{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T11:02:52Z","timestamp":1778065372819,"version":"3.51.4"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"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":["Genetic Epidemiology"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Germline mutations in many genes have been shown to increase the risk of developing cancer. This risk can vary across families who carry mutations in the same gene due to differences in the specific variants, gene\u2013gene interactions, other susceptibility mutations, environmental factors, and behavioral factors. We develop an analytic tool to explore this heterogeneity using family history data. We propose to evaluate the ratio between the number of observed cancer cases in a family and the number of expected cases under a model where risk is assumed to be the same across families. We perform this analysis for both carriers and noncarriers in each family, using carrier probabilities when carrier statuses are unknown, and visualize the results. We first illustrate the approach in simulated data and then apply it to data on colorectal cancer risk in families carrying mutations in Lynch syndrome genes from Creighton University's Hereditary Cancer Center. We show that colorectal cancer risk in carriers can vary widely across families, and that this variation is not matched by a corresponding variation in the noncarriers from the same families. This suggests that the sources of variation in these families are to be found predominantly in variants harbored in the mutated MMR genes considered, or in variants interacting with them.<\/jats:p>","DOI":"10.1002\/gepi.22366","type":"journal-article","created":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T11:39:56Z","timestamp":1602157196000},"page":"209-221","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Variation in cancer risk among families with genetic susceptibility"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-6999","authenticated-orcid":false,"given":"Theodore","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute Boston Massachusetts USA"},{"name":"Department of Biostatistics Harvard T.H. Chan School of Public Health Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5177-8598","authenticated-orcid":false,"given":"Danielle","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute Boston Massachusetts USA"},{"name":"Department of Biostatistics Harvard T.H. Chan School of Public Health Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry T.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Center Creighton University School of Medicine Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-5961","authenticated-orcid":false,"given":"Giovanni","family":"Parmigiani","sequence":"additional","affiliation":[{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute Boston Massachusetts USA"},{"name":"Department of Biostatistics Harvard T.H. Chan School of Public Health Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6600008"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2007.55-a"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c120005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61049-0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.12.1479"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31611"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2307\/2284155"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000152448"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/86.21.1600"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.2013.818001"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10985-013-9260-x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22323"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1214\/009053604000000030"},{"key":"e_1_2_9_15_1","volume-title":"The statistical analysis of failure time data","author":"Kalbfleisch J. D.","year":"2011"},{"key":"e_1_2_9_16_1","first-page":"1059","article-title":"Founder brca1 and brca2 mutations in Ashkenazi Jews in Israel: Frequency and differential penetrance in ovarian cancer and in breast\u2010ovarian cancer families","volume":"60","author":"Levy\u2010Lahad E.","year":"1997","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1966.03870080050009"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-4608(96)00290-7"},{"key":"e_1_2_9_19_1","first-page":"359","article-title":"The role of Creighton University's Hereditary Cancer Center","volume":"4","author":"Lynch H. T.","year":"2015","journal-title":"Translational Gastrointestinal Cancer"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.9952"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.5985"},{"key":"e_1_2_9_22_1","first-page":"275","article-title":"False discovery rates: A new deal","volume":"18","author":"Stephens M.","year":"2017","journal-title":"Biostatistics"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199705153362001"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr525"},{"key":"e_1_2_9_25_1","unstructured":"US Department of Health and Human Services. (2004).The health consequences of smoking: A report of the surgeon general.US Department of Health and Human Services Centers for Disease Control and Prevention National Center for Chronic Disease Prevention and Health Promotion Office on Smoking and Health 62."},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.2307\/2061224"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq174"}],"container-title":["Genetic Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gepi.22366","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/gepi.22366","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gepi.22366","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T07:16:49Z","timestamp":1692861409000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gepi.22366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,8]]},"references-count":26,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1002\/gepi.22366"],"URL":"https:\/\/doi.org\/10.1002\/gepi.22366","archive":["Portico"],"relation":{},"ISSN":["0741-0395","1098-2272"],"issn-type":[{"value":"0741-0395","type":"print"},{"value":"1098-2272","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,8]]},"assertion":[{"value":"2020-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}