{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:59:09Z","timestamp":1786636749589,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,10]]},"group-title":"Epidemiology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Contemporary cardiovascular disease (CVD) risk equations may not fully capture cumulative biological aging or long-term exposure burden. DNA methylation (DNAm) biomarkers may capture aging- and exposure-related biology, but their incremental prognostic value beyond clinical risk-factor models like PREVENT remains uncertain. To our knowledge, no prior study has benchmarked DNAm-based biomarkers with PREVENT.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In a population-based cohort study, we analyzed NHANES 1999-2002 participants with DNAm biomarkers and mortality follow-up. We derived a DNAmScore from candidate DNAm biomarkers using elastic-net Cox regression with repeated nested cross-validation. A PREVENT-like clinical model was defined as a Cox model fit in NHANES using PREVENT predictors. Weighted Cox models estimated the association between DNAmScore and mortality after adjustment for PREVENT-like clinical predictors. We then compared the PREVENT-like clinical model, DNAmScore alone, and a combined model (PREVENT-like clinical predictors plus DNAmScore) using cross-fitted C-index, time-dependent AUC, calibration, and Brier score.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our cohort included 2,282 participants; 597 and 937 deaths occurred by 10 and 15 years, respectively. After adjustment for PREVENT-like clinical predictors, the cross-fitted DNAmScore was strongly associated with all-cause mortality (HR per 1-SD increase, 2.43; 95% CI, 1.97\u20132.99). At 10 years, AUCs were 0.791 for the PREVENT-like model, 0.791 for DNAmScore, and 0.803 for the combined model. At 15 years, corresponding AUCs were 0.825, 0.822, and 0.835. Compared with the PREVENT-like model, the combined model improved AUC by 0.013 (95% CI, 0.006\u20130.020) at 10 years and 0.010 (95% CI, 0.004\u20130.015) at 15 years. The combined model had lower Brier scores at all three horizons with similar calibration. DNAmScore remained associated with CVD mortality after clinical adjustment.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>DNAmScore identified residual biological risk beyond PREVENT-like clinical predictors, with strong independent mortality associations and modest, consistent improvements in cross-fitted prediction performance. These findings support development and external validation of CVD-specific DNAm biomarkers.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>What Is Known<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Contemporary cardiovascular risk models may not fully capture cumulative biological aging and exposure burden.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>DNA methylation biomarkers are associated with mortality, but their incremental predictive value beyond clinical risk predictors remains uncertain.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>What the Study Adds<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>In a nationally representative NHANES cohort, a cross-fitted composite DNAmScore remained strongly associated with mortality after adjustment for PREVENT predictors.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Adding DNAmScore produced modest improvements in discrimination and prediction error at 5, 10, and 15 years, and DNAmScore was also associated with cardiovascular mortality in secondary analyses.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.07.26359993","type":"posted-content","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T20:30:14Z","timestamp":1786393814000},"source":"Crossref","is-referenced-by-count":0,"title":["DNA Methylation Biomarkers Capture Residual Biological Risk Beyond PREVENT"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1570-134X","authenticated-orcid":false,"given":"Diensn G.","family":"Xing","sequence":"first","affiliation":[{"name":"Department of Biochemistry, LSU Health Shreveport"},{"name":"Department of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0073-3071","authenticated-orcid":false,"given":"Md. Shenuarin","family":"Bhuiyan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"},{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4014-969X","authenticated-orcid":false,"given":"Steven A.","family":"Conrad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, LSU Health Shreveport"},{"name":"Department of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7613-6313","authenticated-orcid":false,"suffix":"Jr.","given":"Arif","family":"Yurdagul","sequence":"additional","affiliation":[{"name":"Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"},{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9272-086X","authenticated-orcid":false,"given":"Oren","family":"Rom","sequence":"additional","affiliation":[{"name":"Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"},{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2377-213X","authenticated-orcid":false,"given":"A. 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