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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></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><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff></affiliation><affiliation><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></affiliation></author><author><name sortKey="Pejaver, Vikas" sort="Pejaver, Vikas" uniqKey="Pejaver V" first="Vikas" last="Pejaver">Vikas Pejaver</name><affiliation><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff></affiliation></author><author><name sortKey="Middha, Sumit" sort="Middha, Sumit" uniqKey="Middha S" first="Sumit" last="Middha">Sumit Middha</name><affiliation><nlm:aff id="aff6">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA</nlm:aff></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><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Baheti, Saurabh" sort="Baheti, Saurabh" uniqKey="Baheti S" first="Saurabh" last="Baheti">Saurabh Baheti</name><affiliation><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Musolf, Anthony" sort="Musolf, Anthony" uniqKey="Musolf A" first="Anthony" last="Musolf">Anthony Musolf</name><affiliation><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Li, Qing" sort="Li, Qing" uniqKey="Li Q" first="Qing" last="Li">Qing Li</name><affiliation><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Holzinger, Emily" sort="Holzinger, Emily" uniqKey="Holzinger E" first="Emily" last="Holzinger">Emily Holzinger</name><affiliation><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Karyadi, Danielle" sort="Karyadi, Danielle" uniqKey="Karyadi D" first="Danielle" last="Karyadi">Danielle Karyadi</name><affiliation><nlm:aff id="aff9">Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</nlm:aff></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><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff></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><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff></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><nlm:aff id="aff11">Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA</nlm:aff></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><nlm:aff id="aff12">Brady Urological Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</nlm:aff></affiliation></author><author><name sortKey="Xu, Jianfeng" sort="Xu, Jianfeng" uniqKey="Xu J" first="Jianfeng" last="Xu">Jianfeng Xu</name><affiliation><nlm:aff id="aff13">NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA</nlm:aff></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><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff14">Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA</nlm:aff></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><nlm:aff id="aff15">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Schleutker, Johanna" sort="Schleutker, Johanna" uniqKey="Schleutker J" first="Johanna" last="Schleutker">Johanna Schleutker</name><affiliation><nlm:aff id="aff16">Department of Medical Biochemistry and Genetics, University of Turku, Turku 20014, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff17">Department of Medical Genetics, Tyks Microbiology and Genetics, Turku University Hospital, Turku 20520, Finland</nlm:aff></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><nlm:aff id="aff18">Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA</nlm:aff></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><nlm:aff id="aff19">Department of Urology, Wayne State University, Detroit, MI 48201, USA</nlm:aff></affiliation></author><author><name sortKey="Cussenot, Olivier" sort="Cussenot, Olivier" uniqKey="Cussenot O" first="Olivier" last="Cussenot">Olivier Cussenot</name><affiliation><nlm:aff id="aff20">Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</nlm:aff></affiliation></author><author><name sortKey="Cancel Tassin, Geraldine" sort="Cancel Tassin, Geraldine" uniqKey="Cancel Tassin G" first="Geraldine" last="Cancel-Tassin">Geraldine Cancel-Tassin</name><affiliation><nlm:aff id="aff20">Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff21">Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Macinnis, Robert J" sort="Macinnis, Robert J" uniqKey="Macinnis R" first="Robert J." last="Macinnis">Robert J. Macinnis</name><affiliation><nlm:aff id="aff21">Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name><affiliation><nlm:aff id="aff23">Institute of Human Genetics, University Hospital of Ulm, Ulm 89075, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Department of Urology, University Hospital of Ulm, Ulm 89075, Germany</nlm:aff></affiliation></author><author><name sortKey="Hsieh, Chih Lin" sort="Hsieh, Chih Lin" uniqKey="Hsieh C" first="Chih-Lin" last="Hsieh">Chih-Lin Hsieh</name><affiliation><nlm:aff id="aff25">Department of Urology, University of Southern California, Los Angeles, CA 90033, USA</nlm:aff></affiliation></author><author><name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name><affiliation><nlm:aff id="aff26">Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden</nlm:aff></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><nlm:aff id="aff27">Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA</nlm:aff></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><nlm:aff id="aff28">Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4, Canada</nlm:aff></affiliation></author><author><name sortKey="Mandal, Diptasri" sort="Mandal, Diptasri" uniqKey="Mandal D" first="Diptasri" last="Mandal">Diptasri Mandal</name><affiliation><nlm:aff id="aff29">Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA</nlm:aff></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><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff></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><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff></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><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff></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><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Hastie, Trevor" sort="Hastie, Trevor" uniqKey="Hastie T" first="Trevor" last="Hastie">Trevor Hastie</name><affiliation><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff32">Department