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However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single\u2010nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred\u2010funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12205","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T09:53:14Z","timestamp":1631613194000},"page":"1387-1397","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data: a multi\u2010phased study of prostate cancer"],"prefix":"10.34133","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8400-1785","authenticated-orcid":false,"given":"Chong","family":"Wu","sequence":"first","affiliation":[{"name":"Florida State University","place":["Tallahassee, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Zhu","sequence":"additional","affiliation":[{"name":"University of Hawaii at Manoa","place":["Honolulu, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin","family":"King","sequence":"additional","affiliation":[{"name":"Florida State University","place":["Tallahassee, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoran","family":"Tong","sequence":"additional","affiliation":[{"name":"Michigan State University","place":["East Lansing, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Lu","sequence":"additional","affiliation":[{"name":"University of Florida","place":["Gainesville, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Y.","family":"Park","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute","place":["Tampa, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Wang","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute","place":["Tampa, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guimin","family":"Gao","sequence":"additional","affiliation":[{"name":"University of Chicago","place":["Chicago, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong\u2010Wen","family":"Deng","sequence":"additional","affiliation":[{"name":"Tulane University","place":["New Orleans, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaohua","family":"Yang","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center","place":["Nashville, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen E.","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Thomas Jefferson University","place":["Philadelphia, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy R.","family":"Rebbeck","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber Cancer Institute","place":["Boston, USA"]},{"name":"Harvard TH Chan School of Public Health","place":["Boston, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jirong","family":"Long","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center","place":["Nashville, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center","place":["Nashville, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Pan","sequence":"additional","affiliation":[{"name":"University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David V.","family":"Conti","sequence":"additional","affiliation":[{"name":"University of Southern California\/Norris Comprehensive Cancer Center","place":["Los Angeles, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher A","family":"Haiman","sequence":"additional","affiliation":[{"name":"University of Southern California\/Norris Comprehensive Cancer Center","place":["Los Angeles, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9938-3627","authenticated-orcid":false,"given":"Lang","family":"Wu","sequence":"additional","affiliation":[{"name":"University of Hawaii at Manoa","place":["Honolulu, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21590"},{"issue":"5","key":"e_1_3_2_3_2","first-page":"S3","article-title":"Risk factors for prostate cancer","volume":"4","author":"Gann PH","year":"2002","unstructured":"Gann PH. 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