Robust prediction of drug combination side effects in realistic settings

Abstract Side effects caused by drug combinations pose a major challenge in healthcare. Knowledge of these side effects is limited because often they are not detected in clinical trials, which typically involve a restricted number of participants and tested drug combinations. We introduce DCSE (Drug Combinations Side Effects), a novel machine learning method for predicting polypharmacy side effects. DCSE learns latent signatures for drugs, drug pairs, and side effects to predict the probability that a side effect occurs in a given drug combination. We first evaluate its performance in the commonly adopted experimental settings in the literature. Then, a key contribution of this paper is the introduction of more realistic experimental settings that incorporate warm-start and cold-start scenarios under a prospective evaluation. Here, we attempt to predict side effects reported between 2009 and 2014 after training only on data available prior to that period. Our results indicate that DCSE consistently outperforms state-of-the-art methods, demonstrating its robustness and efficacy in real-world applications. Author summary Understanding the risks of combining medications is a central problem in healthcare. Clinical trials rarely capture the full range of adverse reactions, and many side effects are identified only after drugs reach the market, leaving many possible drug combinations insufficiently tested. Computational approaches can help fill this gap by predicting which combinations are likely to cause specific side effects. Our approach works by learning signatures for both drugs and side effects, which can be thought of as representations that describe how drugs act and what is required to trigger a side effect. A key challenge is how to combine the signatures of two drugs into one representation for the pair. We show that simple linear models fail to capture the complexity of drug interactions, so we use a deep neural network to combine them in a non-linear way. Our tests, which use reports collected at different points in time to mirror how information about drug pairs becomes available, show that our approach is useful for monitoring risks after drugs have been approved and for exploring new uses of pairs of existing drugs. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* alberto.paccanaro{at}rhul.ac.uk