future. When 2000 patients have already been randomized, the respective figures are between 0.74- and 1.35-fold for pregnancy/perinatal medicine and between 0.83- and 1.21-fold for myocardial infarction studies. Extreme early fluctuations in the treatment effect were observed in three interventions (magnesium in myocardial infarction, calcium and antiplatelet agents for prevention of preeclampsia), where recent mega-trials have contradicted prior metaanalyses, as well as in four other examples where early large treatment effects were dissipated when more data appeared. Past experience may help quantify the uncertainty surrounding the treatment effects reported in early clinical trials and their metaanalyses. Early wide oscillations in the evolution of the treatment effect for specific interventions may sometimes signal further major changes in the future.

    View details for Web of Science ID 000166807300016

    View details for PubMedID 11158556

  • Completeness of safety reporting in randomized trials - An evaluation of 7 medical areas JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Lau, J. 2001; 285 (4): 437-443

    Abstract

    Randomized trials with adequate sample size offer an opportunity to assess the safety of new medications in a controlled setting; however, generalizable data on drug safety reporting are sparse.To scrutinize the completeness of safety reporting in randomized trials.Survey of safety reporting in 192 randomized drug trials 7 diverse topics with sample sizes of at least 100 patients and at least 50 patients in a study arm (N = 130074 patients). Trial reports were identified from comprehensive meta-analyses in 7 medical areas.Adequate reporting of specific adverse effects and frequency and reasons for withdrawals due to toxic effects; article space allocated to safety reporting and predictors of such reporting.Severity of clinical adverse effects and laboratory-determined toxicity was adequately defined in only 39% and 29% of trial reports, respectively. Only 46% of trials stated the frequency of specific reasons for discontinuation of study treatment due to toxicity. For these 3 parameters, there was significant heterogeneity in rates of adequate reporting across topics (P =.003, P<.001, and P =.02, respectively). Overall, the median space allocated to safety results was 0.3 page. A similar amount of space was devoted to contributor names and affiliations (P =.16). On average, the percentage of space devoted to safety in the results section was 9.3% larger in trials involving dose comparisons than in those that did not (P<.001) and 3.8% smaller in trials reporting statistically significant results for efficacy outcomes (P =.047).The quality and quantity of safety reporting vary across medical areas, study designs, and settings but they are largely inadequate. Current standards for safety reporting in randomized trials should be revised to address this inadequacy.

    View details for Web of Science ID 000166506000031

    View details for PubMedID 11242428

  • Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions. BMC medical research methodology Papanikolaou, G. N., Baltogianni, M. S., Contopoulos-Ioannidis, D. G., Haidich, A. B., Giannakakis, I. A., Ioannidis, J. P. 2001; 1: 3-?

    Abstract

    Guidelines published in major medical journals are very influential in determining clinical practice. It would be essential to evaluate whether conflicts of interests are disclosed in these publications. We evaluated the reporting of conflicts of interest and the factors that may affect such disclosure in a sample of 191 guidelines on therapeutic and/or preventive measures published in 6 major clinical journals (Annals of Internal Medicine, BMJ, JAMA, Lancet, New England Journal of Medicine, Pediatrics) in 1979, 1984, 1989, 1994 and 1999.Only 7 guidelines (3.7%) mentioned conflicts of interest and all were published in 1999 (17.5% (7/40) of guidelines published in 1999 alone). Reporting of conflicts of interest differed significantly by journal (p=0.026), availability of disclosure policy by the journal (p=0.043), source of funding (p < 0.001) and number of authors (p=0.004). In the entire database of 191 guidelines, a mere 18 authors disclosed a total of 24 potential conflicts of interest and most pertained to minor issues.Despite some recent improvement, reporting of conflicts of interest in clinical guidelines published in influential journals is largely neglected.

    View details for PubMedID 11405896

    View details for PubMedCentralID PMC32303

  • Determinants of patient recruitment in a multicenter clinical trials group: trends, seasonality and the effect of large studies. BMC medical research methodology Haidich, A. B., Ioannidis, J. P. 2001; 1: 4-?

    Abstract

    We examined whether quarterly patient enrollment in a large multicenter clinical trials group could be modeled in terms of predictors including time parameters (such as long-term trends and seasonality), the effect of large trials and the number of new studies launched each quarter. We used the database of all clinical studies launched by the AIDS Clinical Trials Group (ACTG) between October 1986 and November 1999. Analyses were performed in two datasets: one included all studies and substudies (n = 475, total enrollment 69,992 patients) and the other included only main studies (n = 352, total enrollment 57,563 patients).Enrollment differed across different months of the year with peaks in spring and late fall. Enrollment accelerated over time (+27 patients per quarter for all studies and +16 patients per quarter for the main studies, p < 0.001) and was affected by the performance of large studies with target sample size > 1,000 (p < 0.001). These relationships remained significant in multivariate autoregressive modeling. A time series based on enrollment during the first 32 quarters could forecast adequately the remaining 21 quarters.The fate and popularity of large trials may determine the overall recruitment of multicenter groups. Modeling of enrollment rates may be used to comprehend long-term patterns and to perform future strategic planning.

    View details for PubMedID 11423002

    View details for PubMedCentralID PMC33393

  • Management of cancer pain. Evidence report/technology assessment (Summary) Goudas, L., Carr, D. B., Bloch, R., Balk, E., Ioannidis, J. P., Terrin, N., Gialeli-Goudas, M., Chew, P., Lau, J. 2001: 1-5

    View details for PubMedID 11253288

  • The Sp1 COLIA1 gene polymorphism, and not vitamin D receptor or estrogen receptor gene polymorphisms, determines bone mineral density in postmenopausal Greek women OSTEOPOROSIS INTERNATIONAL Efstathiadou, Z., Kranas, V., Ioannidis, J. P., Georgiou, I., Tsatsoulis, A. 2001; 12 (4): 326-331

    Abstract

    Several genetic polymorphisms are implicated as determinants of bone mineral density (BMD) in postmenopausal women. These include the Sp1 polymorphism of the collagen type I alpha 1 (COLIA1) gene, the FokI and BsmI polymorphisms of the vitamin D receptor (VDR) gene, and the PvuII and XbaI polymorphisms of the estrogen receptor (ER) gene. The relative importance and the independence of these genetic effects have not been studied simultaneously in the same population. We evaluated the effects of these polymorphisms on lumbar spine BMD among 154 postmenopausal Greek women. BMD tended to differ across Sp1 genotypes (mean 0.842 g/cm2 in SS, 0.851 g/cm2 in Ss, 0.763 in ss, age-adjusted p = 0.056), mostly because ss homozygotes had lower BMD (p = 0.018 compared with SS and Ss). No other polymorphisms were associated with BMD in this population (p = 0.53 for FokI, p = 0.94 for BsmI, p = 0.80 for PvuII, p = 0.91 for XbaI). In multivariate modeling, the effect of ss homozygosity was clinically and statistically significant (-0.105 g/cm2, p = 0.013) after adjusting for age, weight, height, hormone replacement use, and the other four polymorphisms. None of the other four polymorphisms was retained as an independent predictor of BMD in a backward elimination model and no significant synergistic effects were observed when gene interactions were tested. When all five polymorphisms are considered simultaneously, the Sp1 COLIA1 polymorphism seems to have the most unequivocal effect on BMD, at least in postmenopausal women.

    View details for Web of Science ID 000169185700011

    View details for PubMedID 11420783

  • Right ventricular diastolic dysfunction in patients with anticardiolipin antibodies and antiphospholipid syndrome ANNALS OF THE RHEUMATIC DISEASES Tektonidou, M. G., Ioannidis, J. P., Moyssakis, I., Boki, K. A., Vassiliou, V., Vlachoyiannopoulos, P. G., Kyriakidis, M. K., Moutsopoulos, H. M. 2001; 60 (1): 43-48

    Abstract

    To evaluate the prevalence of diastolic dysfunction in patients with anticardiolipin antibodies (aCL) and to examine whether the antiphospholipid syndrome (APS) is associated with diastolic dysfunction independently of valvular abnormalities and systolic dysfunction.Pulsed, continuous, colour Doppler echocardiography was performed in 179 subjects, of whom 15 were excluded from the analysis because of systolic dysfunction or severe valvular disease. The remaining 164 subjects included 29 patients with primary APS, 26 patients with secondary APS (APS in the presence of systemic lupus erythematosus (SLE)), and 30 patients with SLE and aCL but without APS; 43 patients with SLE without aCL and 36 normal volunteers served as control groups.The groups compared differed significantly in all measures of right ventricular function. There was a gradation of increasing diastolic function impairment as manifested by prolonged deceleration time (DT) and isovolumic relaxation time (IVRT) across the groups of patients with SLE without aCL, SLE with aCL, secondary APS, and primary APS. Differences in left ventricular diastolic function measures were less prominent. In regression analysis, DT increased by 19.6 ms (p=0.002) in the presence of primary APS and by 20.1 ms (p=0.038) in the presence of pulmonary hypertension. The titre of IgG aCL was the strongest predictor of a prolonged IVRT.Diastolic dysfunction, in particular of the right ventricle-that is, independent of valvular disease and systolic dysfunction, is a prominent feature of APS and may be related to the pathogenesis of the syndrome.

    View details for Web of Science ID 000166008100009

    View details for PubMedID 11114281

  • Appendicectomies in Albanians in Greece: outcomes in a highly mobile immigrant patient population BMC HEALTH SERVICES RESEARCH Tatsioni, A., Charchanti, A., Kitsiou, E., Ioannidis, J. P. 2001; 1

    Abstract

    Albanian immigrants in Greece comprise a highly mobile population with unknown health care profile. We aimed to assess whether these immigrants were more or less likely to undergo laparotomy for suspected appendicitis with negative findings (negative appendicectomy), by performing a controlled study with individual (1:4) matching. We used data from 6 hospitals in the Greek prefecture of Epirus that is bordering Albania.Among a total of 2027 non-incidental appendicectomies for suspected appendicitis performed in 1994-1999, 30 patients with Albanian names were matched (for age, sex, time of operation and hospital) to 120 patients with Greek names. The odds for a negative appendicectomy were 3.4-fold higher (95% confidence interval [CI], 1.24-9.31, p = 0.02) in Albanian immigrants than in matched Greek-name subjects. The difference was most prominent in men (odds ratio 20.0, 95% CI, 1.41-285, p = 0.02) while it was not formally significant in women (odds ratio 1.56, 95% CI, 0.44-5.48). The odds for perforation were 1.25-fold higher in Albanian-name immigrants than in Greek-name patients (95% CI 0.44- 3.57).Albanian immigrants in Greece are at high risk for negative appendicectomies. Socioeconomic, cultural and language parameters underlying health care inequalities in highly mobile immigrant populations need better study.

    View details for Web of Science ID 000179726600005

    View details for PubMedID 11472640

  • Arabian nights-1001 tales of how pharmaceutical companies cater to the material needs of doctors: case report BRITISH MEDICAL JOURNAL Giannakakis, I. A., Ioannidis, J. P. 2000; 321 (7276): 1563-1564

    Abstract

    To describe how pharmaceutical companies cater to the material needs of doctors.Case report of memoirs.Facilities that have nothing to do with medicine, somewhere in the Arabian peninsula.Random sample of doctors.Promotion by the pharmaceutical industry.Short term outcomes were travel, pleasure, amusement, and gifts, and long term outcomes were the market share of specific companies.Short term outcomes were heterogeneous, underlying the diversity of the means employed by the pharmaceutical industry to subvert, divert, and influence medical practice. Overall, 200 doctors were dressed in white gowns, a doctor in preventive medicine quoted Hippocrates in favour of smoking, a senior doctor became a poet, a doctor trying to understand the Methods section of a poster paper wondered whether he should have been sunbathing at the beach instead, and two women doctors were kidnapped by Bedouin warriors. Long term outcomes on the sales of the company drugs are pending but are likely to be most favourable.Eat, drink, be merry, and boost prescriptions.

    View details for Web of Science ID 000166134500013

    View details for PubMedID 11124175

  • Predictors of clinical outcome and radiologic progression in patients with neuropsychiatric manifestations of systemic lupus erythematosus AMERICAN JOURNAL OF MEDICINE Karassa, F. B., Ioannidis, J. P., Boki, K. A., Touloumi, G., Argyropoulou, M. I., Strigaris, K. A., Moutsopoulos, H. M. 2000; 109 (8): 628-634

    Abstract

    We sought to identify the predictors of clinical outcome and of the evolution of cerebral abnormalities in patients with neuropsychiatric systemic lupus erythematosus (SLE).Thirty-two patients with SLE (including 14 with the antiphospholipid syndrome) who had been hospitalized with primary neuropsychiatric disease were observed prospectively for at least 2 years. Laboratory and clinical characteristics and data from magnetic resonance imaging (MRI) studies obtained during the hospitalization and 2 years later were evaluated. We ascertained nonreversible or new MRI changes and clinical outcomes, including neuropsychiatric events, during follow-up.Cranial MRI scans on admission were abnormal in 26 (81%) of the 32 patients. Patients with the antiphospholipid syndrome were more likely to have focal cerebral white matter lesions (odds ratio [OR] = 12, 95% confidence interval [CI]: 2.0 to 72). After 2 years, neuropsychiatric deficits substantially improved in 22 (69%) of the patients, stabilized in 6 (19%), and deteriorated in 4 (12%). The number of prior neuropsychiatric events was associated with persistent MRI lesions (OR = 4.8 per each event, 95% CI: 1.1 to 21) and unfavorable clinical outcome (OR = 4.3 per each event, 95% CI: 1.4 to 13) at 2 years. The antiphospholipid syndrome also predicted an unfavorable clinical outcome at 2 years (OR = 11, 95% CI: 1.7 to 65).Among patients with SLE who have neuropsychiatric disease, prior neuropsychiatric events and the antiphospholipid syndrome increase the risk of adverse outcomes.

