{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T16:00:40Z","timestamp":1747152040850,"version":"3.40.5"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Statistics in Medicine"],"published-print":{"date-parts":[[2021,2,10]]},"abstract":"<jats:p>Commercialized multigene panel testing brings unprecedented opportunities to understand germline genetic contributions to hereditary cancers. Most genetic testing companies classify the pathogenicity of variants as pathogenic, benign, or variants of unknown significance (VUSs). The unknown pathogenicity of VUSs poses serious challenges to clinical decision\u2010making. This study aims to assess the frequency of VUSs that are likely pathogenic in disease\u2010susceptibility genes. Using estimates of probands' probability of having a pathogenic mutation (ie, the carrier score) based on a family history probabilistic risk prediction model, we assume the carrier score distribution for probands with VUSs is a mixture of the carrier score distribution for probands with positive results and the carrier score distribution for probands with negative results. Under this mixture model, we propose a likelihood\u2010based approach to assess the frequency of pathogenicity among probands with VUSs, while accounting for the existence of possible pathogenic mutations on genes not tested. We conducted simulations to assess the performance of the approach and show that under various settings, the approach performs well with very little bias in the estimated proportion of VUSs that are likely pathogenic. We also estimate the positive predictive value across the entire range of carrier scores. We apply our approach to the USC\u2010Stanford Hereditary Cancer Panel Testing cohort, and estimate the proportion of probands that have VUSs in BRCA1\/2 that are likely pathogenic to be 10.12% [95%CI: 0%, 43.04%]. This approach will enable clinicians to target high\u2010risk patients who have VUSs, allowing for early prevention interventions.<\/jats:p>","DOI":"10.1002\/sim.8791","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T23:25:47Z","timestamp":1604013947000},"page":"593-606","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A likelihood\u2010based approach to assessing frequency of pathogenicity among variants of unknown significance in susceptibility genes"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-9697","authenticated-orcid":false,"given":"Yunqi","family":"Yang","sequence":"first","affiliation":[{"name":"Committee on Genetics, Genomics and Systems Biology The University of Chicago  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Hong","sequence":"additional","affiliation":[{"name":"Keck School of Medicine University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane W.","family":"Liang","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Cente  Duarte California USA"},{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Gruber","sequence":"additional","affiliation":[{"name":"Keck School of Medicine University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Parmigiani","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Cente  Duarte California USA"},{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory","family":"Idos","sequence":"additional","affiliation":[{"name":"Keck School of Medicine University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Braun","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Cente  Duarte California USA"},{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"CIN\u2013S618","DOI":"10.4137\/CIN.S618","article-title":"Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios","volume":"6","author":"Karchin R","year":"2008","journal-title":"Cancer Inf"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-3546"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.2690"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2017.09.003"},{"issue":"469","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1198\/016214504000001817","article-title":"Classification of missense mutations of disease genes","volume":"100","author":"Zhou X","year":"2005","journal-title":"J Am Stat Assoc"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1086\/521032"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-014-3065-9"},{"issue":"3","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1186\/1471-2164-14-S3-S7","article-title":"Assessment of computational methods for predicting the effects of missense mutations in human cancers","volume":"14","author":"Gnad F","year":"2013","journal-title":"BMC Genomics"},{"issue":"1","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2202\/1544-6115.1063","article-title":"BayesMendel: an R environment for Mendelian risk prediction","volume":"3","author":"Chen S","year":"2004","journal-title":"Stat Appl Genet Mol Biol"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602175"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/89.3.227"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/301670"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.12.1479"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.09.2452"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-2653"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.09.1066"},{"volume-title":"R: A Language and Environment for Statistical Computing","year":"2013","author":"R Core Team","key":"e_1_2_9_18_1"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00180-010-0217-1"},{"key":"e_1_2_9_20_1","first-page":"495","volume-title":"Density Estimation for Statistics and Data Analysis","author":"Dehnad K","year":"1987"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1524-4741.2001.20012.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2009.1529"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.383"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2015.12.013"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/94.18.1365"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.2.185"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603535"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.18.5546"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2020.0017"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-013-2564-4"}],"container-title":["Statistics in Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.8791","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/sim.8791","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.8791","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T16:22:21Z","timestamp":1693758141000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/sim.8791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,29]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,2,10]]}},"alternative-id":["10.1002\/sim.8791"],"URL":"https:\/\/doi.org\/10.1002\/sim.8791","archive":["Portico"],"relation":{},"ISSN":["0277-6715","1097-0258"],"issn-type":[{"type":"print","value":"0277-6715"},{"type":"electronic","value":"1097-0258"}],"subject":[],"published":{"date-parts":[[2020,10,29]]},"assertion":[{"value":"2019-10-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}