Recalibration and external validation of vascular risk calculators for multiple sclerosis: A population-based study using CPRD data in England, 1987–2023

BACKGROUND: People with multiple sclerosis (PwMS) have an elevated risk of macrovascular disease that may be underestimated by vascular risk calculators (VRCs) validated in the general population. OBJECTIVES: This study evaluated, recalibrated and externally validated five commonly used VRCs for PwMS using population-based data from England, 1987-2023. METHODS: PwMS and matched controls were identified from Clinical Practice and Research Datalink (CPRD) GOLD (calibration) and CPRD Aurum (validation). Exposure variables included multiple sclerosis (MS) status and risk factors as defined in Atherosclerotic Cardiovascular Disease, Framingham Risk Score (FRS), FRS-BMI (body mass index), QRESEARCH risk estimator version 3 score and Systematic Coronary Risk Evaluation version 2 score (SCORE2). Model performance was assessed using Somers' D statistic, area under the receiver operating characteristic (ROC) curve and Hosmer-Lemeshow chi-square test. VRCs with ROC < 0.70 in PwMS were recalibrated using Cox regression, incorporating MS status. Ten-fold cross-validation was used to estimate Somers' D. RESULTS: Calibration: 9411 PwMS and 57,805 controls; validation: 45,934 PwMS and 278,452 controls. Discrimination declined with standard thresholds (e.g. SCORE2 sensitivity in PwMS, 30.0%). Only FRS-BMI retained all significant predictors and was successfully recalibrated, improving discrimination (Somers' D = 0.815 vs. 0.792; Δ = 0.023) and showing good calibration. External validation showed modest gain (Somers' D = 0.716; Δ = 0.003). CONCLUSION: These findings underscore the limitations of general-population VRCs in PwMS and support the development of MS-specific vascular risk models.