REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Identifieur interne : 001854 ( Main/Merge ); précédent : 001853; suivant : 001855REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Auteurs : Nilah M. Ioannidis [États-Unis] ; Joseph H. Rothstein [États-Unis] ; Vikas Pejaver [États-Unis] ; Sumit Middha [États-Unis] ; Shannon K. Mcdonnell [États-Unis] ; Saurabh Baheti [États-Unis] ; Anthony Musolf [États-Unis] ; Qing Li [États-Unis] ; Emily Holzinger [États-Unis] ; Danielle Karyadi [États-Unis] ; Lisa A. Cannon-Albright [États-Unis] ; Craig C. Teerlink [États-Unis] ; Janet L. Stanford [États-Unis] ; William B. Isaacs [États-Unis] ; Jianfeng Xu [États-Unis] ; Kathleen A. Cooney [États-Unis] ; Ethan M. Lange [États-Unis] ; Johanna Schleutker [Finlande] ; John D. Carpten [États-Unis] ; Isaac J. Powell [États-Unis] ; Olivier Cussenot [France] ; Geraldine Cancel-Tassin [France] ; Graham G. Giles [Australie] ; Robert J. Macinnis [Australie] ; Christiane Maier [Allemagne] ; Chih-Lin Hsieh [États-Unis] ; Fredrik Wiklund [Suède] ; William J. Catalona [États-Unis] ; William D. Foulkes [Canada] ; Diptasri Mandal [États-Unis] ; Rosalind A. Eeles [Royaume-Uni] ; Zsofia Kote-Jarai [Royaume-Uni] ; Carlos D. Bustamante [États-Unis] ; Daniel J. Schaid [États-Unis] ; Trevor Hastie [États-Unis] ; Elaine A. Ostrander [États-Unis] ; Joan E. Bailey-Wilson [États-Unis] ; Predrag Radivojac [États-Unis] ; Stephen N. Thibodeau [États-Unis] ; Alice S. Whittemore [États-Unis] ; Weiva Sieh [États-Unis]Source :
- American Journal of Human Genetics [ 0002-9297 ] ; 2016.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- genetics : Disease, Exome, Mutation, Missense.
- Area Under Curve, DNA Mutational Analysis, Gene Frequency, Humans, ROC Curve, Software.
Abstract
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10−12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046–0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027–0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.
Url:
DOI: 10.1016/j.ajhg.2016.08.016
PubMed: 27666373
PubMed Central: 5065685
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<author><name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name>
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<orgName type="university">Université de Californie du Sud</orgName>
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<author><name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name>
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<wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77</wicri:regionArea>
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<author><name sortKey="Catalona, William J" sort="Catalona, William J" uniqKey="Catalona W" first="William J." last="Catalona">William J. Catalona</name>
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<affiliation wicri:level="1"><nlm:aff id="aff28">Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
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<author><name sortKey="Mandal, Diptasri" sort="Mandal, Diptasri" uniqKey="Mandal D" first="Diptasri" last="Mandal">Diptasri Mandal</name>
<affiliation wicri:level="2"><nlm:aff id="aff29">Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112</wicri:regionArea>
<placeName><region type="state">Louisiane</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Eeles, Rosalind A" sort="Eeles, Rosalind A" uniqKey="Eeles R" first="Rosalind A." last="Eeles">Rosalind A. Eeles</name>
<affiliation wicri:level="1"><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG</wicri:regionArea>
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</affiliation>
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<affiliation wicri:level="1"><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG</wicri:regionArea>
<wicri:noRegion>London SM2 5NG</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bustamante, Carlos D" sort="Bustamante, Carlos D" uniqKey="Bustamante C" first="Carlos D." last="Bustamante">Carlos D. Bustamante</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schaid, Daniel J" sort="Schaid, Daniel J" uniqKey="Schaid D" first="Daniel J." last="Schaid">Daniel J. Schaid</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hastie, Trevor" sort="Hastie, Trevor" uniqKey="Hastie T" first="Trevor" last="Hastie">Trevor Hastie</name>
<affiliation wicri:level="2"><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff32">Department of Statistics, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Statistics, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ostrander, Elaine A" sort="Ostrander, Elaine A" uniqKey="Ostrander E" first="Elaine A." last="Ostrander">Elaine A. Ostrander</name>
<affiliation wicri:level="2"><nlm:aff id="aff9">Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bailey Wilson, Joan E" sort="Bailey Wilson, Joan E" uniqKey="Bailey Wilson J" first="Joan E." last="Bailey-Wilson">Joan E. Bailey-Wilson</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405</wicri:regionArea>
