Machine learning methods for predicting adverse drug events: A systematic review

Predicting adverse drug events (ADEs) in outpatient settings is crucial for improving medication safety, identifying high-risk patients and reducing health-care costs. While traditional methods struggle with the complexity of health-care data, machine learning (ML) models offer improved prediction capabilities; however, their effectiveness in ADE prediction remains unclear. This systematic review evaluated ML algorithms used for this purpose, analysing studies that focussed on outpatient care or utilized large-scale data sources (e.g. electronic health records, administrative claims and spontaneous reporting systems) that primarily represent the outpatient continuum. We systematically searched MEDLINE and Embase up to December 2024 to identify studies developing or validating ML models for ADE prediction. Study characteristics, ML methods, ADE types, model performance and risk of bias were assessed using the PROBAST tool. From 59 included studies comprising 191 ML implementations, Logistic regression, Random forest and XGBoost emerged as the most commonly used algorithms. The majority of studies (67.8%) reported area under the curve (AUC), with 85% demonstrating moderate to high performance (AUC > 0.70) for internal validation. However, only 33.9% of studies addressed class imbalance, and merely 18.6% conducted external validation, raising concerns about methodological rigour, particularly in missing data handling and validation procedures. Our findings indicate that ML models, especially ensemble methods, show promise in predicting ADEs, although challenges with class imbalance and limited external validation currently hinder their clinical applicability. Future research should focus on adopting more rigorous methodologies and developing specialized frameworks for ML-based ADE prediction that build upon established pharmacovigilance practices to ensure models are accurate, generalizable, and seamlessly integrated into clinical workflows for ongoing monitoring and improved medication safety.