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Mendelian models predict future risk of cancer by using family history with estimated cancer penetrances (age\u2010 and sex\u2010specific risk of cancer given the genotype of the mutations) and mutation prevalences. However, there is often residual risk heterogeneity across families even after accounting for the mutations in the model, due to environmental or unobserved genetic risk factors. We aim to improve Mendelian risk prediction by incorporating a frailty model that contains a family\u2010specific frailty vector, impacting the cancer hazard function, to account for this heterogeneity. We use a discrete uniform population frailty distribution and implement a marginalized approach that averages each family's risk predictions over the family's frailty distribution. We apply the proposed approach to improve breast cancer prediction in BRCAPRO, a Mendelian model that accounts for inherited mutations in the <jats:italic>BRCA1<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic> genes to predict breast and ovarian cancer. We evaluate the proposed model's performance in simulations and real data from the Cancer Genetics Network and show improvements in model calibration and discrimination. We also discuss alternative approaches for incorporating frailties and their strengths and limitations.<\/jats:p>","DOI":"10.1002\/gepi.22323","type":"journal-article","created":{"date-parts":[[2020,6,7]],"date-time":"2020-06-07T13:11:13Z","timestamp":1591535473000},"page":"564-578","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Practical implementation of frailty models in Mendelian risk prediction"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-6999","authenticated-orcid":false,"given":"Theodore","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Biostatistics Harvard T.H. Chan School of Public Health  Boston Massachusetts"},{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1577-6624","authenticated-orcid":false,"given":"Malka","family":"Gorfine","sequence":"additional","affiliation":[{"name":"Department of Statistics and Operations Research Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8168-4712","authenticated-orcid":false,"given":"Li","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Public Health Sciences Fred Hutchinson Cancer Research Center  Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-5961","authenticated-orcid":false,"given":"Giovanni","family":"Parmigiani","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Harvard T.H. Chan School of Public Health  Boston Massachusetts"},{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5177-8598","authenticated-orcid":false,"given":"Danielle","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Harvard T.H. Chan School of Public Health  Boston Massachusetts"},{"name":"Department of Data Sciences Dana\u2010Farber Cancer Institute  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1159\/000078165"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.1014"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604305"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/89.3.227"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-013-2564-4"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.09.1066"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2202\/1544-6115.1063"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.23.1824"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199705153362002"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00223750"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/81.24.1879"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.2013.818001"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10985-013-9260-x"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781118032985"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1088759"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0406-9"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djv036"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13191"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1086\/301670"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-147-7-200710020-00002"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.5985"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e3181c30fb2"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1198\/016214507000000149"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2000.1626"}],"container-title":["Genetic Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fgepi.22323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gepi.22323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/gepi.22323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gepi.22323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T07:38:51Z","timestamp":1693899531000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gepi.22323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,7]]},"references-count":24,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,9]]}},"alternative-id":["10.1002\/gepi.22323"],"URL":"https:\/\/doi.org\/10.1002\/gepi.22323","archive":["Portico"],"relation":{},"ISSN":["0741-0395","1098-2272"],"issn-type":[{"value":"0741-0395","type":"print"},{"value":"1098-2272","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,7]]},"assertion":[{"value":"2019-10-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}