    View details for Web of Science ID 000165604000004

    View details for PubMedID 11099682

  • Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: A meta-analysis of randomized evidence JOURNAL OF CLINICAL ONCOLOGY Ioannidis, J. P., Hesketh, P. J., Lau, J. 2000; 18 (19): 3409-3422

    Abstract

    To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy.A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library's Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data.Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well.Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.

    View details for Web of Science ID 000089700800013

    View details for PubMedID 11013282

  • Diagnosis and treatment of uncomplicated acute sinusitis in children. Evidence report/technology assessment (Summary) Lau, J., Ioannidis, J. P., Wald, E. R. 2000: 1-3

    View details for PubMedID 11089497

  • 23-valent pneumococcal vaccination and HIV LANCET Spoulou, V., Theodoridou, M., Papaevangelou, V. G., Mostrou, G. I., Ioannidis, J. P. 2000; 356 (9234): 1027-1028

    View details for Web of Science ID 000089293600045

    View details for PubMedID 11041419

  • Kinetics of antibody concentration and avidity for the assessment of immune response to pneumococcal vaccine among children with bone marrow transplants Pneumococcal Vaccines for the World Conference Spoulou, V., Victoratos, P., Ioannidis, J. P., Grafakos, S. OXFORD UNIV PRESS INC. 2000: 965–69

    Abstract

    The kinetics of the immune response to the 23-valent pneumococcal polysaccharide vaccine (PPV) were studied in 38 children who received bone marrow transplants (BMTs). Anti-pneumococcal antibody concentrations increased 1 and 3 months after vaccination for all 5 serotypes tested, but, in 21 children, the vaccine was not adequately immunogenic. Children vaccinated <18 months after receiving a BMT had a 4.2-fold increased odds of poor response (P=. 06). Antibody concentrations returned close to baseline levels 9 months after vaccination. Avidity declined significantly as early as 1 month after vaccination and remained low thereafter. Antibody concentration responses to PPV were superior among 9 healthy control children (P=.001); 37 of 38 children with a BMT elicited adequate, persistent immune responses to Haemophilus influenzae conjugate vaccine. Immune responses to PPV in children with a BMT are suboptimal, short lived, and associated with declining avidity. The different kinetics of antibody concentration and avidity indicate that both markers should be used for evaluating pneumococcal vaccines in this high-risk population.

    View details for Web of Science ID 000089386800045

    View details for PubMedID 10950799

  • Evaluation of technologies for identifying acute cardiac ischemia in emergency departments. Evidence report/technology assessment (Summary) Lau, J., Ioannidis, J. P., Balk, E., Milch, C., Chew, P., Terrin, N., Lang, T. A., Salem, D., Wong, J. B. 2000: 1-4

    View details for PubMedID 11079073

  • Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome QJM-AN INTERNATIONAL JOURNAL OF MEDICINE Tektonidou, M. G., Ioannidis, J. P., Boki, K. A., Vlachoyiannopoulos, P. G., Moutsopoulos, H. M. 2000; 93 (8): 523-530

    Abstract

    We assessed whether initial clinical presentations suggestive of antiphospholipid syndrome (APS) predicted the subsequent rate and type of serious clinical outcomes. Eighty-two consecutive patients with anticardiolipin antibodies or lupus anticoagulant were followed for 814 person-years after a first event suggestive of APS (livedo reticularis, thrombocytopenia, autoimmune haemolysis, thrombosis, central nervous system manifestations, recurrent abortions). The hazard of developing a second event was largest in patients with antibodies recognizing beta2 glycoprotein I who had autoimmune haemolysis as the first event (hazard ratio HR 2.70, p=0.018) and smallest in patients without such antibodies who had recurrent abortions as their first event (HR 0.37, p=0.028). Subsequent serious events in patients with venous and arterial thromboses, recurrent abortions, central nervous system manifestations and autoimmune haemolytic anaemia were likely to be of the same type as the presenting event (odds ratio (OR) 3.76, 5.90, 77.7, 6.92, and 7.13, respectively. Adjusting for therapy, the rate of subsequent serious events was 6.86-fold higher (p=0.0001) in patients presenting with two events, 1.56-fold higher (p=0.038) in autoimmune haemolysis presentations, 1.69-fold higher (p=0.004) in patients with anti-beta2-glycoprotein-I antibodies, and 46% (p=0.063) lower in thrombocytopenia presentations. Initial clinical features determine the long-term evolution of APS, and specific types of clinical manifestations cluster during the course of the disease.

    View details for Web of Science ID 000088755900005

    View details for PubMedID 10924534

  • Meta-analysis in hematology and oncology HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Ioannidis, J. P., Schmid, C. H., Lau, J. 2000; 14 (4): 973-?

    Abstract

    In 1992, a review article about meta-analysis identified only 15 meta-analyses of randomized, controlled trials of cancer therapy. Since then, the total number of meta-analyses in this field has increased almost sixfold. More importantly, the number of randomized, controlled trials in this discipline has also grown tremendously. The expansion in the literature will provide a fertile ground for future meta-analyses. The quality of the recent publications has also improved. An ongoing world-wide effort, the Cochrane Collaboration, is systematically assembling and synthesizing several hundred thousand randomized, controlled trials to improve the delivery of health care. Meta-analysis has many important advantages. It allows the viewing of the complete picture of the evidence. The advent of meta-analysis has sensitized researchers to issues of quality and has improved methodology in clinical research. Detection and explanation of bias and heterogeneity are prime objectives of meta-analysis in clinical research. An array of methods has been developed that allows a better understanding of bias and heterogeneity, beyond simple averaging of results from diverse studies. Meta-analyses of individual patient data, in particular, may promote the development of international collaborations. Several examples of their application are already available in oncology. Meta-analysis may point out deficiencies in the study design of past and current studies, suggest the need for new studies, and inform researchers about the size and design of these studies. In the end, meta-analysis helps to integrate evidence and make recommendations for medical care and medical practice.

    View details for Web of Science ID 000088799300015

    View details for PubMedID 10949784

  • Dynamics of HIV-1 viral load rebound among patients with previous suppression of viral replication AIDS Ioannidis, J. P., Havlir, D. V., Tebas, P., Hirsch, M. S., Collier, A. C., Richman, D. D. 2000; 14 (11): 1481-1488

    Abstract

    To model the dynamics of HIV-1 rebound in patients receiving suboptimal therapy after suppression of plasma viremia to < 200 copies/ml by triple combination therapy.Mathematical modeling of data from 23 patients switched to indinavir maintenance therapy after viral replication was suppressed with a combination of indinavir, zidovudine and lamivudine. Modeling of HIV-1 rebound among 24 patients on zidovudine/lamivudine maintenance was also performed for comparison.Evaluation of slopes of rebound and of their heterogeneity; calculation of the basic reproductive number (Ro, the number of newly infected cells arising from each productively infected cell); regression analyses for predictors of the slope of rebound.Rebound of plasma HIV RNA followed a sigmoid curve with an initial exponential phase. There was significant heterogeneity in the slopes of rebound for individual patients (P < 0.001). In the indinavir maintenance rebounds, the average initial slope was estimated to be 0.587/day (doubling time 1.2 days). The slopes of rebound in patients on zidovudine/lamivudine maintenance tended to be less steep on average (P = 0.025). Among patients taking indinavir maintenance, the average Ro for the initial rebound of viremia was 4.3; in multivariate regressions, the slope of rebound was steeper during early rebound and in patients with higher viral load at the start of triple therapy or a higher CD4 cell count when indinavir monotherapy was initiated. The slope was less steep in patients with a greater increase in the number of CD4 cells during triple therapy.The rates of viral load increase among patients with viral rebound while receiving less than triple therapy are similar to those reported in patients interrupting therapy. Variability among patients may depend on viral fitness, target cell availability and extent of immune reconstitution.

    View details for Web of Science ID 000089021600002

    View details for PubMedID 10983634

  • Clinical importance of antibodies against platelet activating factor in antiphospholipid syndrome manifestations EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Tektonidou, M. G., Petrovas, C. A., Ioannidis, J. P., Vlachoyiannopoulos, P. G., Moutsopoulos, H. M. 2000; 30 (7): 646-652

    Abstract

    We assessed whether antibodies against platelet activating factor (PAF) are related to the presence of antiphospholipid syndrome (APS) clinical manifestations, in particular thrombosis, in patients with connective tissue diseases.Anti-PAF, anticardiolipin (aCL), antibeta2 glycoprotein I (antibeta2GPI) and antiphosphatidylcholine (anti-PC) antibodies were determined in 52 patients with APS, 29 patients with systemic lupus erythematosus (SLE) aCL but without APS, 30 patients with SLE without aCL, and 30 patients with scleroderma. A new enzyme-linked immunosorbent assay (ELISA) was developed for determining anti-PAF antibodies in a bovine serum-free fashion.The ELISA showed high specificity. Homologous inhibition experiments showed 60-70% inhibition. Anti-PAF antibodies were found in 18/52 APS patients, 10/29 SLE/aCL+ patients, 9/30 SLE/aCL- patients and 3/30 scleroderma patients. Anti-PAF antibodies were significantly associated with anti-PC antibodies (odds ratio [OR] 12. 7, P < 0.01), and there was a modest association with immunoglobulin G (IgG) aCL (OR 3.1, P > 0.10), but not with IgM aCL or antibeta2GPI. Three SLE/aCL+ patients and five SLE/aCL- patients had clinical manifestations characteristic of APS. All these patients had anti-PAF antibodies, while none had high titres of aCL or antibeta2GPI antibodies and only one had anti-PC antibodies. Among the combined APS and SLE groups, the presence of anti-PAF antibodies was significantly associated with clinical manifestations which are characteristic of APS (OR 2.6, P = 0.02). The effect was independent of IgG aCL and antibeta2GPI antibodies.Anti-PAF antibodies are common in APS and SLE and comprise an independent factor for the development of thrombosis. Several patients experiencing thromboses have anti-PAF antibodies without other antiphospholipid specificities.

    View details for Web of Science ID 000088005000013

    View details for PubMedID 10886305

  • Clinically significant and biopsy-documented renal involvement in primary Sjogren syndrome MEDICINE Goules, A., Masouridi, S., Tziofas, A. G., Ioannidis, J. P., Skopouli, F. N., Moutsopoulos, H. M. 2000; 79 (4): 241-249

    Abstract

    Clinically significant renal involvement in patients with primary Sjögren syndrome (pSS) has been described previously only in isolated case reports. The prevalence and significance of the 2 described syndromes, interstitial nephritis (IN) and glomerulonephritis (GMN), are not well known. In a cohort of 471 patients with pSS who were followed for a mean of 10 years, 20 patients (4.2%) developed overt renal disease. Eighteen patients underwent a percutaneous renal biopsy; 2 patients declined. Ten patients had IN, 8 patients had GMN, and 2 patients presented with both entities. Glomerular histology disclosed changes compatible with membranoproliferative GMN in 5 patients and mesangial proliferative GMN in 4 patients. Patients with IN had a younger disease onset compared with patients with GMN (mean, 36.8 compared with 46.0 yr, p 5 0.063). Patients with GMN had longer disease duration compared with patients with IN (mean, 2.2 compared with 8.0 yr, p 5 0.001). The majority of patients with GMN (80%) had mixed monoclonal cryoglobulinemia IgMk (type II) and lower complement C4 levels. Two patients (both with GMN) developed chronic renal failure requiring hemodialysis. Overall, clinically significant renal involvement is infrequent in pSS. IN occurs early in the disease process, while GMN is a late sequela and may have a less favorable prognosis.