of Statistics, Stanford University, Stanford, CA 94305, USA</nlm:aff></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><nlm:aff id="aff9">Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</nlm:aff></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><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name><affiliation><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff></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><nlm:aff id="aff33">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></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><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation></author><author><name sortKey="Sieh, Weiva" sort="Sieh, Weiva" uniqKey="Sieh W" first="Weiva" last="Sieh">Weiva Sieh</name><affiliation><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff></affiliation><affiliation><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></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27666373</idno><idno type="pmc">5065685</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065685</idno><idno type="RBID">PMC:5065685</idno><idno type="doi">10.1016/j.ajhg.2016.08.016</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">001696</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001696</idno></publicationStmt><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><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></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><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff></affiliation><affiliation><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></affiliation></author><author><name sortKey="Pejaver, Vikas" sort="Pejaver, Vikas" uniqKey="Pejaver V" first="Vikas" last="Pejaver">Vikas Pejaver</name><affiliation><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff></affiliation></author><author><name sortKey="Middha, Sumit" sort="Middha, Sumit" uniqKey="Middha S" first="Sumit" last="Middha">Sumit Middha</name><affiliation><nlm:aff id="aff6">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA</nlm:aff></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><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Baheti, Saurabh" sort="Baheti, Saurabh" uniqKey="Baheti S" first="Saurabh" last="Baheti">Saurabh Baheti</name><affiliation><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Musolf, Anthony" sort="Musolf, Anthony" uniqKey="Musolf A" first="Anthony" last="Musolf">Anthony Musolf</name><affiliation><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Li, Qing" sort="Li, Qing" uniqKey="Li Q" first="Qing" last="Li">Qing Li</name><affiliation><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Holzinger, Emily" sort="Holzinger, Emily" uniqKey="Holzinger E" first="Emily" last="Holzinger">Emily Holzinger</name><affiliation><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Karyadi, Danielle" sort="Karyadi, Danielle" uniqKey="Karyadi D" first="Danielle" last="Karyadi">Danielle Karyadi</name><affiliation><nlm:aff id="aff9">Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</nlm:aff></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><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff></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><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff></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><nlm:aff id="aff11">Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA</nlm:aff></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><nlm:aff id="aff12">Brady Urological Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</nlm:aff></affiliation></author><author><name sortKey="Xu, Jianfeng" sort="Xu, Jianfeng" uniqKey="Xu J" first="Jianfeng" last="Xu">Jianfeng Xu</name><affiliation><nlm:aff id="aff13">NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA</nlm:aff></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><nlm:aff id="aff10">Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff14">Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA</nlm:aff></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><nlm:aff id="aff15">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Schleutker, Johanna" sort="Schleutker, Johanna" uniqKey="Schleutker J" first="Johanna" last="Schleutker">Johanna Schleutker</name><affiliation><nlm:aff id="aff16">Department of Medical Biochemistry and Genetics, University of Turku, Turku 20014, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff17">Department of Medical Genetics, Tyks Microbiology and Genetics, Turku University Hospital, Turku 20520, Finland</nlm:aff></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><nlm:aff id="aff18">Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA</nlm:aff></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><nlm:aff id="aff19">Department of Urology, Wayne State University, Detroit, MI 48201, USA</nlm:aff></affiliation></author><author><name sortKey="Cussenot, Olivier" sort="Cussenot, Olivier" uniqKey="Cussenot O" first="Olivier" last="Cussenot">Olivier Cussenot</name><affiliation><nlm:aff id="aff20">Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</nlm:aff></affiliation></author><author><name sortKey="Cancel Tassin, Geraldine" sort="Cancel Tassin, Geraldine" uniqKey="Cancel Tassin G" first="Geraldine" last="Cancel-Tassin">Geraldine Cancel-Tassin</name><affiliation><nlm:aff id="aff20">Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff21">Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Macinnis, Robert J" sort="Macinnis, Robert J" uniqKey="Macinnis R" first="Robert J." last="Macinnis">Robert J. Macinnis</name><affiliation><nlm:aff id="aff21">Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name><affiliation><nlm:aff id="aff23">Institute of Human Genetics, University Hospital of Ulm, Ulm 89075, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Department of Urology, University Hospital of Ulm, Ulm 89075, Germany</nlm:aff></affiliation></author><author><name sortKey="Hsieh, Chih Lin" sort="Hsieh, Chih Lin" uniqKey="Hsieh C" first="Chih-Lin" last="Hsieh">Chih-Lin Hsieh</name><affiliation><nlm:aff id="aff25">Department of Urology, University of Southern California, Los Angeles, CA 