<placeName><region type="state">Indiana</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Thibodeau, Stephen N" sort="Thibodeau, Stephen N" uniqKey="Thibodeau S" first="Stephen N." last="Thibodeau">Stephen N. Thibodeau</name>
<affiliation wicri:level="2"><nlm:aff id="aff33">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Whittemore, Alice S" sort="Whittemore, Alice S" uniqKey="Whittemore A" first="Alice S." last="Whittemore">Alice S. Whittemore</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Research and Policy, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sieh, Weiva" sort="Sieh, Weiva" uniqKey="Sieh W" first="Weiva" last="Sieh">Weiva Sieh</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Research and Policy, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff4">Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants</title>
<author><name sortKey="Ioannidis, Nilah M" sort="Ioannidis, Nilah M" uniqKey="Ioannidis N" first="Nilah M." last="Ioannidis">Nilah M. Ioannidis</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Research and Policy, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rothstein, Joseph H" sort="Rothstein, Joseph H" uniqKey="Rothstein J" first="Joseph H." last="Rothstein">Joseph H. Rothstein</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Research and Policy, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff4">Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pejaver, Vikas" sort="Pejaver, Vikas" uniqKey="Pejaver V" first="Vikas" last="Pejaver">Vikas Pejaver</name>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405</wicri:regionArea>
<placeName><region type="state">Indiana</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Middha, Sumit" sort="Middha, Sumit" uniqKey="Middha S" first="Sumit" last="Middha">Sumit Middha</name>
<affiliation wicri:level="2"><nlm:aff id="aff6">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mcdonnell, Shannon K" sort="Mcdonnell, Shannon K" uniqKey="Mcdonnell S" first="Shannon K." last="Mcdonnell">Shannon K. Mcdonnell</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Baheti, Saurabh" sort="Baheti, Saurabh" uniqKey="Baheti S" first="Saurabh" last="Baheti">Saurabh Baheti</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Musolf, Anthony" sort="Musolf, Anthony" uniqKey="Musolf A" first="Anthony" last="Musolf">Anthony Musolf</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Li, Qing" sort="Li, Qing" uniqKey="Li Q" first="Qing" last="Li">Qing Li</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Holzinger, Emily" sort="Holzinger, Emily" uniqKey="Holzinger E" first="Emily" last="Holzinger">Emily Holzinger</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Karyadi, Danielle" sort="Karyadi, Danielle" uniqKey="Karyadi D" first="Danielle" last="Karyadi">Danielle Karyadi</name>
<affiliation wicri:level="2"><nlm:aff id="aff9">Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cannon Albright, Lisa A" sort="Cannon Albright, Lisa A" uniqKey="Cannon Albright L" first="Lisa A." last="Cannon-Albright">Lisa A. Cannon-Albright</name>
<affiliation wicri:level="2"><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108</wicri:regionArea>
<placeName><region type="state">Utah</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Teerlink, Craig C" sort="Teerlink, Craig C" uniqKey="Teerlink C" first="Craig C." last="Teerlink">Craig C. Teerlink</name>
<affiliation wicri:level="2"><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108</wicri:regionArea>
<placeName><region type="state">Utah</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Stanford, Janet L" sort="Stanford, Janet L" uniqKey="Stanford J" first="Janet L." last="Stanford">Janet L. Stanford</name>
<affiliation wicri:level="2"><nlm:aff id="aff11">Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109</wicri:regionArea>
<placeName><region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Isaacs, William B" sort="Isaacs, William B" uniqKey="Isaacs W" first="William B." last="Isaacs">William B. Isaacs</name>
<affiliation wicri:level="2"><nlm:aff id="aff12">Brady Urological Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Brady Urological Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Xu, Jianfeng" sort="Xu, Jianfeng" uniqKey="Xu J" first="Jianfeng" last="Xu">Jianfeng Xu</name>
<affiliation wicri:level="2"><nlm:aff id="aff13">NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>NorthShore University HealthSystem Research Institute, Evanston, IL 60201</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cooney, Kathleen A" sort="Cooney, Kathleen A" uniqKey="Cooney K" first="Kathleen A." last="Cooney">Kathleen A. Cooney</name>
<affiliation wicri:level="2"><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108</wicri:regionArea>
<placeName><region type="state">Utah</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff14">Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lange, Ethan M" sort="Lange, Ethan M" uniqKey="Lange E" first="Ethan M." last="Lange">Ethan M. Lange</name>