    View details for Web of Science ID 000088498700005

    View details for PubMedID 10941353

  • A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy AIDS Baxter, J. D., MAYERS, D. L., Wentworth, D. N., Neaton, J. D., Hoover, M. L., Winters, M. A., Mannheimer, S. B., Thompson, M. A., Abrams, D. I., Brizz, B. J., Ioannidis, J. P., Merigan, T. C. 2000; 14 (9): F83-F93

    Abstract

    To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors.Prospective randomized controlled trial.Multicenter community-based clinical trials network.One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy.Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input.Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels.The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible.In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

    View details for Web of Science ID 000087735700001

    View details for PubMedID 10894268

  • Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy AIDS O'Brien, T. R., McDermott, D. H., Ioannidis, J. P., Carrington, M., Murphy, P. M., Havlir, D. V., Richman, D. D. 2000; 14 (7): 821-826

    Abstract

    Both the natural history of HIV infection and the response to antiretroviral therapy are heterogeneous. Polymorphisms in chemokine receptor genes modulate the natural history of HIV-1 infection. In comparison with subjects with other genotypes, the prognosis for HIV-1-infected CCR5-delta32 heterozygotes is more favorable and that for CCR5 promoter allele 59029A homozygotes is less favorable.HIV-1-infected adults with a CD4+ lymphocyte count > or = 200 cells x 10(6)/l and a plasma HIV RNA level > or = 1000 copies/ml were treated with indinavir, zidovudine and lamivudine for 6 months. HIV RNA levels were measured at 4-week intervals. Genotyping for chemokine receptor gene polymorphisms (CCR5-delta32, CCR5 59029A/G, CCR2-641) was performed. We examined whether the time to first HIV RNA < 200 copies/ml, frequency of viral suppression failure (HIV RNA > or = 200 copies/ml between weeks 16 and 28 of therapy), or reduction from the pre-treatment HIV RNA level differed by genotype.Time to first HIV RNA < 200 copies/ml was not predicted by genotype. Among 272 Caucasian patients, viral suppression failure was more common among patients with the CCR5 +/+ ¿ CCR2+/+ ¿ CCR5-59029 A/A genotype (28%) than among all other subjects combined (relative risk, 2.0; P = 0.06). After 24 weeks of therapy, genotype groups differed in the reduction of the HIV RNA level from baseline (P = 0.02); patients with the CCR5 +/+ ¿ CCR2+/+ ¿ CCR5-59029 A/A genotype had a mean reduction of 2.12 log10 copies/ml compared to 2.64 log10 copies/ml among all other groups combined.Polymorphisms in chemokine receptor genes may explain some of the heterogeneity in sustaining viral suppression observed among patients receiving potent antiretroviral therapy.

    View details for Web of Science ID 000086969100008

    View details for PubMedID 10839590

  • Clinical evolution, and morbidity and mortality of primary Sjogren's syndrome SEMINARS IN ARTHRITIS AND RHEUMATISM Skopouli, F. N., Dafni, U., Ioannidis, J. P., Moutsopoulos, H. M. 2000; 29 (5): 296-304

    Abstract

    To study the clinical and laboratory profile evolution, as well as morbidity and mortality impact, of primary Sjögren's syndrome (pSS), in a large cohort of patients followed-up longitudinally.We studied the evolution of the clinical picture and laboratory profile of pSS, the incidence and predictors for systemic sequelae, and the impact of pSS on overall survival in a prospective cohort study of 261 patients with pSS. Analyses included calculation of incidence rates, Cox proportional hazards predictive models, and estimation of standardized mortality ratios (SMRs) compared with the general Greek population, adjusting for age and sex.Glandular manifestations of the syndrome were typically present at the time of diagnosis. Systemic manifestations such as arthritis, Raynaud's phenomenon, purpura, interstitial nephritis, and liver involvement, as well as the serological profile, also did not change substantially during subsequent follow-up. Incidence rates for peripheral neuropathy, glomerulonephritis, and lymphoproliferative disorders were 3.3, 6.6, and 12.2 per 1,000 person-years, respectively. Glomerulonephritis and lymphoma tended to co-exist in the same patients (relative risk, 34.0; P < .0001). The development of lymphoproliferative disorders was associated with low levels of C4 complement (relative risk, 7.5; P = .0016), the presence of mixed monoclonal cryoglobulins (relative risk, 7.9; P = .0012), and purpura (relative risk, 3.9; P = .037). Low levels of C4 was the strongest predictor for mortality after adjusting for age (relative risk, 6.5; P =.0041). Patients with pSS had an SMR of 2.07 (95% CI, 1.03 to 3.71). However, when patients with adverse predictors were excluded, the mortality rate was identical to that of the general population (SMR 1.02).The initial presentation of pSS determines subsequent outcome. Purpura, decreased C4 complement levels, and mixed monoclonal cryoglobulinemia are adverse prognostic factors. The overall mortality of patients with pSS compared with the general population is increased only in patients with adverse predictors.

    View details for Web of Science ID 000086608000003

    View details for PubMedID 10805354

  • B-cell epitope mapping of DNA topoisomerase I defines epitopes strongly associated with pulmonary fibrosis in systemic sclerosis AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Rizou, C., Ioannidis, J. P., Panou-Pomonis, E., Sakarellos-Daitsiotis, M., Sakarellos, C., Moutsopoulos, H. M., Vlachoyiannopoulos, P. G. 2000; 22 (3): 344-351

    Abstract

    We hypothesized that B-cell epitope mapping of DNA Topoisomerase I (type-I topoisomerase, or Topo I) may define epitopes strongly associated with pulmonary interstitial fibrosis (PIF) in systemic sclerosis (SSc). B-cell epitope mapping of Topo I was performed using 63 20-mer peptides overlapping by eight residues and spanning the entire length of the Topo I sequence. These peptides, coupled to polystyrene pins, were tested for antibody binding by enzyme-linked immunosorbent assays (ELISAs) using immunoglobulin G fractions from anti-Topo I, anticentromere, anti-U3RNP-positive, and normal sera. Four major epitopes were recognized by anti-Topo I sera, but not from the control sera: WWEEERYPEGIKWKFLEHKG (205-224, epitope I), RIANFKIEPPGLFRGRGNHP (349-368, epitope II), PGHKWKEVRHDNKVTWLVSW (397-416, epitope III), and ELDGQEYVVEFDFLGKDSIR (517-536, epitope IV). Peptide-epitopes were then synthesized in their soluble forms and ELISA systems were developed. Epitopes II to IV are localized at highly exposed sites of the Topo I tertiary structure, whereas epitope I is localized at a less accessible site. In a cohort of 81 patients with SSc with clinical data on the evolution of their disease, patients with antibodies in their sera recognizing at least three of the four epitopes had 3.1 times (P = 0.02) the hazard of developing PIF compared with patients whose sera recognized no epitopes or only one or two of the four epitopes. The discrimination was much stronger than that achieved by the simple determination of Topo I antibodies by counterimmunoelectrophoresis and immunoblot (hazard ratio 1.7, P = 0.30) in the same patients. B-cell epitope mapping of the anti-Topo I response has identified four major epitopes which cumulatively show a strong association with the development of PIF in SSc.

    View details for Web of Science ID 000086065000012

    View details for PubMedID 10696071

  • Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin ANNALS OF THE RHEUMATIC DISEASES Voulgarelis, M., Kokori, S. I., Ioannidis, J. P., Tzioufas, A. G., Kyriaki, D., Moutsopoulos, H. M. 2000; 59 (3): 217-222

    Abstract

    To study the prevalence of different causes of anaemia in patients with systemic lupus erythematosus (SLE) and their associations with immunological and clinical parameters and to evaluate the contribution of erythropoietin (Epo) and anti-erythropoietin (anti-Epo) autoantibodies to the development of SLE anaemia.132 SLE patients with anaemia (defined as haemoglobin of 12 g/dl or less for women and 13.5 g/dl or less for men) from among a total of 345 consecutive SLE patients were prospectively enrolled into the study. Standard haematological and immunological tests were performed and serum Epo and anti-Epo antibodies were assayed.The identified causes were anaemia of chronic disease (ACD) n=49 (37.1%), iron deficiency anaemia (IDA) n = 47 (35.6%), autoimmune haemolytic anaemia (AHA) n = 19 (14.4%) and other causes n = 17 (12.9%). There was significant heterogeneity in the severity of anaemia between the four groups (p<0.01) with AHA cases being on average more severe. The proportion of patients with anticardiolipin antibodies, low complement levels and anti-dsDNA differed significantly among the four groups; these markers were particularly common in patients with AHA, and uncommon in patients with IDA. Twenty one of 100 tested patients had anti-Epo antibodies. Such antibodies were seen practically only in patients with ACD (odds ratio 3.1, p = 0.041) and in patients with high lupus activity (ECLAM) scores (odds ratio 1.27 per point, p = 0.055). Epo response was inadequate in 42.4% and 41.2% of patients with ACD and AHA, respectively.Anaemia in SLE usually takes the form of ACD and IDA, however autoimmune haemolysis is not uncommon. SLE patients with different causes of anaemia differ in regard to several immunological parameters. Epo response is blunted in anaemic SLE patients, particularly those with ACD and AHA.

    View details for Web of Science ID 000085777200011

    View details for PubMedID 10700431

  • Risk factors for central nervous system involvement in systemic lupus erythematosus QJM-AN INTERNATIONAL JOURNAL OF MEDICINE Karassa, F. B., Ioannidis, J. P., Touloumi, G., Boki, K. A., Moutsopoulos, H. M. 2000; 93 (3): 169-174

    Abstract

    We investigated risk factors for central nervous system (CNS) involvement in systemic lupus erythematosus (SLE), in 32 such patients individually matched 1 : 3 to 96 control SLE patients without CNS events. Univariate analysis showed that CNS involvement was significantly associated with the antiphospholipid syndrome (APS) as well as its features: arterial thrombosis, recurrent fetal loss, livedo reticularis and IgG anticardiolipin (aCL) antibodies in high titres. Other potential associations included cutaneous vasculitic lesions, thrombocytopenia, positive ANA, anti-SS-B/La and low serum levels of C(3) and C(4) complement components, while articular manifestations and discoid rash were significantly less common in patients with neuropsychiatric (NP) disease. In multivariate modeling, CNS involvement was strongly associated with cutaneous vasculitic lesions OR 33, 95% CI 1.5-720) and arterial thromboses (OR 13, 95%CI 0.82-220), and negatively related to the presence of articular manifestations (OR 0.015, 95%CI 0.00-0.17) and discoid rash (OR 0.004, 95%CI 0.00-0.35). Associations with APS-related arterial thromboses and vasculitis point to the importance of arterial vascular pathophysiology in the pathogenesis of NP disease in SLE. Patients with articular manifestations and discoid rash are at very low risk of NP events. Patients with an adverse SLE disease profile may require closer observation and may be the target group for studying pre-emptive interventions.

    View details for Web of Science ID 000085753400006

    View details for PubMedID 10751236

  • Autoimmune hemolytic anemia in patients with systemic lupus erythematosus AMERICAN JOURNAL OF MEDICINE Kokori, S. I., Ioannidis, J. P., Voulgarelis, M., Tzioufas, A. G., Moutsopoulos, H. M. 2000; 108 (3): 198-204

    Abstract

    We sought to evaluate the clinical and serologic associations with, and outcomes of, autoimmune hemolytic anemia, as compared with other types of anemia, in patients with systemic lupus erythematosus (SLE).We studied 41 consecutive patients with SLE with clinically manifest autoimmune hemolytic anemia, including 27 (66%) in whom hemolysis was the initial disease manifestation. We matched each patient for age and disease duration with a patient with SLE with anemia resulting from a different cause.The 41 patients had a total of 50 episodes of autoimmune hemolytic anemia. The recurrence rate was 4 per 100 person-years. Cases and controls had similar mean (+/- SD) lupus activity indexes (2.1 +/- 1.5 vs 2.4 +/- 1.3, P = 0.5). Patients with autoimmune hemolytic anemia at any time could be distinguished from patients with other causes of anemia, because they were more likely to have elevated titers of IgG anticardiolipin antibodies [odds ratio (OR) = 5.8; 95% confidence interval (CI), 1.4 to 24] and thrombosis (OR = 4.6; 95% CI, 1.0 to 21). Autoimmune hemolytic anemia at the onset of SLE was independently associated with renal involvement (OR = 5.4; 95% CI, 1.0 to 28), thrombocytopenia (OR = 7.3; 95% CI, 1.1 to 48), and possibly thrombotic episodes during follow-up (OR = 11; 95% CI, 0.8 to 160) when compared with controls with other types of anemia at the onset of SLE.Autoimmune hemolytic anemia usually occurs at the onset of SLE, and its recurrence rate is low among treated patients. The association with IgG anticardiolipin antibodies and thrombosis suggests that the occurrence of autoimmune hemolytic anemia may define a subgroup of patients with SLE who have characteristic serologic and clinical manifestations.

