Robust causal inference of drug-drug interactions.

There is growing interest in developing causal inference methods for multi-valued treatments with a focus on pairwise average treatment effects. Here we focus on a clinically important, yet less-studied estimand: causal drug-drug interactions (DDIs), which quantifies the degree to which the causal effect of drug A is altered by the presence versus the absence of drug B. Confounding adjustment when studying the effects of DDIs can be accomplished via inverse probability of treatment weighting (IPTW), a standard approach originally developed for binary treatments and later generalized to multi-valued treatments. However, this approach generally results in biased results when the propensity score model is misspecified. Motivated by the need for more robust techniques, we propose two empirical likelihood-based weighting approaches that allow for specifying a set of propensity score models, with the second method balancing user-specified covariates directly, by incorporating additional, nonparametric constraints. The resulting estimators from both methods are consistent when the postulated set of propensity score models contains a correct one; this property has been termed multiple robustness. In this paper, we derive two multiply-robust estimators of the causal DDI, and develop inference procedures. We then evaluate their finite sample performance through simulation. The results demonstrate that the proposed estimators outperform the standard IPTW method in terms of both robustness and efficiency. Finally, we apply the proposed methods to evaluate the impact of renin-angiotensin system inhibitors (RAS-I) on the comparative nephrotoxicity of nonsteroidal anti-inflammatory drugs (NSAID) and opioids, using data derived from electronic medical records from a large multi-hospital health system.