Article | Published:

Phrank measures phenotype sets similarity to greatly improve Mendelian diagnostic disease prioritization

Genetics in Medicine (2018) | Download Citation

Subjects

Abstract

Purpose

Exome sequencing and diagnosis is beginning to spread across the medical establishment. The most time-consuming part of genome-based diagnosis is the manual step of matching the potentially long list of patient candidate genes to patient phenotypes to identify the causative disease.

Methods

We introduce Phrank (for phenotype ranking), an information theory–inspired method that utilizes a Bayesian network to prioritize candidate diseases or genes, as a stand-alone module that can be run with any underlying knowledgebase and any variant filtering scheme.

Results

Phrank outperforms existing methods at ranking the causative disease or gene when applied to 169 real patient exomes with Mendelian diagnoses. Phrank’s greatest improvement is in disease space, where across all 169 patients it ranks only 3 diseases on average ahead of the true diagnosis, whereas Phenomizer ranks 32 diseases ahead of the causal one.

Conclusions

Using Phrank to rank all patient candidate genes or diseases, as they start working through a new case, will save the busy clinician much time in deriving a genetic diagnosis.

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      Acknowledgements

      We thank Yosuke Tanigawa, Ethan Dyer, Golan Yona, and all other members of the Bejerano Lab for valuable discussions and project feedback. We would also like to thank the European Genome-Phenome Archive (EGA) and the Deciphering Developmental Diseases (DDD) project. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. as well as the patients and professionals involved in the Deciphering Developmental Disorders (DDD) study deposited in the European Genome Archive (EGA). This work was funded in part by the Stanford Graduate Fellowship and CEHG Fellowship to K.A.J., a Bio-X Stanford Interdisciplinary Graduate Fellowship to J.B., the Stanford Pediatrics Department, DARPA, a Packard Foundation Fellowship, and a Microsoft Faculty Fellowship to G.B.

      Author information

      1. These authors contributed equally: Karthik A. Jagadeesh, Johannes Birgmeier

      Affiliations

      1. Department of Computer Science, Stanford University, Stanford, California, 94305, USA

        • Karthik A. Jagadeesh MSc
        • , Johannes Birgmeier MSc
        • , Cole A. Deisseroth
        •  & Gill Bejerano PhD

      2. Department of Pediatrics, Stanford University, Stanford, California, 94305, USA

        • Harendra Guturu PhD
        • , Aaron M. Wenger PhD
        • , Jonathan A. Bernstein MD, PhD
        •  & Gill Bejerano PhD

      3. Department of Developmental Biology, Stanford University, Stanford, California, 94305, USA

        • Gill Bejerano PhD

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      The authors declare no conflicts of interest.

      Corresponding author

      Correspondence to Gill Bejerano PhD.

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      DOI

      https://doi.org/10.1038/s41436-018-0072-y