    View details for Web of Science ID 000085334500003

    View details for PubMedID 10723973

  • NF-kappa B modulates TNF-alpha production by alveolar macrophages in asymptomatic HIV-seropositive individuals JOURNAL OF IMMUNOLOGY Mathys, J. M., Melanson, S. M., Schiffer-Alberts, D. J., Ioannidis, J. P., Koziel, H., Skolnik, P. R. 2000; 164 (3): 1588-1594

    Abstract

    Local TNF-alpha production in different organs may affect HIV replication and pathogenesis. Alveolar macrophages (AMs) obtained by bronchoalveolar lavage from asymptomatic HIV-seropositive and HIV-seronegative individuals did not spontaneously release TNF-alpha, but LPS stimulation of these cells significantly increased TNF-alpha production. We tested whether NF-kappa B affects TNF-alpha production by AMs using N-tosyl-l -phenylalanine chloromethylketone (TPCK) or N-benzoyl-l -tyrosine ethyl ester (BTEE), which inhibit the degradation of I kappa B, or tricyclodecan-9-yl-xanthogenate-potassium (D609), which inhibits phospholipase C. Alveolar macrophages were exposed to LPS alone and with the chemical protease inhibitors TPCK, BTEE, and D609. NF-kappa B DNA binding induced by LPS treatment of AMs was inhibited by TPCK, BTEE, and D609. These agents also inhibited TNF-alpha mRNA and TNF-alpha protein production. After 24 h, the levels of TNF-alpha mRNA reached equilibrium, as assessed by RT-PCR. The levels of NF-kappa B mRNA remained constant under all conditions. The levels of I kappa B-alpha mRNA were similar after 30, 60, and 180 min, but the I kappa B-beta mRNA concentration was initially low and increased over time under all conditions. I kappa B-alpha and I kappa B-beta protein production was not affected by the chemical protease inhibitors. Our data show that TNF-alpha production by LPS-stimulated AMs from asymptomatic HIV-seropositive and -seronegative individuals is regulated via the phospholipase C pathway and by NF-kappa B DNA binding activity without obvious changes in I kappa B-alpha or I kappa B-beta protein concentrations.

    View details for Web of Science ID 000084910300057

    View details for PubMedID 10640779

  • Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide KIDNEY INTERNATIONAL Ioannidis, J. P., Boki, K. A., Katsorida, M. E., Drosos, A. A., Skopouli, F. N., Boletis, J. N., Moutsopoulos, H. M. 2000; 57 (1): 258-264

    Abstract

    Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide.Long-term intravenous cyclophosphamide (IVC) in combination with corticosteroids is standard therapy for proliferative lupus nephritis, but it has limitations. There are few data on long-term remission rates, predictors of relapse, and the ability to achieve a second remission with currently recommended IVC regimens.A cohort of 85 patients with proliferative lupus glomerulonephritis (focal N = 33, diffuse N = 52) treated with IVC was assembled in three institutions. Timing and predictors of remission, relapse, and re-remission were evaluated with Kaplan-Meier analyses and Cox models.The median time to remission was 10 months, whereas an estimated 22% of patients had not remitted after 2 years. The median time to relapse among 63 patients who had achieved remission was 79 months. In multivariate models, adverse predictors of remission were a delay in the initiation of therapy from the time nephritis was clinically diagnosed [hazard ratio (HR) 0.58, P = 0. 063] and a higher amount of proteinuria (HR 0.86 per 1 g/24 hours, P = 0.014). Predictors of earlier relapse for patients entering remission included a longer time to remission (HR 1.029 per month, P = 0.025), a history of central nervous system involvement (HR 8.41, P = 0.002), and World Health Organization histology (P = 0.01). Among the 23 patients who relapsed during follow-up, the median time to re-remission was 32 months, and with three exceptions, all patients took substantially longer time to remit the second time compared with their first remission (P = 0.01). The time to re-remission was longer in patients who had taken longer to remit the first time (HR 0.979 per month, P = 0.16), in patients who had relapsed earlier after the first remission (HR 1.071 per month, P = 0.002), and in those with evidence of chronicity in the original kidney biopsy (P = 0.015).Prolonged courses with a cumulative risk of toxicity are needed to achieve remission in many first-treated patients and in most patients treated for a second time. The optimal management of patients with identified adverse predictors of response needs further study.

    View details for Web of Science ID 000084868200027

    View details for PubMedID 10620207

  • HLA associations of anti-beta2 glycoprotein I response in a Greek cohort with antiphospholipid syndrome and meta-analysis of four ethnic groups HUMAN IMMUNOLOGY Ioannidis, J. P., Tektonidou, M. G., Vlachoyiannopoulos, P. G., Stavropoulos-Giokas, C., Spyropoulou-Vlachou, M., Reveille, J. D., Arnett, F. C., Moutsopoulos, H. M. 1999; 60 (12): 1274-1280

    Abstract

    Using molecular typing, we evaluated the strength of class II HLA associations in 67 Greek patients with antiphospholipid syndrome (APS), 54 of whom had antibodies against beta2-glycoprotein I (beta2GPI), as compared to 246 controls. To further clarify and delineate HLA associations of the beta2GPI response, we combined these data with individual patient data from three other ethnic groups including an additional 74 patients with beta2GPI response and 403 ethnically matched controls of white, African-American, and Mexican-American origin in a formal meta-analysis. The major alleles associated with anti-beta2GPI response are HLA-DQA1*03 (in particular *0301) and the HLA-DRB1*1302-DQB1*0604 haplotype, while protection against developing an anti-beta2GPI response is related primarily to the HLA-DRB1*0101-DQA1*0101 haplotype and the HLA-DRB1*1101 allele. These effects are not significantly heterogeneous across ethnic groups. The previously observed association with HLA-DQB1*0302 may simply reflect linkage disequilibrium with HLA-DQA1*0301 and the previously reported HLA-DQB1*06 effect is limited to HLA-DQB1*0604/0605, while HLA-DQB1*0602 is unlikely to be important. The meta-analysis clearly documents that the anti-beta2GPI response is determined by a few specific class II alleles and haplotypes.

    View details for Web of Science ID 000084355100011

    View details for PubMedID 10626742

  • Circulating autoantibodies to erythropoietin are associated with human immunodeficiency virus type 1-related anemia JOURNAL OF INFECTIOUS DISEASES Sipsas, N. V., Kokori, S. I., Ioannidis, J. P., Kyriaki, D., Tzioufas, A. G., Kordossis, T. 1999; 180 (6): 2044-2047

    Abstract

    In a cohort of 204 unselected consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients, the association of circulating autoantibodies to endogenous erythropoietin (EPO) with HIV-1-related anemia was studied. Circulating autoantibodies to EPO were present in 48 (23.5%) of the 204 patients studied. Circulating autoantibodies were an independent predictor of anemia (odds ratio [OR]=5.0; 95% confidence interval [CI], 2.5-9.9), as strong as other known causes of anemia. The association of anti-EPO antibodies with anemia became stronger when the analysis was limited to the group of patients without any medical condition causing anemia (OR=10.4; 95% CI, 3.2-33.9). Moreover, the effect on hemoglobin levels remained significant even after adjusting for other anemia parameters. Anti-EPO autoantibodies were associated with higher EPO levels (r=.25, P=.012) and with a more prominent EPO response to anemia. Our findings suggest that autoimmunity, among other factors, may contribute to the pathogenesis of HIV-1-related anemia.

    View details for Web of Science ID 000084137600040

    View details for PubMedID 10558967

  • Recurrent pregnancy loss and autoantibody profile in autoimmune diseases RHEUMATOLOGY Mavragani, C. P., Ioannidis, J. P., Tzioufas, A. G., Hantoumi, I. E., Moutsopoulos, H. M. 1999; 38 (12): 1228-1233

    Abstract

    To explore the association of non-organ-specific autoimmune responses against three distinct Ro antigen-related reactivities (Ro52, Ro60, p57) with a history of pregnancy loss in women with autoimmune disorders. Materials and methods. Seventy unselected anti-Ro/SSA-positive women were studied in a retrospective cohort study. Forty anti-Ro/SSA-positive women were age matched to an equal number of women with autoimmune disorders who were anti-Ro/SSA negative in a case-control study. The association of reactivities against three distinct antigen specificities (Ro52, Ro60, p57) with recurrent pregnancy loss was investigated. Independence and modification of these associations from the effect of antithyroglobulin, antithyroid peroxidase and anticardiolipin antibodies were also examined.In the cohort study, reactivity against each of the three antigen specificities (Ro52, Ro60, p57) was independently associated with a history of recurrent pregnancy loss. In the case-control study, the effects were still independent and were not modified when other autoantibodies were considered. In particular, the number of reactivities against Ro52, Ro60 and p57 peptides, and the presence of antithyroglobulin antibodies, were independent predictors of recurrent pregnancy loss (odds ratios 3.35 per each additional reactivity and 5.54 in the presence of antithyroglobulin; P=0.002 and 0.025, respectively).In women with autoimmune disorders, a history of recurrent pregnancy loss is independently associated with reactivity against each of the three antigen specificities (Ro52, Ro60, p57) and also with the presence of antithyroglobulin antibodies, suggesting that cumulative autoimmune responses against these non-organ-specific and organ-specific antigens correlate with the risk of stillbirth and spontaneous abortion.

    View details for Web of Science ID 000084421800011

    View details for PubMedID 10587550

  • Maternal viral load and the risk of perinatal transmission of HIV-1 NEW ENGLAND JOURNAL OF MEDICINE Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 1999; 341 (22): 1698-1699

    View details for Web of Science ID 000083847500017

    View details for PubMedID 10610439

  • State of the evidence: Current status and prospects of meta-analysis in infectious diseases CLINICAL INFECTIOUS DISEASES Ioannidis, J. P., Lau, J. 1999; 29 (5): 1178-1185

    Abstract

    Meta-analysis is increasingly applied in infectious diseases to summarize clinical data and to evaluate the strength, diversity, and deficiencies of evidence for medical questions of interest. We present an overview of the current status of meta-analysis in the area of infectious diseases and the lessons learnt from its applications. Recently published meta-analyses show that several important areas of research on infectious diseases lack sufficient randomized evidence. Often evidence is scattered across a large number of small trials, making meta-analysis a promising way to integrate diverse results. Quality of trials in the field is often poor. There are several examples where evidence was accumulated primarily for marketing rather than for scientific purposes. Finally, meta-analyses are also raising the problem of what constitutes clinically significant treatment benefits, as well as interesting issues about the reproducibility of clinical evidence and its evolving nature. The increasing applications of meta-analytic methods in the study of infectious diseases may enhance data sharing and international collaborations.

    View details for Web of Science ID 000083512600011

    View details for PubMedID 10524960

  • Pooling research results: benefits and limitations of meta-analysis. Joint Commission journal on quality improvement Ioannidis, J. P., Lau, J. 1999; 25 (9): 462-469

    Abstract

    Meta-analysis, the systematic and quantitative synthesis of evidence, has developed considerably in the 1990s and is emerging as an important methodology in medical decision making. As a research methodology, meta-analysis has benefits and limitations that must be acknowledged in its application. EXAMPLES OF BENEFITS: The benefits of meta-analysis include the ability to improve the power of small or inconclusive studies to answer questions and the ability to identify sources of diversity across various types of studies. Meta-analysis may reveal how heterogeneity among populations affects the effectiveness of medical interventions in different settings and in different patients. It can also help detect biases, such as publication bias and "Tower of Babel" bias, as well as deficiencies in the design, conduct, analysis, and interpretation of research. In this way, it can also stimulate improvements in the quality of the data needed to optimize medical care. EXAMPLES OF LIMITATIONS: Meta-analysis cannot improve the quality or reporting of the original studies. Other limitations come from misapplications of the method, such as when study diversity is ignored or mishandled in the analysis or when the variability of patient populations, the quality of the data, and the potential for underlying biases are not addressed.Meta-analysis has promoted the sense that obtaining evidence is a global enterprise and that complete information needs to be evaluated and synthesized to obtain the most unbiased results. Analyzing sources of bias and diversity is essential to performing, understanding, and using meta-analyses in medical care.

    View details for PubMedID 10481815

  • Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis LANCET Boletis, J. N., Ioannidis, J. P., Boki, K. A., Moutsopoulos, H. M. 1999; 354 (9178): 569-570

    Abstract

    Among 14 randomised patients with proliferative lupus nephritis, monthly intravenous immunoglobulin maintained remission over 18 months, similar to standard intravenous cyclophosphamide treatment. Pulsed immunoglobulin may be a useful alternative therapy in lupus nephritis.

    View details for Web of Science ID 000081991000021

    View details for PubMedID 10470708

  • Predictors and impact of losses to follow-up in an HIV-1 perinatal transmission cohort in Malawi INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Taha, T. E., Kumwenda, N., Broadhead, R., Mtimavalye, L., Miotti, P., Yellin, F., Contopoulos-Ioannidis, D. G., Biggar, R. J. 1999; 28 (4): 769-775

    Abstract

    Large simple trials which aim to study therapeutic interventions and epidemiological associations of human immunodeficiency virus (HIV) infection, including perinatal transmission, in Africa may have substantial rates of loss to follow-up. A better understanding of the characteristics and the impact of women and children lost to follow-up is needed.We studied predictors and the impact of losses to follow-up of infants born in a large cohort of delivering women in urban Malawi. The cohort was established as part of a trial of vaginal cleansing with chlorhexidine during delivery to prevent mother-to-infant transmission of HIV.The HIV infection status could not be determined for 797 (36.9%) of 2156 infants born to HIV-infected mothers; 144 (6.7%) with missing status because of various sample problems and 653 (30.3%) because they never returned to the clinic. Notably, the observed rates of perinatal transmission were significantly lower in infants who returned later for determination of their infection status (odds ratio = 0.94 per month, P = 0.03), even though these infants must have had an additional risk of infection from breastfeeding. In multivariate models, infants of lower birthweight (P = 0.003) and, marginally, singletons (P = 0.09) were less likely to return for follow-up. The parents of infants lost to follow-up tended to be less educated (P < 0.001) and more likely to be in farming occupations, although one educated group, teachers and students, were also significantly less likely to return. Of these variables, infant birthweight, twins versus singletons, and maternal education were also associated with significant variation in the observed risk of perinatal transmission among infants of known HIV status.Several predictors of loss to follow-up were identified in this large HIV perinatal cohort. Losses to follow-up can impact the observed transmission rate and the risk associations in different studies.