<affiliation wicri:level="4"><nlm:aff id="aff15">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author><name sortKey="Schleutker, Johanna" sort="Schleutker, Johanna" uniqKey="Schleutker J" first="Johanna" last="Schleutker">Johanna Schleutker</name>
<affiliation wicri:level="4"><nlm:aff id="aff16">Department of Medical Biochemistry and Genetics, University of Turku, Turku 20014, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Medical Biochemistry and Genetics, University of Turku, Turku 20014</wicri:regionArea>
<placeName><settlement type="city">Turku</settlement>
<region type="région" nuts="2">Finlande occidentale</region>
<settlement type="city">Turku</settlement>
</placeName>
<orgName type="university">Université de Turku</orgName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff17">Department of Medical Genetics, Tyks Microbiology and Genetics, Turku University Hospital, Turku 20520, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Medical Genetics, Tyks Microbiology and Genetics, Turku University Hospital, Turku 20520</wicri:regionArea>
<placeName><settlement type="city">Turku</settlement>
<region type="région" nuts="2">Finlande occidentale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Carpten, John D" sort="Carpten, John D" uniqKey="Carpten J" first="John D." last="Carpten">John D. Carpten</name>
<affiliation wicri:level="2"><nlm:aff id="aff18">Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004</wicri:regionArea>
<placeName><region type="state">Arizona</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Powell, Isaac J" sort="Powell, Isaac J" uniqKey="Powell I" first="Isaac J." last="Powell">Isaac J. Powell</name>
<affiliation wicri:level="2"><nlm:aff id="aff19">Department of Urology, Wayne State University, Detroit, MI 48201, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Urology, Wayne State University, Detroit, MI 48201</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cussenot, Olivier" sort="Cussenot, Olivier" uniqKey="Cussenot O" first="Olivier" last="Cussenot">Olivier Cussenot</name>
<affiliation wicri:level="3"><nlm:aff id="aff20">Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013</wicri:regionArea>
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<author><name sortKey="Cancel Tassin, Geraldine" sort="Cancel Tassin, Geraldine" uniqKey="Cancel Tassin G" first="Geraldine" last="Cancel-Tassin">Geraldine Cancel-Tassin</name>
<affiliation wicri:level="3"><nlm:aff id="aff20">Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004</wicri:regionArea>
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<affiliation wicri:level="4"><nlm:aff id="aff22">Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
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</author>
<author><name sortKey="Macinnis, Robert J" sort="Macinnis, Robert J" uniqKey="Macinnis R" first="Robert J." last="Macinnis">Robert J. Macinnis</name>
<affiliation wicri:level="1"><nlm:aff id="aff21">Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004</wicri:regionArea>
<wicri:noRegion>VIC 3004</wicri:noRegion>
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<affiliation wicri:level="4"><nlm:aff id="aff22">Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
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</affiliation>
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<author><name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name>
<affiliation wicri:level="3"><nlm:aff id="aff23">Institute of Human Genetics, University Hospital of Ulm, Ulm 89075, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, University Hospital of Ulm, Ulm 89075</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Tübingen</region>
<settlement type="city">Ulm</settlement>
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</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff24">Department of Urology, University Hospital of Ulm, Ulm 89075, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Urology, University Hospital of Ulm, Ulm 89075</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Tübingen</region>
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</affiliation>
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<author><name sortKey="Hsieh, Chih Lin" sort="Hsieh, Chih Lin" uniqKey="Hsieh C" first="Chih-Lin" last="Hsieh">Chih-Lin Hsieh</name>
<affiliation wicri:level="4"><nlm:aff id="aff25">Department of Urology, University of Southern California, Los Angeles, CA 90033, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Urology, University of Southern California, Los Angeles, CA 90033</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name>
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<country xml:lang="fr">Suède</country>
<wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77</wicri:regionArea>
<wicri:noRegion>Stockholm 171 77</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Catalona, William J" sort="Catalona, William J" uniqKey="Catalona W" first="William J." last="Catalona">William J. Catalona</name>
<affiliation wicri:level="2"><nlm:aff id="aff27">Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Foulkes, William D" sort="Foulkes, William D" uniqKey="Foulkes W" first="William D." last="Foulkes">William D. Foulkes</name>
