medRxiv (Medicine)
2026-06-24
DOI: HASH:2c5ad125f294e4fd8a22addca8246438
Importance: Machine-learning models for ischemic stroke risk prediction are rarely validated across ancestrally distinct cohorts, and the contributions of polygenic risk scores (PRS) and self-reported race in such models remain unclear. Objective: To develop and externally validate a 10-year ischemic stroke risk model and quantify the incremental contributions of laboratory trajectories, PRS, and self-reported race and ethnicity across populations. Design, Setting, and Participants: Retrospective cohort study with model development in the All of Us (AoU) Research Program (n = 34,987; 1,920 incident strokes) and external validation in the BioMe Biobank at Mount Sinai (n = 10,693; 107 incident strokes). Adults aged 45 years or older with at least 1 year of pre-baseline electronic health record data were anchored to a January 2010 baseline with 10-year follow-up. Exposures: Three XGBoost model tiers added laboratory feature trajectories (M2) and 20 PRS (M3) to clinical baseline features (M1); evaluated under race-blind and race-aware specifications. Main Outcomes and Measures: First inpatient ischemic stroke within 10 years; discrimination (area under the receiver operating characteristic curve [AUROC]) and calibration (observed-to-expected [O/E] ratio). Results: In the AoU test partition (n = 6,998; 384 cases), M3 achieved an AUROC of 0.813 (95% CI, 0.788-0.837), outperforming the Revised Framingham Stroke Risk Profile (AUROC difference, 0.164) and Pooled Cohort Equations (AUROC difference, 0.181; both P < 0.001). Discrimination transferred to BioMe (AUROC, 0.745), but predictions were systematically high (aggregate O/E ratio, 0.12 vs 1.00 in AoU), consistent with intercept-shift miscalibration; BioMe-fitted intercept recalibration restored calibration in African American and Hispanic participants but not European American participants. The PRS contribution was significant only among Hispanic participants in BioMe (AUROC difference, 0.042; P = 0.003), with no significant within-stratum gain in the other 5 cohort-by-race combinations. Adding self-reported race produced small gains when combined with PRS (BioMe AUROC difference, 0.022; P = 0.034; AoU AUROC difference, 0.006; P = 0.052) but not when added without PRS. Conclusions and Relevance: A machine-learning ensemble combining clinical, laboratory, and polygenic features outperformed traditional risk scores by 0.16 to 0.18 AUROC and retained discriminative validity in an ancestrally distinct external cohort but required site-specific recalibration of absolute risk. The marginal contribution of self-reported race overlapped with polygenic signal, supporting per-ancestry calibration over universal race-aware model deployment.