title: A probabilistic model to predict clinical phenotypic traits from genome sequencing.
abstract: Genetic screening is becoming possible on an unprecedented scale. However, its utility remains controversial. Although most variant genotypes cannot be easily interpreted, many individuals nevertheless attempt to interpret their genetic information. Initiatives such as the Personal Genome Project (PGP) and Illumina's Understand Your Genome are sequencing thousands of adults, collecting phenotypic information and developing computational pipelines to identify the most important variant genotypes harbored by each individual. These pipelines consider database and allele frequency annotations and bioinformatics classifications. We propose that the next step will be to integrate these different sources of information to estimate the probability that a given individual has specific phenotypes of clinical interest. To this end, we have designed a Bayesian probabilistic model to predict the probability of dichotomous phenotypes. When applied to a cohort from PGP, predictions of Gilbert syndrome, Graves' disease, non-Hodgkin lymphoma, and various blood groups were accurate, as individuals manifesting the phenotype in question exhibited the highest, or among the highest, predicted probabilities. Thirty-eight PGP phenotypes (26%) were predicted with area-under-the-ROC curve (AUC)>0.7, and 23 (15.8%) of these were statistically significant, based on permutation tests. Moreover, in a Critical Assessment of Genome Interpretation (CAGI) blinded prediction experiment, the models were used to match 77 PGP genomes to phenotypic profiles, generating the most accurate prediction of 16 submissions, according to an independent assessor. Although the models are currently insufficiently accurate for diagnostic utility, we expect their performance to improve with growth of publicly available genomics data and model refinement by domain experts.
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Douville
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Noushin
authors.initials: N
authors.lastname: Niknafs
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: Yeo
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Violeta
authors.initials: V
authors.lastname: Beleva-Guthrie
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Mooney
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
mesh_terms: D001499:Bayes Theorem; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D016045:Human Genome Project; D006801:Humans; D015233:Models, Statistical; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*