<affiliation wicri:level="1"><nlm:aff id="aff28">Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4</wicri:regionArea>
<wicri:noRegion>QC H3G 1A4</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mandal, Diptasri" sort="Mandal, Diptasri" uniqKey="Mandal D" first="Diptasri" last="Mandal">Diptasri Mandal</name>
<affiliation wicri:level="2"><nlm:aff id="aff29">Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112</wicri:regionArea>
<placeName><region type="state">Louisiane</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Eeles, Rosalind A" sort="Eeles, Rosalind A" uniqKey="Eeles R" first="Rosalind A." last="Eeles">Rosalind A. Eeles</name>
<affiliation wicri:level="1"><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG</wicri:regionArea>
<wicri:noRegion>London SM2 5NG</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kote Jarai, Zsofia" sort="Kote Jarai, Zsofia" uniqKey="Kote Jarai Z" first="Zsofia" last="Kote-Jarai">Zsofia Kote-Jarai</name>
<affiliation wicri:level="1"><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG</wicri:regionArea>
<wicri:noRegion>London SM2 5NG</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bustamante, Carlos D" sort="Bustamante, Carlos D" uniqKey="Bustamante C" first="Carlos D." last="Bustamante">Carlos D. Bustamante</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schaid, Daniel J" sort="Schaid, Daniel J" uniqKey="Schaid D" first="Daniel J." last="Schaid">Daniel J. Schaid</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hastie, Trevor" sort="Hastie, Trevor" uniqKey="Hastie T" first="Trevor" last="Hastie">Trevor Hastie</name>
<affiliation wicri:level="2"><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff32">Department of Statistics, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Statistics, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ostrander, Elaine A" sort="Ostrander, Elaine A" uniqKey="Ostrander E" first="Elaine A." last="Ostrander">Elaine A. Ostrander</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
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<author><name sortKey="Bailey Wilson, Joan E" sort="Bailey Wilson, Joan E" uniqKey="Bailey Wilson J" first="Joan E." last="Bailey-Wilson">Joan E. Bailey-Wilson</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405</wicri:regionArea>
<placeName><region type="state">Indiana</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Thibodeau, Stephen N" sort="Thibodeau, Stephen N" uniqKey="Thibodeau S" first="Stephen N." last="Thibodeau">Stephen N. Thibodeau</name>
<affiliation wicri:level="2"><nlm:aff id="aff33">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Whittemore, Alice S" sort="Whittemore, Alice S" uniqKey="Whittemore A" first="Alice S." last="Whittemore">Alice S. Whittemore</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Research and Policy, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sieh, Weiva" sort="Sieh, Weiva" uniqKey="Sieh W" first="Weiva" last="Sieh">Weiva Sieh</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Health Research and Policy, Stanford University, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff4">Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">American Journal of Human Genetics</title>
<idno type="ISSN">0002-9297</idno>
<idno type="eISSN">1537-6605</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Area Under Curve</term>
<term>DNA Mutational Analysis</term>
<term>Disease (genetics)</term>
<term>Exome (genetics)</term>
<term>Gene Frequency</term>
<term>Humans</term>
<term>Mutation, Missense (genetics)</term>
<term>ROC Curve</term>
<term>Software</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Aire sous la courbe</term>
<term>Analyse de mutations d'ADN</term>
<term>Courbe ROC</term>
<term>Exome (génétique)</term>
<term>Fréquence d'allèle</term>
<term>Humains</term>
<term>Logiciel</term>
<term>Maladie (génétique)</term>
<term>Mutation faux-sens (génétique)</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Disease</term>
<term>Exome</term>
<term>Mutation, Missense</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Exome</term>
<term>Maladie</term>
<term>Mutation faux-sens</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Area Under Curve</term>
<term>DNA Mutational Analysis</term>
<term>Gene Frequency</term>
<term>Humans</term>
<term>ROC Curve</term>
<term>Software</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Aire sous la courbe</term>
<term>Analyse de mutations d'ADN</term>
<term>Courbe ROC</term>
<term>Fréquence d'allèle</term>
<term>Humains</term>
<term>Logiciel</term>
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<front><div type="abstract" xml:lang="en"><p>The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10<sup>−12</sup>
) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046–0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027–0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.</p>
</div>
</front>
</TEI>
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