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We assessed the clinical validity of the model in a large independent prospective cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We validated BOADICEA (V.6) in the Swedish KARolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort including 66\u2009415 women of European ancestry (median age 54 years, IQR 45\u201363; 816 incident breast cancers) without previous cancer diagnosis. We calculated 5-year risks on the basis of questionnaire-based risk factors, pedigree-structured first-degree family history, mammographic density (BI-RADS), a validated breast cancer polygenic risk score (PRS) based on 313-SNPs, and pathogenic variant status in 8 breast cancer susceptibility genes:\n                      <jats:italic>BRCA1<\/jats:italic>\n                      ,\n                      <jats:italic>BRCA2<\/jats:italic>\n                      ,\n                      <jats:italic>PALB2<\/jats:italic>\n                      ,\n                      <jats:italic>CHEK2<\/jats:italic>\n                      ,\n                      <jats:italic>ATM<\/jats:italic>\n                      ,\n                      <jats:italic>RAD51C<\/jats:italic>\n                      ,\n                      <jats:italic>RAD51D<\/jats:italic>\n                      and\n                      <jats:italic>BARD1<\/jats:italic>\n                      . Calibration was assessed by comparing observed and expected risks in deciles of predicted risk and the calibration slope. The discriminatory ability was assessed using the area under the curve (AUC).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among the individual model components, the PRS contributed most to breast cancer risk stratification. BOADICEA was well calibrated in predicting the risks for low-risk and high-risk women when all, or subsets of risk factors are included in the risk prediction. Discrimination was maximised when all risk factors are considered (AUC=0.70, 95%\u2009CI: 0.66 to 0.73; expected-to-observed ratio=0.88, 95%\u2009CI: 0.75 to 1.04; calibration slope=0.97, 95%\u2009CI: 0.95 to 0.99). The full multifactorial model classified 3.6% women as high risk (5-year risk \u22653%) and 11.1% as very low risk (5-year risk &lt;0.33%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The multifactorial BOADICEA model provides valid breast cancer risk predictions and a basis for personalised decision-making on disease prevention and screening.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2022-108806","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T08:20:11Z","timestamp":1664180411000},"page":"1196-1205","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":98,"title":["Prospective validation of the BOADICEA multifactorial breast cancer risk prediction model in a large prospective cohort study"],"prefix":"10.1136","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-3790","authenticated-orcid":false,"given":"Xin","family":"Yang","sequence":"first","affiliation":[{"name":"Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Czene","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 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