    View details for Web of Science ID 000082344000026

    View details for PubMedID 10480709

  • Sjogren's syndrome: Too many associations, too limited evidence. The enigmatic example of CNS involvement SEMINARS IN ARTHRITIS AND RHEUMATISM Ioannidis, J. P., Moutsopoulos, H. M. 1999; 29 (1): 1-3

    View details for Web of Science ID 000082047600001

    View details for PubMedID 10468409

  • Antibiotics for acute sinusitis in general practice - Entry criteria were too dissimilar for studies to be combined for meta-analysis - Reply BRITISH MEDICAL JOURNAL Ioannidis, J. P., De Ferranti, S. D., Barza, M., Lau, J. 1999; 318 (7198): 1624-1624

    View details for Web of Science ID 000080913100056

  • Relationship between event rates and treatment effects in clinical site differences within multicenter trials: An example from primary Pneumocystis carinii prophylaxis CONTROLLED CLINICAL TRIALS Ioannidis, J. P., Dixon, D. O., McIntosh, M., Albert, J. M., Bozzette, S. A., Schnittman, S. M. 1999; 20 (3): 253-266

    Abstract

    The results of multicenter clinical trials may differ across participating clinical sites. We present a diagnostic approach for evaluating this diversity that emphasizes the relationship between the observed event rates and treatment effects. We use as an example a trial of sequential strategies of Pneumocystis prophylaxis in human immunodeficiency virus infection with 842 patients randomly allocated to start prophylaxis with trimethoprim/sulfamethoxazole, dapsone, or pentamidine. Prophylaxis failure rates varied significantly across the 30 clinical sites (0-30.3%, p = 0.002 by Fisher's exact test) with prominent variability in the pentamidine arm (0-63.6%). Starting with oral regimens was better than starting with pentamidine in sites with high rates of events, whereas the three strategies had more similar efficacy in other sites. Sites enrolling fewer patients had lower event rates and had more patients who withdrew prematurely or were lost to follow-up. In a hierarchical regression model adjusting for random measurement error in the observed event rates, starting with trimethoprim/sulfamethoxazole was predicted to be increasingly better than starting with aerosolized pentamidine as the risk of prophylaxis failure increased (p = 0.01), reducing the risk of failure by 47% when the failure rate of pentamidine was 30%, whereas the two regimens were predicted to be equivalent when the failure rate was 17%. Differences in event rates could reflect a combination of heterogeneity in diagnosis, administration of treatments, and disease risk in patients across sites. The evaluation of clinical site differences with a systematic approach focusing on event rates may give further insight in the interpretation of the results of multicenter trials beyond an average treatment effect.

    View details for Web of Science ID 000080455200004

    View details for PubMedID 10357498

  • Recursive cumulative meta-analysis: A diagnostic for the evolution of total randomized evidence from group and individual patient data JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Contopoulos-Ioannidis, D. G., Lau, J. 1999; 52 (4): 281-291

    Abstract

    Meta-analyses of randomized evidence may include published, unpublished, and updated data in an ongoing estimation process that continuously accommodates more data. Synthesis may be performed either with group data or with meta-analysis of individual patient data (MIPD). Although MIPD with updated data is considered the gold standard of evidence, there is a need for a careful study of the impact different sources of data have on a meta-analysis and of the change in the treatment effect estimates over sequential information steps. Unpublished data and late-appearing data may be different from early-appearing data. Updated information after the end of the main study follow-up may be affected by cross-overs, missing information, and unblinding. The estimated treatment effect may thus depend on the completeness and updating of the available evidence. To address these issues, we present recursive cumulative meta-analysis (RCM) as an extension of cumulative metaanalysis. Recursive cumulative meta-analysis is based on the principle of recalculating the results of a cumulative meta-analysis with each new or updated piece of information and focuses on the evolution of the treatment effect as a more complete and updated picture of the evidence becomes available. An examination of the perturbations of the cumulative treatment effect over sequential information steps may signal the presence of bias or heterogeneity in a meta-analysis. Recursive cumulative meta-analysis may suggest whether there is a true underlying treatment effect to which the meta-analysis is converging and how treatment effects are sequentially altered by new or modified evidence. The method is illustrated with an example from the conduct of an MIPD on acyclovir in human immunodeficiency virus infection. The relative strengths and limitations of both metaanalysis of group data and MIPD are discussed through the RCM perspective.

    View details for Web of Science ID 000080058300002

    View details for PubMedID 10235168

  • Comparison of viral load and human leukocyte antigen statistical and neural network predictive models for the rate of HIV-1 disease progression across two cohorts of homosexual men 5th Conference on Retroviruses and Opportunistic Infections Ioannidis, J. P., Goedert, J. J., McQueen, P. G., Enger, C., Kaslow, R. A. LIPPINCOTT WILLIAMS & WILKINS. 1999: 129–36

    Abstract

    We compared the performance of HIV-1 RNA and models based on human leukocyte antigen (HLA) in predicting the rate of HIV-1 disease progression using both linear regression and neural network models across two different cohorts of homosexual men. In all, 139 seroconverters from the Multicenter AIDS Cohort Study were used as the training set and 97 seroconverters from the District of Columbia Gay (DCG) cohort were used for validation to assess the generalizability of trained predictive models. Both viral load and HLA markers were strongly predictive of disease progression (p < .0001 and p = .001, respectively), with viral load superior to HLA (change in -2 log likelihood [-2LL] 26.7 and 10.2, respectively, in proportional hazards models). Consideration of both HLA markers and viral load offered no significant predictive advantage over viral load alone in most cases; however, HLA-based predictions obtained from neural networks modeling improved the discrimination among patients with high viral load (p = .02). Viral load, HLA scores, and rapid disease progression were moderately correlated (p < .01 for all three pairs of these variables). The median viral load was 10(3.70) copies/ml among DCG patients who had more favorable than unfavorable HLA markers and 10(4.66) copies/ml among patients with more unfavorable than favorable HLA markers. Viral load is a simpler, stronger predictor of disease progression than early developed HLA models, but neural network methods and further refined HLA models may offer additional prognostic information, especially for rapid progressors. The correlation between viral load and HLA markers suggests a possible HLA effect on setting viral load levels.

    View details for Web of Science ID 000078390800004

    View details for PubMedID 10048899

  • Evaluation of guidelines for initiation of highly active antiretroviral therapy in a longitudinal cohort of HIV-infected individuals AIDS Ioannidis, J. P., O'Brien, T. R., Goedert, J. J. 1998; 12 (18): 2417-2423

    Abstract

    Expert panels have developed several guidelines for initiating highly active antiretroviral therapy (HAART) in patients with HIV infection. To evaluate these guidelines, we simulated their application in a cohort of HIV-infected patients established and followed before HAART was available, and determined how long such patients survived without disease progression in the absence of HAART.Longitudinal data was used that had been collected from 1982 to 1995 on a prospective cohort of 133 homosexual men with known or closely approximated dates of HIV-1 seroconversion and negligible antiretroviral exposure. The main definition of disease progression was CD4 cell count < or = 300x10(6)/l or development of clinical AIDS diagnosis within 12 months.The mean number of years between the recommended initiation of therapy and when disease progression occurred in the absence of HAART were as follows: initiation of treatment at first visit, 4.81 years [median, 3.78 years; interquartile range (IQR), 1.85-6.59 years]; CD4 cell count <500x10(6)/l or serum RNA >5000 copies/ml (at least 10000 copies/ml fresh plasma), 4.35 years (median, 3.22 years; IQR, 1.56-6.19 years); CD4 cells <500x10(6)/l or serum RNA >20000 copies/ml (at least 40000 copies/ml fresh plasma), 3.61 years (median, 2.70 years; IQR, 1.40-5.11 years); and CD4 cells <500x10(6)/l, 2.72 years (median, 2.17 years; IQR, 0.81-4.25 years). The percentage of patients who had disease progression before HAART would have been recommended was 0.8, 1.6, 3.2 and 13.6% with each of these four approaches, respectively.Implementation of recommended treatment guidelines will result in a substantial proportion of patients being treated for long periods before immunologic or clinical disease progression would have occurred in the absence of HAART. These findings should be considered in the clinical care of HIV-infected patients and in future recommendations for the initiation of HAART.

    View details for Web of Science ID 000077550000010

    View details for PubMedID 9875579

  • Heterogeneity of the baseline risk within patient populations of clinical trials - A proposed evaluation algorithm AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Lau, J. 1998; 148 (11): 1117-1126

    Abstract

    In this paper, the authors present an evaluation algorithm for systematic assessment of the observed heterogeneity in disease risk within trial populations. Predictive models are used to estimate the predicted patient hazards, the odds of having an event in the upper risk quartile (ODU) and the lower risk quartile (ODL), and the odds ratio (rate ratio for time-to-event analyses) for having an event in the upper risk quartile versus the lower risk quartile (extreme quartile odds ratio (EQuOR) and extreme quartile rate ratio (EQuRR)). The ranges for these metrics depend on the extent to which predictors of the outcome of interest exist and are known and the extent to which data are collected in the trial, as well as on the eligibility criteria and the specific patients who are actually enrolled. ODU, ODL, and EQuOR values are used to systematically interpret the results for patients at different levels of risk, to evaluate generalizability, and to determine the need for subgroup analyses. Individual data for five outcomes from three trials (n = 842, 913, and 1,001, respectively) are used as examples. Observed EQuOR values ranged from 1.5 (very little predicted heterogeneity) to 59 (large heterogeneity). EQuRR values ranged from 2 to 46. ODU values ranged from 0.24 to 3.19 (generally high risk), and ODL values ranged from 0.01 (clinically negligible risk) to 0.16 (clinically meaningful risk). The algorithm may also be used for comparing diverse trials (e.g., in meta-analyses) and used prospectively for designing future trials, as shown in simulations.

    View details for Web of Science ID 000077353900013

    View details for PubMedID 9850135

  • Reporting of safety data from randomised trials LANCET Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 1998; 352 (9142): 1752-1753

    View details for Web of Science ID 000077246500014

    View details for PubMedID 9848355

  • Statistical issues for HIV surrogate endpoints: Point/counterpoint STATISTICS IN MEDICINE Albert, J. M., Ioannidis, J. P., Reichelderfer, P., Conway, B., COOMBS, R. W., Crane, L., DeMasi, R., Dixon, D. O., Flandre, P., Hughes, M. D., Kalish, L. A., Larntz, K., Lin, D. Y., Marschner, I. C., Munoz, A., Murray, J., Neaton, J., Pettinelli, C., Rida, W., Taylor, J. M., Welles, S. L. 1998; 17 (21): 2435-2462

    Abstract

    This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.

    View details for Web of Science ID 000076626000002

    View details for PubMedID 9819838

  • Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy NEW ENGLAND JOURNAL OF MEDICINE Havlir, D. V., Marschner, I. C., Hirsch, M. S., Collier, A. C., Tebas, P., Bassett, R. L., Ioannidis, J. P., Holohan, M. K., Leavitt, R., Boone, G., Richman, D. D. 1998; 339 (18): 1261-1268

    Abstract

    Combination antiretroviral therapy with indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy.HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy.During maintenance treatment, 23 percent of the subjects receiving indinavir and 23 percent of those receiving zidovudine and lamivudine, but only 4 percent of those receiving all three drugs, had loss of viral suppression (P<0.001 for the comparison between triple-drug therapy and the other two maintenance regimens). Subjects with greater increases in CD4 cell counts during induction therapy, higher viral loads at base line (i.e., at the beginning of induction therapy), and slower rates of viral clearance were at greater risk for loss of viral suppression. The presence of zidovudine-resistance mutations in HIV RNA at base line was strongly predictive of the loss of viral suppression in subjects treated with zidovudine and lamivudine.The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavir alone or zidovudine and lamivudine.

