Evaluating Individual Level Performance of Polygenic Risk Scores Using Early Onset High Genetic Risk Coronary Artery Disease as a Benchmark.

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 "benchmark" cohort (N=1184) of "unexpected coronary artery disease (CAD)": early-onset patients (<55 years) with a clinical profile-low 10-year risk, no diabetes or severe hypercholesterolemia-that excludes therapy indications. The occurrence of early CAD in these clinically low-risk individuals establishes a "ground truth" 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.