90033, USA</nlm:aff></affiliation></author><author><name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name><affiliation><nlm:aff id="aff26">Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden</nlm:aff></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><nlm:aff id="aff27">Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA</nlm:aff></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><nlm:aff id="aff28">Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4, Canada</nlm:aff></affiliation></author><author><name sortKey="Mandal, Diptasri" sort="Mandal, Diptasri" uniqKey="Mandal D" first="Diptasri" last="Mandal">Diptasri Mandal</name><affiliation><nlm:aff id="aff29">Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA</nlm:aff></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><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff></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><nlm:aff id="aff30">Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</nlm:aff></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><nlm:aff id="aff1">Department of Genetics, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff></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><nlm:aff id="aff7">Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Hastie, Trevor" sort="Hastie, Trevor" uniqKey="Hastie T" first="Trevor" last="Hastie">Trevor Hastie</name><affiliation><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff32">Department of Statistics, Stanford University, Stanford, CA 94305, USA</nlm:aff></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><nlm:aff id="aff9">Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</nlm:aff></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><nlm:aff id="aff8">Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</nlm:aff></affiliation></author><author><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name><affiliation><nlm:aff id="aff5">Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</nlm:aff></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><nlm:aff id="aff33">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></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><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation></author><author><name sortKey="Sieh, Weiva" sort="Sieh, Weiva" uniqKey="Sieh W" first="Weiva" last="Sieh">Weiva Sieh</name><affiliation><nlm:aff id="aff2">Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</nlm:aff></affiliation><affiliation><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></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></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27666373</article-id><article-id pub-id-type="pmc">5065685</article-id><article-id pub-id-type="publisher-id">S0002-9297(16)30370-6</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2016.08.016</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ioannidis</surname><given-names>Nilah M.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">34</xref></contrib><contrib contrib-type="author"><name><surname>Rothstein</surname><given-names>Joseph H.</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="fn1" ref-type="fn">34</xref></contrib><contrib contrib-type="author"><name><surname>Pejaver</surname><given-names>Vikas</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Middha</surname><given-names>Sumit</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>McDonnell</surname><given-names>Shannon K.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Baheti</surname><given-names>Saurabh</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Musolf</surname><given-names>Anthony</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Qing</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Holzinger</surname><given-names>Emily</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Karyadi</surname><given-names>Danielle</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Cannon-Albright</surname><given-names>Lisa A.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Teerlink</surname><given-names>Craig C.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Stanford</surname><given-names>Janet L.</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Isaacs</surname><given-names>William B.</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Jianfeng</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Cooney</surname><given-names>Kathleen A.</given-names></name><xref rid="aff10" ref-type="aff">10</xref><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>Lange</surname><given-names>Ethan M.</given-names></name><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Schleutker</surname><given-names>Johanna</given-names></name><xref rid="aff16" ref-type="aff">16</xref><xref rid="aff17" ref-type="aff">17</xref></contrib><contrib contrib-type="author"><name><surname>Carpten</surname><given-names>John D.</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Powell</surname><given-names>Isaac J.</given-names></name><xref rid="aff19" ref-type="aff">19</xref></contrib><contrib contrib-type="author"><name><surname>Cussenot</surname><given-names>Olivier</given-names></name><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Cancel-Tassin</surname><given-names>Geraldine</given-names></name><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Graham G.</given-names></name><xref rid="aff21" ref-type="aff">21</xref><xref rid="aff22" ref-type="aff">22</xref></contrib><contrib contrib-type="author"><name><surname>MacInnis</surname><given-names>Robert J.</given-names></name><xref rid="aff21" ref-type="aff">21</xref><xref rid="aff22" ref-type="aff">22</xref></contrib><contrib contrib-type="author"><name><surname>Maier</surname><given-names>Christiane</given-names></name><xref rid="aff23" ref-type="aff">23</xref><xref rid="aff24" ref-type="aff">24</xref></contrib><contrib contrib-type="author"><name><surname>Hsieh</surname><given-names>Chih-Lin</given-names></name><xref rid="aff25" ref-type="aff">25</xref></contrib><contrib contrib-type="author"><name><surname>Wiklund</surname><given-names>Fredrik</given-names></name><xref rid="aff26" ref-type="aff">26</xref></contrib><contrib contrib-type="author"><name><surname>Catalona</surname><given-names>William J.