Abstract
PURPOSE: SCORE2 is a 10-year CVD risk prediction model developed for use in European populations. This study aimed to externally validate the SCORE2 model and assess its clinical usefulness in an Iranian adult population using data from the TLGS cohort. METHODS: A total of 4,942 individuals aged 40-69 years participated in the TLGS cohort, which was randomly sampled from the population. A Fine and Gray competing risk model was fitted to estimate sex-specific regression coefficients in the TLGS cohort for comparison with the original SCORE2 model. The outcome was first fatal or non-fatal CVD event (myocardial infarction, stroke, or CVD death), considering non-CVD mortality as a competing event. The predictors included age, sex, smoking status, history of diabetes, SBP, total cholesterol, and HDL cholesterol. Model performance was evaluated as statistical performance (discrimination using Harrell's C-index , calibration via plots and O/E ratio) and clinical performance (sensitivity, specificity, decision curve analysis, and net benefit fraction) across different SCORE2 risk thresholds. RESULTS: A total of 4,579 adults without a history of CVD were included in this study. During the follow-up period, CVD events occurred in 211 (11.05%) men and 151 (5.70%) women. The 10-year cumulative incidence of CVD was 8.00% (95% CI: 6.90-9.40) in men and 3.70% (3.00-4.50) in women. The validated SCORE2 model showed higher discrimination in women (C-index: 0.80; 0.76-0.83) than in men (0.70; 0.67-0.74), but it underestimated the CVD risk in both sexes (men: O/E: 2.05; 2.02-2.08, women: O/E: 1.50; 1.40-1.50). At the risk threshold of ≤ 2.5% for individuals under 50 years and ≤ 5% for those aged 50 years and older, sensitivity in men was 0.65 (0.57-0.73) and specificity was 0.63 (0.60-0.65). In women, sensitivity was 0.54 (0.44-0.64) and specificity was 0.88 (0.87-0.89). Decision curve analysis supported its clinical usefulness, particularly at intermediate risk levels (7.5-15%) in both sexes. The net benefit fraction ranged from 0.13 to 0.49 in men and 0.07-0.42 in women. CONCLUSION: The validated SCORE2 model demonstrated good discriminatory performance, particularly in women, but calibration tended to underestimate risk. Although net benefit indicated that the model provides meaningful clinical usefulness in identifying individuals who may benefit from preventive interventions, recalibration and updating the model according to national data is recommended. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-025-01730-5.