Unveiling new insights into migraine risk stratification using machine learning models of adjustable risk factors.

Abstract

Background: Migraine ranks as the second-leading cause of global neurological disability, affecting approximately 1.1 billion individuals worldwide with severe quality-of-life impairments. Although adjustable risk factors-including environmental exposures, sleep disturbances, and dietary patterns-are increasingly implicated in pathogenesis of migraine, their causal roles remain insufficiently characterized, and the integration of multimodal evidence lags behind epidemiological needs.

Methods: We developed a three-step analytical framework combining causal inference, predictive modeling, and burden projection to systematically evaluate modifiable factors associated with migraine. First, two-sample mendelian randomization (MR) assessed causality between five domains (metabolic profiles, body composition, cardiovascular markers, behavioral traits, and psychological states) and the risk of migraine. Second, we trained ensemble machine learning (ML) algorithms that incorporated these factors, with Shapley Additive exPlanations (SHAP) value analysis quantifying predictor importance. Finally, spatiotemporal burden mapping synthesized global incidence, prevalence, and disability-adjusted life years (DALYs) data to project region-specific risk and burden trajectories through 2050.

Results: MR analyses identified significant causal associations between multiple adjustable factors (including overweight, obesity class 2, type 2 diabetes [T2DM], hip circumference [HC], body mass index [BMI], myocardial infarction, and feeling miserable) and the risk of migraine (P < 0.05, FDR-q < 0.05). The Random Forest (RF)-based model achieved excellent discrimination (Area under receiver operating characteristic curve [AUROC] = 0.927), identifying gender, age, HC, waist circumference [WC], BMI, and systolic blood pressure [SBP] as the predictors. Burden mapping projected a global decline in migraine incidence by 2050, yet persistently high prevalence and DALYs burdens underscored the urgency of timely interventions to maximize health gains.

Conclusions: Integrating causal inference, predictive modeling, and burden projection, this study establishes hierarchical evidence for adjustable migraine determinants and translates findings into scalable prevention frameworks. These findings bridge the gap between biological mechanisms, clinical practice, and public health policy, providing a tripartite framework that harmonizes causal inference, individualized risk prediction, and global burden mapping for migraine prevention.