    View details for Web of Science ID 000076655300001

    View details for PubMedID 9791141

  • Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis BRITISH MEDICAL JOURNAL De Ferranti, S. D., Ioannidis, J. P., Lau, J., Anninger, W. V., Barza, M. 1998; 317 (7159): 632-637

    Abstract

    To examine whether antibiotics are indicated in treating uncomplicated acute sinusitis and, if so, whether newer and more expensive antibiotics with broad spectra of antimicrobial activity are more effective than amoxycillin or folate inhibitors.Meta-analysis of randomised trials.Outpatient clinics.2717 patients with acute sinusitis or acute exacerbation of chronic sinusitis from 27 trials.Any antibiotic versus placebo; amoxycillin or folate inhibitors versus newer, more expensive antibiotics.Clinical failures and cures.Compared with placebo, antibiotics decreased the incidence of clinical failures by half (risk ratio 0.54 (95% confidence interval 0.37 to 0.79)). Risk of clinical failure among 1553 randomised patients was not meaningfully decreased with more expensive antibiotics as compared with amoxycillin (risk ratio 0.86 (0.62 to 1.19); risk difference 0.9 fewer failures per 100 patients (1.4 more failures to 3.1 fewer failures per 100 patients)). The results were similar for other antibiotics versus folate inhibitors (risk ratio 1.01 (0.52 to 1.97)), but data were sparse (n=410) and of low quality.Amoxycillin and folate inhibitors are essentially as effective as more expensive antibiotics for the initial treatment of uncomplicated acute sinusitis. Small differences in efficacy may exist, but are unlikely to be clinically important.

    View details for Web of Science ID 000075830200021

    View details for PubMedID 9727991

  • Can quality of clinical trials and meta-analyses be quantified? LANCET Ioannidis, J. P., Lau, J. 1998; 352 (9128): 590-591

    View details for Web of Science ID 000075567400002

    View details for PubMedID 9746014

  • Comparing results from meta-analyses vs large trials - Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Cappelleri, J. C., Lau, J. 1998; 280 (6): 518-519

    View details for Web of Science ID 000075244900022

  • Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: A meta-analysis of randomized individual patient data 5th Conference on Retroviruses and Opportunistic Infections Ioannidis, J. P., Collier, A. C., Cooper, D. A., Corey, L., FIDDIAN, A. P., Gazzard, B. G., Griffiths, P. D., Contopoulos-Ioannidis, D. G., Lau, J., Pavia, A. T., Saag, M. S., Spruance, S. L., Youle, M. S. UNIV CHICAGO PRESS. 1998: 349–59

    Abstract

    A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (> or = 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P < .001), higher hemoglobin level (P < .001), and younger age (P < .001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (> or = 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the meta-analysis supports the importance of pathogenetic interactions between herpesviruses and HIV.

    View details for Web of Science ID 000075153000009

    View details for PubMedID 9697714

  • Uncontrolled pearls, controlled evidence, meta-analysis and the individual patient JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Lau, J. 1998; 51 (8): 709-711

    Abstract

    Medicine has been dominated by uncontrolled data, often of unproven validity and insufficient to answer clinically important questions pertaining to individual patients. Controlled clinical trials, when designed and conducted rigorously, offer advantages over uncontrolled data, but they cannot be done for everything and often cater to the interests of sponsors rather than medical knowledge. With such sparse evidence, clinical research is doomed to look at main effects across populations rather than diversity of effects among individuals. By accumulating data from a large number of studies, meta-analysis provides a unique opportunity to address individual- and study-level heterogeneity. Diversity may be due to biases or may be real. Both sources must be scrutinized and meta-analysis may find a prime role in dissecting these components of diversity. Concurrent progress in basic sciences revolutionizing our predictive power for disease outcomes will heighten the importance of considering individual heterogeneity.

    View details for Web of Science ID 000075012700011

    View details for PubMedID 9743320

  • Analysis of life-long strategies to prevent Pneumocystis carinii pneumonia in patients with variable HIV progression rates Meeting of American-Federation-for-Clinical-Research / Society-of-General-Internal-Medicine Wynia, M. K., Ioannidis, J. P., Lau, J. LIPPINCOTT WILLIAMS & WILKINS. 1998: 1317–25

    Abstract

    To compare strategies for life-long prophylaxis of Pneumocystis carinii pneumonia (PCP) in a group of AIDS patients with a wide range of disease progression rates.Markov decision models.Prophylaxis strategies using high and low doses of trimethoprim-sulfamethoxazole (TS), dapsone, and/or aerosolized pentamidine in sequence, were compared. Efficacy and toxicity rates for prophylaxis regimens were taken from a meta-analysis of pertinent randomized controlled trials. Outcomes measured included lifetime episodes of PCP and drug toxicity per 100 patients treated, average life expectancy, and cost.For patients with an expected survival of 3 years after commencement of prophylaxis, the use of standard or low dose TS as the first choice agent was comparable, and both were superior to the other strategies for preventing PCP (between nine and 26 fewer episodes of PCP per 100 patients treated) though they were more toxic (11-44 more episodes of toxicity per 100 patients treated). Life expectancy was similar for all of the treatment strategies. With slower rates of disease progression (expected survival > 3.8 years), as seen with current antiretroviral regimens, the use of low dose TS as the first choice agent dominated the use of standard dose TS; when the expected survival time was 7 years, initial use of low dose TS led to 2.8 fewer episodes of PCP per 100 patients treated, 32 fewer episodes of toxicity per 100 patients treated, and US$1381 per patient lower cost, compared with prophylaxis with standard dose TS.For patients with AIDS and expected survival > 3.8 years, low dose TS is better than standard dose TS as the first choice agent for preventing PCP. As patients with AIDS live longer, the routine use of low dose TS will be more than adequate for patients at risk for PCP.

    View details for Web of Science ID 000074968600013

    View details for PubMedID 9708411

  • Maternal cell-free viremia in the natural history of perinatal HIV-1 transmission - A meta-analysis JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 1998; 18 (2): 126-135

    Abstract

    We performed a meta-analysis of the predictive value of maternal cell-free viral load in vertical HIV-1 transmission, including 9 cohorts with 1115 mother-infant pairs (696 untreated and 419 treated women). The pooled rate of transmission in untreated women was 21.3% (95% confidence interval [CI], 18.3%-24.5%). The rates of transmission for untreated women in the <1000 copies/ml, 1000 to 9999 copies/ml, and > or = 10,000 copies/ml categories were 5% (95% CI, 2%-11%), 15% (95% CI, 11%-20%) and 37% (95% CI, 29%-46% by random effects), respectively. The area under the receiver operating characteristic (ROC) curve in individual studies ranged from 0.67 to 1.00. The predictive performance of RNA differed between cohorts in which different percentages of transmitters had RNA values >10,000 copies/ml. When 95% of transmitters have RNA values >1000 copies/ml, 77% of nontransmitters would also have values above this cutoff. Transmission rates for treated women in the 1000 to 9999 copies/ml category (7%; 95% CI, 4%-11%,) and > or = 10,000 copies/ml category (18%; 95% CI, 12%-27%) were probably lower than those for untreated women, whereas the transmission rate for treated women with <1000 copies/ml was 5% (95% CI, 2%-11 %). Thus, the risk gradient between RNA categories seems attenuated in treated women. Several aspects of the design, analysis, and reporting of research in this area may be improved in the future with attention to selection and observer biases, multivariate adjustment, and technical consistency. Maternal HIV-1 RNA is a modest predictor of transmission for individual mothers, but a strong predictor of the average risk in groups of untreated mothers. Its discriminatory power is better in untreated than in treated populations and is better in cohorts with a high prevalence of elevated viral load values than in cohorts with generally low levels of viremia.

    View details for Web of Science ID 000074168900004

    View details for PubMedID 9637577

  • Genetic effects on HIV disease progression NATURE MEDICINE Ioannidis, J. P., O'Brien, T. R., Rosenberg, P. S., Contopoulos-Ioannidis, D. G., Goedert, J. J. 1998; 4 (5): 536-536

    View details for Web of Science ID 000073399900002

    View details for PubMedID 9585207

  • Issues in comparisons between meta-analyses and large trials JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Cappelleri, J. C., Lau, J. 1998; 279 (14): 1089-1093

    Abstract

    The extent of concordance between meta-analyses and large trials on the same topic has been investigated with different protocols. Inconsistent conclusions created confusion regarding the validity of these major tools of clinical evidence.To evaluate protocols comparing meta-analyses and large trials in order to understand if and why they disagree on the concordance of these 2 clinical research methods.Systematic comparison of protocol designs, study selection, definitions of agreement, analysis methods, and reported discrepancies between large trials and meta-analyses.More discrepancies were claimed when large trials were selected from influential journals (which may prefer trials disagreeing with prior evidence) than from already performed meta-analyses (which may target homogeneous trials) and when both primary and secondary (rather than only primary) end points were considered. Depending on how agreement was defined, kappa coefficients varied from 0.22 (low agreement) to 0.72 (excellent agreement). The correlation of treatment effects between large trials and meta-analyses varied from -0.12 to 0.76, but was more similar (0.50-0.76) when only primary end points were considered. When both the magnitude and uncertainty of treatment effects were considered, large trials disagreed with meta-analyses 10% to 23% of the time. Discrepancies were attributed to different disease risks, variable protocols, quality, and publication bias.Comparisons of large trials with meta-analyses may reach different conclusions depending on how trials and meta-analyses are selected and how end points and agreement are defined. Scrutiny of these 2 major research methods can enhance our appreciation of both for guiding medical practice.

    View details for Web of Science ID 000072875300033

    View details for PubMedID 9546568

  • Use of neural networks to model complex immunogenetic associations of disease: Human leukocyte antigen impact on the progression of human immunodeficiency virus infection AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., McQueen, P. G., Goedert, J. J., Kaslow, R. A. 1998; 147 (5): 464-471

    Abstract

    Complex immunogenetic associations of disease involving a large number of gene products are difficult to evaluate with traditional statistical methods and may require complex modeling. The authors evaluated the performance of feed-forward backpropagation neural networks in predicting rapid progression to acquired immunodeficiency syndrome (AIDS) for patients with human immunodeficiency virus (HIV) infection on the basis of major histocompatibility complex variables. Networks were trained on data from patients from the Multicenter AIDS Cohort Study (n = 139) and then validated on patients from the DC Gay cohort (n = 102). The outcome of interest was rapid disease progression, defined as progression to AIDS in <6 years from seroconversion. Human leukocyte antigen (HLA) variables were selected as network inputs with multivariate regression and a previously described algorithm selecting markers with extreme point estimates for progression risk. Network performance was compared with that of logistic regression. Networks with 15 HLA inputs and a single hidden layer of five nodes achieved a sensitivity of 87.5% and specificity of 95.6% in the training set, vs. 77.0% and 76.9%, respectively, achieved by logistic regression. When validated on the DC Gay cohort, networks averaged a sensitivity of 59.1% and specificity of 74.3%, vs. 53.1% and 61.4%, respectively, for logistic regression. Neural networks offer further support to the notion that HIV disease progression may be dependent on complex interactions between different class I and class II alleles and transporters associated with antigen processing variants. The effect in the current models is of moderate magnitude, and more data as well as other host and pathogen variables may need to be considered to improve the performance of the models. Artificial intelligence methods may complement linear statistical methods for evaluating immunogenetic associations of disease.

    View details for Web of Science ID 000072564200007

    View details for PubMedID 9525533

  • Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 1998; 279 (4): 281-286

    Abstract

    Medical evidence may be biased over time if completion and publication of randomized efficacy trials are delayed when results are not statistically significant.To evaluate whether the time to completion and the time to publication of randomized phase 2 and phase 3 trials are affected by the statistical significance of results and to describe the natural history of such trials.Prospective cohort of randomized efficacy trials conducted by 2 trialist groups from 1986 to 1996.Multicenter trial groups in human immunodeficiency virus infection sponsored by the National Institutes of Health.A total of 109 efficacy trials (total enrollment, 43708 patients).Time from start of enrollment to completion of follow-up and time from completion of follow-up to peer-reviewed publication assessed with survival analysis.The median time from start of enrollment to publication was 5.5 years and was substantially longer for negative trials than for results favoring an experimental arm (6.5 vs 4.3 years, respectively; P<.001; hazard ratio for time to publication for positive vs negative trials, 3.7; 95% confidence interval [CI], 1.8-7.7). This difference was mostly attributable to differences in the time from completion to publication (median, 3.0 vs 1.7 years for negative vs positive trials; P<.001). On average, trials with significant results favoring any arm completed follow-up slightly earlier than trials with nonsignificant results (median, 2.3 vs 2.5 years; P=.045), but long-protracted trials often had low event rates and failed to reach statistical significance, while trials that were terminated early had significant results. Positive trials were submitted for publication significantly more rapidly after completion than were negative trials (median, 1.0 vs 1.6 years; P=.001) and were published more rapidly after submission (median, 0.8 vs 1.1 years; P=.04).Among randomized efficacy trials, there is a time lag in the publication of negative findings that occurs mostly after the completion of the trial follow-up.

    View details for Web of Science ID 000071607000034

    View details for PubMedID 9450711

  • Summing up evidence: one answer is not always enough LANCET Lau, J., Ioannidis, J. P., Schmid, C. H. 1998; 351 (9096): 123-127

    Abstract

    Are meta-analyses the brave new world, or are the critics of such combined analyses right to say that the biases inherent in clinical trials make them uncombinable? Negative trials are often unreported, and hence can be missed by meta-analysts. And how much heterogeneity between trials is acceptable? A recent major criticism is that large randomised trials do not always agree with a prior meta-analysis. Neither individual trials nor meta-analyses, reporting as they do on population effects, tell how to treat the individual patient. Here we take a more rounded approach to meta-analyses, arguing that their strengths outweigh their weaknesses, although the latter must not be brushed aside.

