Knowledge graph prediction of unknown adverse drug reactions and validation in electronic health records

Unknown adverse reactions to drugs available on the market present a significant health risk and limit accurate judgement of the cost/benefit trade-off for medications. Machine learning has the potential to predict unknown adverse reactions from current knowledge. We constructed a knowledge graph containing four types of node: drugs, protein targets, indications and adverse reactions. Using this graph, we developed a machine learning algorithm based on a simple enrichment test and first demonstrated this method performs extremely well at classifying known causes of adverse reactions (AUC 0.92). A cross validation scheme in which 10% of drug-adverse reaction edges were systematically deleted per fold showed that the method correctly predicts 68% of the deleted edges on average. Next, a subset of adverse reactions that could be reliably detected in anonymised electronic health records from South London and Maudsley NHS Foundation Trust were used to validate predictions from the model that are not currently known in public databases. High-confidence predictions were validated in electronic records significantly more frequently than random models, and outperformed standard methods (logistic regression, decision trees and support vector machines). This approach has the potential to improve patient safety by predicting adverse reactions that were not observed during randomised trials.