</given-names></name><xref rid="aff27" ref-type="aff">27</xref></contrib><contrib contrib-type="author"><name><surname>Foulkes</surname><given-names>William D.</given-names></name><xref rid="aff28" ref-type="aff">28</xref></contrib><contrib contrib-type="author"><name><surname>Mandal</surname><given-names>Diptasri</given-names></name><xref rid="aff29" ref-type="aff">29</xref></contrib><contrib contrib-type="author"><name><surname>Eeles</surname><given-names>Rosalind A.</given-names></name><xref rid="aff30" ref-type="aff">30</xref></contrib><contrib contrib-type="author"><name><surname>Kote-Jarai</surname><given-names>Zsofia</given-names></name><xref rid="aff30" ref-type="aff">30</xref></contrib><contrib contrib-type="author"><name><surname>Bustamante</surname><given-names>Carlos D.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff31" ref-type="aff">31</xref></contrib><contrib contrib-type="author"><name><surname>Schaid</surname><given-names>Daniel J.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Hastie</surname><given-names>Trevor</given-names></name><xref rid="aff31" ref-type="aff">31</xref><xref rid="aff32" ref-type="aff">32</xref></contrib><contrib contrib-type="author"><name><surname>Ostrander</surname><given-names>Elaine A.</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Bailey-Wilson</surname><given-names>Joan E.</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Radivojac</surname><given-names>Predrag</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Thibodeau</surname><given-names>Stephen N.</given-names></name><xref rid="aff33" ref-type="aff">33</xref></contrib><contrib contrib-type="author"><name><surname>Whittemore</surname><given-names>Alice S.</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff31" ref-type="aff">31</xref></contrib><contrib contrib-type="author"><name><surname>Sieh</surname><given-names>Weiva</given-names></name><email>weiva.sieh@mssm.edu</email><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Department of Genetics, Stanford University, Stanford, CA 94305, USA</aff><aff id="aff2"><label>2</label>Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA</aff><aff id="aff3"><label>3</label>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</aff><aff id="aff4"><label>4</label>Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA</aff><aff id="aff5"><label>5</label>Department of Computer Science and Informatics, Indiana University, Bloomington, IN 47405, USA</aff><aff id="aff6"><label>6</label>Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA</aff><aff id="aff7"><label>7</label>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA</aff><aff id="aff8"><label>8</label>Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD 21224, USA</aff><aff id="aff9"><label>9</label>Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA</aff><aff id="aff10"><label>10</label>Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA</aff><aff id="aff11"><label>11</label>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA</aff><aff id="aff12"><label>12</label>Brady Urological Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</aff><aff id="aff13"><label>13</label>NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA</aff><aff id="aff14"><label>14</label>Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA</aff><aff id="aff15"><label>15</label>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</aff><aff id="aff16"><label>16</label>Department of Medical Biochemistry and Genetics, University of Turku, Turku 20014, Finland</aff><aff id="aff17"><label>17</label>Department of Medical Genetics, Tyks Microbiology and Genetics, Turku University Hospital, Turku 20520, Finland</aff><aff id="aff18"><label>18</label>Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA</aff><aff id="aff19"><label>19</label>Department of Urology, Wayne State University, Detroit, MI 48201, USA</aff><aff id="aff20"><label>20</label>Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Universite Paris, Paris, 75013, France</aff><aff id="aff21"><label>21</label>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia</aff><aff id="aff22"><label>22</label>Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia</aff><aff id="aff23"><label>23</label>Institute of Human Genetics, University Hospital of Ulm, Ulm 89075, Germany</aff><aff id="aff24"><label>24</label>Department of Urology, University Hospital of Ulm, Ulm 89075, Germany</aff><aff id="aff25"><label>25</label>Department of Urology, University of Southern California, Los Angeles, CA 90033, USA</aff><aff id="aff26"><label>26</label>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden</aff><aff id="aff27"><label>27</label>Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA</aff><aff id="aff28"><label>28</label>Departments of Oncology and Human Genetics, Montreal General Hospital, Montreal, QC H3G 1A4, Canada</aff><aff id="aff29"><label>29</label>Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA</aff><aff id="aff30"><label>30</label>Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK</aff><aff id="aff31"><label>31</label>Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA</aff><aff id="aff32"><label>32</label>Department of Statistics, Stanford University, Stanford, CA 94305, USA</aff><aff id="aff33"><label>33</label>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>weiva.sieh@mssm.edu</email></corresp><fn id="fn1"><label>34</label><p id="ntpara0010">These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>06</day><month>10</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>22</day><month>9</month><year>2016</year></pub-date><volume>99</volume><issue>4</issue><fpage>877</fpage><lpage>885</lpage><history><date date-type="received"><day>18</day><month>4</month><year>2016</year></date><date date-type="accepted"><day>23</day><month>8</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 American Society of Human Genetics.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>American Society of Human Genetics</copyright-holder></permissions><abstract id="abs0010"><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></abstract></article-meta><notes><p id="misc0010">Published: September 22, 2016</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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