    View details for Web of Science ID 000071591900043

    View details for PubMedID 9439507

  • Meta-analyses and large randomized, controlled trials NEW ENGLAND JOURNAL OF MEDICINE Ioannidis, J. P., Cappelleri, J. C., Lau, J. 1998; 338 (1): 59-59

    View details for Web of Science ID 000071209200012

    View details for PubMedID 9424563

  • Quantitative synthesis in systematic reviews ANNALS OF INTERNAL MEDICINE Lau, J., Ioannidis, J. P., Schmid, C. H. 1997; 127 (9): 820-826

    Abstract

    The final common pathway for most systematic reviews is a statistical summary of the data, or meta-analysis. The complex methods used in meta-analyses should always be complemented by clinical acumen and common sense in designing the protocol of a systematic review, deciding which data can be combined, and determining whether data should be combined. Both continuous and binary data can be pooled. Most meta-analyses summarize data from randomized trials, but other applications, such as the evaluation of diagnostic test performance and observational studies, have also been developed. The statistical methods of meta-analysis aim at evaluating the diversity (heterogeneity) among the results of different studies, exploring and explaining observed heterogeneity, and estimating a common pooled effect with increased precision. Fixed-effects models assume that an intervention has a single true effect, whereas random-effects models assume that an effect may vary across studies. Meta-regression analyses, by using each study rather than each patient as a unit of observation, can help to evaluate the effect of individual variables on the magnitude of an observed effect and thus may sometimes explain why study results differ. It is also important to assess the robustness of conclusions through sensitivity analyses and a formal evaluation of potential sources of bias, including publication bias and the effect of the quality of the studies on the observed effect.

    View details for Web of Science ID A1997YD89800007

    View details for PubMedID 9382404

  • The relationship between study design, results, and reporting of randomized clinical trials of HIV infection CONTROLLED CLINICAL TRIALS Ioannidis, J. P., Cappelleri, J. C., Sacks, H. S., Lau, J. 1997; 18 (5): 431-444

    Abstract

    We examined whether the study design of randomized clinical trials for medications against human immunodeficiency virus (HIV) may affect the results and whether the outcomes of these trials affect reporting and publication. We used a database of 71 published randomized HIV-related drug efficacy trials and considered the following study design factors: endpoint definition and method of analysis, masked design, sample size, and duration of follow-up. Large variation was noted in the methods of analysis for surrogate endpoints. Often statistical significance for a surrogate endpoint was not associated with statistical significance for the clinical endpoint or for survival in the same trial, although disagreements in the direction of the treatment effect for surrogate endpoints and survival within individual trials were uncommon. Open-label design seemed to affect the magnitude of the treatment effect for two treatments. The magnitude of the treatment effect in trials of zidovudine monotherapy was inversely related to their sample size, but this probably reflected the confounding effect of longer duration of follow-up in large trials (with a resulting loss of efficacy) rather than publication bias. There was, however, evidence for potential bias in reporting and publication of HIV-related trials. Meta-analyses of published trials for specific treatments demonstrated a sizable treatment benefit for all the examined medications regardless of whether these medications were officially approved, controversial, or abandoned, raising concerns about either publication bias or unjustifiable rejection of potentially useful medications. Compared with trials published in specialized journals, trials published in journals of wide readership were larger (p = 0.001) and 4.4 times more likely to report "positive" results (p = 0.01). We identified several examples of trials with "negative" results that have remained unpublished for a long time. In conclusion, study design factors may have an impact on the magnitude and significance of the treatment effect in HIV-related trials. Bias in reporting can further affect the information that these studies provide.

    View details for Web of Science ID A1997XY54800004

    View details for PubMedID 9315426

  • Correlation of biochemical response to interferon alfa with histological improvement in hepatitis C: A meta-analysis of diagnostic test characteristics HEPATOLOGY Bonis, P. A., Ioannidis, J. P., Cappelleri, J. C., Kaplan, M. M., Lau, J. 1997; 26 (4): 1035-1044

    Abstract

    The current goal of interferon treatment for chronic hepatitis C is to normalize alanine aminotransferase (ALT) and to eradicate detectable viral RNA. Many patients do not achieve this objective during treatment, and most do not sustain these outcomes after interferon is discontinued. However, biochemical or virological responses to interferon may not reflect accurately the histological consequences of therapy. The aim of this study was to determine the extent to which the biochemical measures reflect the histological outcomes in the treatment of hepatitis C with interferon alfa using a meta-analysis of diagnostic test characteristics. The data sources were English and non-English language studies retrieved from Medline (from 1966 to December 1995). The study selection included studies in which interferon alfa was used for treatment of chronic hepatitis C with liver biopsies performed before and after therapy. Data on histological and biochemical outcomes were extracted independently by two reviewers. Two separate criteria were used for defining histological response. When strict definitions of histological improvement were considered, histology improved in 28% (95% confidence interval [95% CI], 17%-43%) of patients after interferon treatment. The sensitivity and specificity of the ALT for determining histological change were 70% (95% CI, 56%-81%) and 66% (95% CI, 56%-75%), respectively. As many as 17% (95% CI, 9%-30%) of subjects with an abnormal ALT at the end of therapy may have improved histologically after interferon therapy. When less stringent definitions of histological improvement were considered, 62% (95% CI, 51%-72%) improved after therapy. The sensitivity and specificity of the ALT for determining histological change were 55% (95% CI, 44%-65%) and 75% (95% CI, 67%-81%), respectively. As many as 51% (95% CI, 38%-64%) may have improved, despite failure to normalize ALT. A substantial number of patients may improve histologically after interferon therapy. The significance of histological changes observed after interferon therapy must be weighed against the limitations of liver biopsy and the uncertain natural history of hepatitis C. Nevertheless, the ALT does not always reflect liver histology accurately after interferon alfa treatment and may underestimate histological improvement.

    View details for Web of Science ID A1997YA72300036

    View details for PubMedID 9328332

  • The impact of high-risk patients on the results of clinical trials JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Lau, J. 1997; 50 (10): 1089-1098

    Abstract

    The results of clinical trials may not reflect equally the experiences of all their individual participants. By modeling populations where patients have very diverse baseline risks of suffering an event of interest, it can be seen that very sick patients of high risk become the major determinants of how many events occur in the whole population, even though they may represent only a small minority. Human immunodeficiency virus-related trials and trials of magnesium in acute myocardial infarction are analyzed. When the benefit or toxicity from a treatment varies with the baseline risk of each patient, the treatment effect may be markedly different in populations with a different representation of high- and low-risk patients. The results of small clinical trials studying heterogeneous populations with binary outcomes depend on the sampling and outcomes of very few high risk participants. Conversely, mega-trials studying homogeneous populations would miss subgroups or individuals with diverse treatment responses. In both cases, aggregate trial results may be misleading for the care of many individuals.

    View details for Web of Science ID A1997YA67300003

    View details for PubMedID 9368516

  • Predictors and impact of patients lost to follow-up in a long-term randomized trial of immediate versus deferred antiretroviral treatment JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Ioannidis, J. P., Bassett, R., Hughes, M. D., Volberding, P. A., Sacks, H. S., Lau, J. 1997; 16 (1): 22-30

    Abstract

    We studied predictors for losses to follow-up and the impact of such losses in the AIDS Clinical Trials Group 019 protocol, a long-term randomized trial of immediate versus deferred antiretroviral therapy in asymptomatic HIV-1-infected patients with >500 CD4 cells/mm3. The trial was selected because of its key importance in determining guidelines for antiretroviral therapy, and because it had the longest follow-up among all antiretroviral trials and the largest percentage of patients whose vital status was unknown at study end. Younger age, a history of parenteral drug use, and nonwhite race were associated with higher rates of loss to follow-up, but race was not an important predictor after adjusting for clinical site. There was large and statistically significant variability in the rates of losses among different clinical sites (p < 0.001). Patient retention was significantly better in clinical sites that enrolled many participants, with 25% of enrollees lost to follow-up in sites enrolling >100 patients and 44% in sites enrolling <33 patients each. As a group, patients lost to follow-up after the 2nd year had steeper declines of CD4 cell counts, and a significantly larger proportion had reached a CD4 cell count <300/mm3 in the year before being lost, compared with patients remaining in the study. Losses to follow-up probably decreased substantially the observed number of primary endpoints, curtailed the power of the trial to demonstrate any difference between immediate and deferred initiation of antiretroviral therapy, and may have introduced large bias in the estimated hazard ratio for the primary endpoint and its statistical significance.

    View details for Web of Science ID A1997YE56800004

    View details for PubMedID 9377121

  • Large trials vs meta-analysis of smaller trials - Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Cappelleri, J. C., Ioannidis, J. P., Schmid, C. H. 1997; 277 (5): 377-378

    View details for Web of Science ID A1997WE77100025

  • Impact of epidemic and individual heterogeneity on the population distribution of disease progression rates - An example from patient populations in trials of human immunodeficiency virus infection AMERICAN JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Cappelleri, J. C., Schmid, C. H., Lau, J. 1996; 144 (11): 1074-1085

    Abstract

    Patients at the same stage of chronic disease may have had different rates of disease progression. The authors developed a mathematical modeling approach that allows reconstructing and comparing populations in terms of the disease progression rates of their participants when the disease onset and progression rates are unknown for individual patients. Human immunodeficiency virus 1 infection was used as an example. Both published and hypothetical models were used to describe the human immunodeficiency virus 1 epidemic (epidemic heterogeneity) and incubation and survival functions for different disease stages (individual heterogeneity). Reconstructions of populations with late disease (e.g., acquired immunodeficiency syndrome patients) show a marked predominance of rapid progressors, unless the incidence of new infections has been decreasing for a long time. Rapid progressors would also predominate in populations of acute seroconverters, unless diagnosis is based on repeated serologic screening rather than symptoms. Populations of patients who have not progressed beyond an early stage of the disease (e.g., patients with CD4 cell counts > 500/microliter) tend to overrepresent slow progressors, especially if the epidemic has been decreasing for a long time. With this approach, one can assess whether the target population of a clinical trial is comparable with other patient populations at different places and times. Epidemic and individual diversity may even affect trial results if patients with different progression rates experience different benefits from a treatment. By modeling the targeted populations in trials of early versus deferred antiretroviral treatment, the authors observed larger treatment benefits in trials in which rapid progressors probably predominated, compared with trials of slow progressors.

    View details for Web of Science ID A1996VV53500011

    View details for PubMedID 8942440

  • Large trials vs meta-analysis of smaller trials - How do their results compare? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Cappelleri, J. C., Ioannidis, J. P., Schmid, C. H., deFerranti, S. D., Aubert, M., Chalmers, T. C., Lau, J. 1996; 276 (16): 1332-1338

    Abstract

    To evaluate the results of large clinical trials vs the pooled results of smaller trials.Meta-analyses with at least 1 "large" study were identified from the Cochrane Pregnancy and Childbirth Database and from MEDLINE (1966-1995).We used a sample size approach to select 79 meta-analyses with at least 1 large study of 1000 or more patients. We used a statistical power approach to select 61 meta-analyses with at least 1 large study based on statistical power considerations.The outcome of interest for each meta-analysis was the primary one stated in the original publication or, when not clearly specified, was decided on clinically.By random effects calculations, we found agreement between large and smaller trials in 90% of the meta-analyses selected by the sample size approach and in 82% of the meta-analyses selected by the statistical power approach. Twice as many disagreements appeared when the variability among large studies and among smaller studies was not considered (ie, fixed effects calculations). Of the 15 disagreements between results of large and smaller trials using the random effects model, plausible explanations were identified in 10 meta-analyses: 5 with differences in the control rate of events between large and smaller trials, 4 with specific protocol or study differences, and 1 with potential publication bias. Two other disagreements were not clinically important, and tentative reasons could be identified for 2 of the remaining 3 disagreements.Results of smaller studies are usually compatible with the results of large studies, but discrepancies do occur even when the diversity among both large studies and smaller studies is considered. Clinically important differences without a potential explanation are extremely uncommon. Future research should further examine sources of heterogeneity between the results of large and smaller trials.

