{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:36:49Z","timestamp":1776775009735,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,18]]},"group-title":"Genetic and Genomic Medicine","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Polygenic risk scores (PRSs) are typically validated using population-level metrics, masking variability in individual-level risk prediction and hindering clinical translation. To address this, we introduced a novel framework using a \u201cbenchmark\u201d cohort (N=1184) of \u201cunexpected coronary artery disease (CAD)\u201d: early-onset patients (&lt;55 years) with a clinical profile\u2014low 10-year risk, no diabetes or severe hypercholesterolemia\u2014that excludes therapy indications. The occurrence of early CAD in these clinically low-risk individuals establishes a \u201cground truth\u201d for high genetic risk. We evaluated 58 published CAD PRSs and demonstrated a disconnection between population-level performance and individual-level accuracy (proportion of benchmark patients captured). The proportion captured by 58 PRSs varied from 10.8% to 33.1%, and the top-performing score was 2-fold more effective at identifying the benchmark group than established non-genetic biomarkers, such as lipoprotein(a). Furthermore, benchmark patients never captured by any score exhibited significantly healthier lipid profiles. Our framework provides an essential method for validating clinical readiness of PRSs.<\/jats:p>","DOI":"10.64898\/2026.04.16.26350801","type":"posted-content","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T20:00:13Z","timestamp":1776542413000},"source":"Crossref","is-referenced-by-count":0,"title":["Evaluating Individual Level Performance of Polygenic Risk Scores Using Early Onset High Genetic Risk Coronary Artery Disease as a Benchmark"],"prefix":"10.64898","author":[{"given":"Shengxin","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Harvard T.H. 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