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An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data (N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92\u20133.00; P = 1.80 \u00d7 10\u221214] in the validation set (Ptrend = 5.26 \u00d7 10\u221220). The OR per SD of PRS increase was 1.26 (95% CI = 1.20\u20131.32; P = 9.69 \u00d7 10\u221223) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/0008-5472.can-20-1237","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T17:40:13Z","timestamp":1611164413000},"page":"1607-1615","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model"],"prefix":"10.1158","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4486-7496","authenticated-orcid":false,"given":"Rayjean J.","family":"Hung","sequence":"first","affiliation":[{"name":"1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada."},{"name":"2Dalla Lana School of Public Health, University of Toronto, Toronto, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8730-3511","authenticated-orcid":false,"given":"Matthew T.","family":"Warkentin","sequence":"additional","affiliation":[{"name":"1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada."},{"name":"2Dalla Lana School of Public Health, University of Toronto, Toronto, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonathan","family":"Brhane","sequence":"additional","affiliation":[{"name":"1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilanjan","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"3Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0301-0242","authenticated-orcid":false,"given":"David C.","family":"Christiani","sequence":"additional","affiliation":[{"name":"4Department of Environmental Health, Harvard TH Chan School of Public Health, and Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Landi","sequence":"additional","affiliation":[{"name":"5Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil E.","family":"Caporaso","sequence":"additional","affiliation":[{"name":"5Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2603-7296","authenticated-orcid":false,"given":"Geoffrey","family":"Liu","sequence":"additional","affiliation":[{"name":"6Princess Margaret Cancer Center, Toronto, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-5081","authenticated-orcid":false,"given":"Mattias","family":"Johansson","sequence":"additional","affiliation":[{"name":"7International Agency for Research on Cancer, Lyon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demetrius","family":"Albanes","sequence":"additional","affiliation":[{"name":"5Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loic Le","family":"Marchand","sequence":"additional","affiliation":[{"name":"8University of Hawaii Cancer Center, Honolulu, Hawaii."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5150-1209","authenticated-orcid":false,"given":"Adonina","family":"Tardon","sequence":"additional","affiliation":[{"name":"9Universidad de Oviedo, ISPA and CIBERESP, Oviedo, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gad","family":"Rennert","sequence":"additional","affiliation":[{"name":"10Department of Community Medicine and Epidemiology, Carmel Medical Center and B. 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Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu","family":"Chen","sequence":"additional","affiliation":[{"name":"12Fred Hutchinson Cancer Research Center, Seattle, Washington."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3951-6365","authenticated-orcid":false,"given":"John K.","family":"Field","sequence":"additional","affiliation":[{"name":"13University of Liverpool Cancer Research Centre, Liverpool, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2368-1326","authenticated-orcid":false,"given":"Lambertus A.","family":"Kiemeney","sequence":"additional","affiliation":[{"name":"14Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Lazarus","sequence":"additional","affiliation":[{"name":"15Washington State University, Spokane, Washington."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanbeth","family":"Zienolddiny","sequence":"additional","affiliation":[{"name":"16National Institute of Occupational Health, Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Lam","sequence":"additional","affiliation":[{"name":"17University of British Columbia, Vancouver, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeline S.","family":"Andrew","sequence":"additional","affiliation":[{"name":"18Dartmouth Medical School, Hanover, New Hampshire."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne M.","family":"Arnold","sequence":"additional","affiliation":[{"name":"19Markey Cancer Center, Lexington, Kentucky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-8448","authenticated-orcid":false,"given":"Melinda C.","family":"Aldrich","sequence":"additional","affiliation":[{"name":"20Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Bickeb\u00f6ller","sequence":"additional","affiliation":[{"name":"21Department of Genetic Epidemiology, University Medical Center, Georg-August-University G\u00f6ttingen, G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8026-5505","authenticated-orcid":false,"given":"Angela","family":"Risch","sequence":"additional","affiliation":[{"name":"22University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3241-3216","authenticated-orcid":false,"given":"Matthew B.","family":"Schabath","sequence":"additional","affiliation":[{"name":"23H. 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