Complementing Observational Signals with Literature-Derived Distributed Representations for Post-Marketing Drug Surveillance

Introduction: As a result of the well documented limitations of data collected by spontaneous reporting systems (SRS), such as bias and under-reporting, a number of authors have evaluated the utility of other data sources for the purpose of pharmacovigilance, including the biomedical literature. Previous work has demonstrated the utility of literature-derived distributed representations (concept embeddings) with machine learning for the purpose of drug side-effect prediction. In terms of data sources, these methods are complementary, observing drug safety from two different perspectives (knowledge extracted from the literature and statistics from SRS data). However, the combined utility of these pharmacovigilance methods has yet to be evaluated.

Objective: This research investigates the utility of directly or indirectly combining an observational signal from SRS with literature-derived distributed representations into a single feature vector or in an ensemble approach for downstream machine learning (logistic regression).

Methods: Leveraging a recently developed representation scheme, concept embeddings were generated from relational connections extracted from the literature and composed to represent drug and associated adverse reactions, as defined by two reference standards of positive (likely causal) and negative (no causal evidence) pairs. Embeddings were presented with and without common measures of observational signal from SRS sources to logistic regressors, and performance was evaluated with the receiver operating characteristic (ROC) area under the curve (AUC) metric.

Results: ROC AUC performance with these composite models improves up to ≈ 20% over SRS-based disproportionality metrics alone and exceeds the best prior results reported in the literature when models leverage both sources of information.

Conclusions: Results from this study support the hypothesis that knowledge extracted from the literature can enhance the performance of SRS-based methods (and vice versa). Across reference sets, using literature and SRS information together performed better than using either source alone, providing strong support for the complementary nature of these approaches to post-marketing drug surveillance.