    View details for Web of Science ID A1996VM82500037

    View details for PubMedID 8861993

  • On meta-analyses of meta-analyses LANCET Ioannidis, J. P., Lau, J. 1996; 348 (9029): 756-756

    View details for Web of Science ID A1996VG37400058

    View details for PubMedID 8806313

  • Single or multiple daily doses of aminoglycosides - Reply BRITISH MEDICAL JOURNAL Barza, M., Ioannidis, J., Lau, J. 1996; 313 (7055): 490-491

    View details for Web of Science ID A1996VE08000036

  • Viral load and response to treatment of HIV NEW ENGLAND JOURNAL OF MEDICINE Ioannidis, J. P., Cappelleri, J. C., Lau, J. 1996; 334 (25): 1671-1671

    View details for Web of Science ID A1996UQ70600019

    View details for PubMedID 8628372

  • Predictive value of viral load measurements in asymptomatic untreated HIV-1 infection a mathematical model AIDS Ioannidis, J. P., Cappelleri, J. C., Lau, J., Sacks, H. S., Skolnik, P. R. 1996; 10 (3): 255-262

    Abstract

    To model the predictive value of viral load measurements in asymptomatic patients with HIV-1 infection, who have CD4 cell counts > 500 x 10(6)/l and no prior antiretroviral therapy, when the time of seroconversion and the prior levels of viremia are unknown.A mathematical model was constructed for the changes in HIV RNA load over time based on data from cohorts of HIV-infected patients followed since the time of seroconversion.For different values of viral load, the time to progression to AIDS or an equivalent state [progression to AIDS equivalent (PAE)] was calculated using a wide range of estimates for the time since seroconversion and the rate of change of the viral load over time.In the absence of antiretroviral treatment, patients with a viral load of 10(5) copies/ml serum are at risk for PAE in less than 3 years (0-3 years) and patients with a viral load half a log higher are at risk in less than 1 year. In contrast, patients with a viral load of 10(4.5) have at least 1.9 years and may have up to 8 years before risk of PAE. Patients with a viral load of 10(4) RNA copies/ml have at least 2.8 years and may have up to 19 years before risk of PAE. The rate of change of the viral load was an important predictor of outcome; the time since seroconversion had only a minor effect.The viral load in the plasma or serum has predictive value even if the time of seroconversion is unknown. The rate of change of viral load over time may also be an important predictive factor. Serial measurements of viral load over time may provide therapeutic guidance.

    View details for Web of Science ID A1996UB18700003

    View details for PubMedID 8882664

  • Single or multiple daily doses of aminoglycosides: A meta-analysis BRITISH MEDICAL JOURNAL Barza, M., Ioannidis, J. P., Cappelleri, J. C., Lau, J. 1996; 312 (7027): 338-344

    Abstract

    To assess relative efficacy and toxicity of aminoglycosides given by single daily dose compared with multiple daily doses.Meta-analysis of 21 randomised trials identified through MEDLARS (1966 to January 1995). Data were overviewed with fixed effects and random effects models and with meta-regression analysis.Total of 3091 patients with bacterial infection, most without pre-existing renal disease.Patients were randomized to receive aminoglycosides once daily or multiple times daily with similar total daily dose.Clinical failure of treatment, nephrotoxicity, ototoxicity, and mortality.Single daily dose regimen produced a non-significant decrease in risk of antibiotic failures (random effects risk ratio 0.83 (95% confidence interval 0.57 to 1.21)). Benefit of once daily dosing was greater when the percentage of pseudomonas isolates in a trial was larger. Once daily administration reduced risk of nephrotoxicity (fixed effects risk ratio 0.74 (0.54 to 1.00)). Similar trends were noted for patients with febrile neutropenia and for children. There was no significant difference in ototoxicity between the two dosing regimens, but the power of the pooled trials to detect a meaningful difference was low. There was no significant difference in mortality.Once daily administration of aminoglycosides in patients without pre-existing renal impairment is as effective as multiple daily dosing, has a lower risk of nephrotoxicity, and no greater risk of ototoxicity. Given the additional convenience and reduced cost, once daily dosing should be the preferred mode of administration.

    View details for Web of Science ID A1996TV69800021

    View details for PubMedID 8611830

  • Zidovudine in patients with HIV infection - Response ANNALS OF INTERNAL MEDICINE Ioannidis, J. P., Lau, J., Sacks, H. S. 1996; 124 (3): 372-373

    View details for Web of Science ID A1996TR59600022

  • A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens ARCHIVES OF INTERNAL MEDICINE Ioannidis, J. P., Capelleri, J. C., Skolnik, P. R., Lau, J., Sacks, H. S. 1996; 156 (2): 177-188

    Abstract

    Finding the optimal strategy for Pneumocystis carinii prophylaxis in patients with human immunodeficiency virus infection can be problematic. Several prophylactic regimens are available, but their relative efficacy and tolerance are not well understood.A meta-analysis overviewed 35 randomized trials comparing different regimens for P carinii prophylaxis directly or with placebo. Analyses were based on intention-to-treat. On-treatment data were also analyzed when available.Regardless of dose, sulfamethoxazole-trimethoprim was almost universally effective for patients who tolerated it. The risk of discontinuing sulfamethoxazole-trimethoprim because of side effects decreased by 43% (95% confidence interval, 30% to 54%) if one double-strength tablet was given three times a week instead of daily. For dapsone, among 100 patients given 100 mg daily instead of twice a week for 1 year (primary prophylaxis), seven fewer patients would develop P carinii pneumonia, but 17 more would have significant toxic reactions. Aerosolized pentamidine was well tolerated regardless of the dose used. Prophylaxis failures might be halved if the dose of aerosolized pentamidine were doubled. Compared with aerosolized pentamidine, oral regimens prevented 73% (95% confidence interval, 57% to 82%) of toxoplasmosis events by on-treatment analysis, but only 33% (95% confidence interval, 12% to 50%) by intention-to-treat. No significant difference in mortality was demonstrated between different regimens.Sulfamethoxazole-trimethoprim is the superior regimen, and low doses could improve tolerance without losing effectiveness for primary prophylaxis. Low doses of dapsone reduce toxic effects, but at the expense of some loss of efficacy. There are few data on the use of low-dose regimens for secondary prophylaxis. High doses of aerosolized pentamidine may improve the efficacy of this regimen. Aerosolized pentamidine is inadequate for prevention of toxoplasmosis, and strategies that improve the tolerance of oral regimens may increase effectiveness in preventing toxoplasmosis.

    View details for Web of Science ID A1996TP95800009

    View details for PubMedID 8546551

  • LONG-TERM PRODUCTIVE HUMAN IMMUNODEFICIENCY VIRUS-1 INFECTION IN HUMAN INFANT MICROGLIA AMERICAN JOURNAL OF PATHOLOGY Ioannidis, J. P., Reichlin, S., Skolnik, P. R. 1995; 147 (5): 1200-1206

    Abstract

    The course of human immunodeficiency virus 1 (HIV-1) infection in human infant microglia was studied using purified primary cultures of microglia derived from brain autopsy tissue. Previous in vitro studies have used fetal or adult brain tissue. Important differences may exist between brain tissues of different maturational ages with regard to HIV-1 replication and other neuropathogenic effects. Infant microglia were infected with four different strains of HIV-1 (JR-FL, JR-CSF, Ba-L, and IIIB). Productive infection was demonstrated by p24 antigen production, immunocytochemistry, and recovery of replication-competent virus from the supernatants of the infected cultures. Multinucleated giant cells developed in culture mimicking the neuropathological changes seen in the brains of patients with HIV encephalopathy. Productive infection was more readily established by monocyte-tropic strains (JR-FL and Ba-L) of HIV-1 than by a lymphocyte-tropic strain (IIIB). p24 antigen production in this system peaked at 47 to 51 days postinfection. Viral persistence in giant cells was demonstrated by immunocytochemistry for the gp120 and gp41 viral antigens as late as 70 days postinfection. This in vitro culture system, using infant microglia that support viral replication for more than 2 months, may provide a useful model for studying the pathogenesis of progressive HIV encephalopathy.

    View details for Web of Science ID A1995TD74100004

    View details for PubMedID 7485383

  • PNEUMOCOCCAL AORTITIS IN THE ANTIBIOTIC ERA ARCHIVES OF INTERNAL MEDICINE Ioannidis, J. P., Merino, F., Drapkin, M. S., Lew, M. A., Cohn, L. H. 1995; 155 (15): 1678-1680

    Abstract

    The pneumococcus remains in the antibiotic era a formidable pathogen, capable of atypical, lethal clinical presentations. We report two fatal cases of thoracic aortitis caused by Streptococcus pneumoniae in the setting of bacteremic illness from this pathogen. One case occurred in an aortic graft and the other arose in a native aorta. We also discuss the indolent clinical presentation and the diagnostic failure of transesophageal echocardiography and leukocyte scintigraphy. Persistent pyrexia with atypical chest pain and unexplained blood loss should alert clinicians to the possibility of this uncommon, yet lethal complication of pneumococcal disease.

    View details for Web of Science ID A1995RL48500017

    View details for PubMedID 7618992

  • SPECTRUM AND SIGNIFICANCE OF BACTEREMIA DUE TO MORAXELLA-CATARRHALIS CLINICAL INFECTIOUS DISEASES Ioannidis, J. P., Worthington, M., Griffiths, J. K., Snydman, D. R. 1995; 21 (2): 390-397

    Abstract

    Fifty-eight cases of bacteremia due to Moraxella catarrhalis, including seven that occurred in patients treated at our facilities, are analyzed. The host's medical history plays a major role in the presentation and outcome of M. catarrhalis bacteremia. Bacteremia is typically accompanied by pneumonia in adults with underlying respiratory disease. Many neutropenic patients do not manifest a focus of infection; in contrast, the source identified in healthy, immunocompetent patients is usually the upper airway or the ears. In the recent literature, it has been reported that a rash is typically absent in adults with bacteremic pneumonia and in immunocompetent hosts and that only some neutropenic patients have a rash. The prognosis is grave for patients with endocarditis and for patients with immunoglobulin deficiency or neutropenia not related to a hematologic malignancy. In addition, mortality is substantial among bacteremic patients with respiratory conditions or other chronic debilities, especially when respiratory copathogens are present. The prognosis is good for febrile neutropenic patients with underlying leukemia or lymphoma when the neutropenia resolves. When healthy, immunocompetent individuals are affected with M. catarrhalis bacteremia, their presentations range from self-limited febrile illness to life-threatening disease.

    View details for Web of Science ID A1995RM81700020

    View details for PubMedID 8562749

  • EARLY OR DEFERRED ZIDOVUDINE THERAPY IN HIV-INFECTED PATIENTS WITHOUT AN AIDS-DEFINING ILLNESS - A METAANALYSIS ANNALS OF INTERNAL MEDICINE Ioannidis, J. P., Cappelleri, J. C., Lau, J., Skolnik, P. R., Melville, B., Chalmers, T. C., Sacks, H. S. 1995; 122 (11): 856-866

    Abstract

    To do a meta-analysis on the efficacy of early or deferred zidovudine monotherapy in patients with human immunodeficiency virus (HIV) infection but not the acquired immunodeficiency syndrome (AIDS).Articles on zidovudine monotherapy published through May 1994.Double-blind, randomized, placebo-controlled trials addressing the efficacy of zidovudine monotherapy in HIV-infected persons without an AIDS-defining illness.Progression to any primary trial end point; any clinical end point; and AIDS or death. Data were stratified according to disease stage at study entry and duration of follow-up (short-term, < 14 months; long-term, > 21 months).Early initiation of zidovudine therapy was of short-term benefit for all the end points evaluated (for example, the risk ratio for progression to any primary end point was 0.51; 95% CI, 0.41 to 0.64). Long-term trials showed a marginally significant trend of decreased progression to any primary end point (risk ratio, 0.73; CI, 0.52 to 1.03). The trend was not significant for other end points. With further stratification according to disease stage, progression to AIDS or death in the short term was significantly decreased for both symptomatic and asymptomatic patients with CD4 cell counts of less than 500 x 10(6)/L (risk ratios, 0.26 [CI, 0.13 to 0.56] and 0.43 [CI, 0.30 to 0.64], respectively). A regression analysis indicated a larger relative benefit in short-term trials and symptomatic patients than in long-term trials and asymptomatic patients.Early initiation of zidovudine therapy offers a benefit that decreases over time. Symptomatic patients experience a larger benefit than asymptomatic patients. The implications beyond 3 years of follow-up remain unknown.

    View details for Web of Science ID A1995RA13900009

    View details for PubMedID 7741372

  • HUMAN-LEUKOCYTE ANTIGEN ASSOCIATIONS OF EPIDEMIC KAPOSIS-SARCOMA AIDS Ioannidis, J. P., Skolnik, P. R., Chalmers, T. C., Lau, J. 1995; 9 (6): 649-651

    View details for Web of Science ID A1995RA00700019

    View details for PubMedID 7662207

  • ASPERGILLUS-FUMIGATUS INFECTION OF A BILOMA CLINICAL INFECTIOUS DISEASES Ioannidis, J. P., Snydman, D. R., Rohrer, R. J., Freeman, R. B., HAUG, C. E. 1995; 20 (5): 1427-1428

    View details for Web of Science ID A1995QY77100057

    View details for PubMedID 7620038

  • INSULIN-DEPENDENT DIABETES IN AIDS AIDS Ioannidis, J. P., IACOVIELLO, V. R., Samore, M. H. 1994; 8 (4): 556-557

    View details for Web of Science ID A1994NC29800022

    View details for PubMedID 8011263

  • RISK OF GASTROINTESTINAL-BLEEDING FROM DEXAMETHASONE IN CHILDREN WITH BACTERIAL-MENINGITIS LANCET Ioannidis, J. P., SAMAREL, M. D., Lau, J., Drapkin, M. S. 1994; 343 (8900): 792-792

    View details for Web of Science ID A1994NC35100040

    View details for PubMedID 7907747