Targeted maximum likelihood estimation in safety analysis

Objectives: To compare the performance of a targeted maximum likelihood estimator (TMLE) and a collaborative TMLE (CTMLE) to other estimators in a drug safety analysis, including a regression-based estimator, propensity score (PS) based estimators, and an alternate doubly robust (DR) estimator in a real example and simulations. Study Design and Setting: The real data set is a subset of observational data from Kaiser Permanente Northern California formatted for use in active drug safety surveillance. Both the real and simulated data sets include potential confounders, a treatment variable indicating use of one of two antidiabetic treatments and an outcome variable indicating occurrence of an acute myocardial infarction (AMI). Results: In the real data example, there is no difference in AMI rates between treatments. In simulations, the double robustness property is demonstrated: DR estimators are consistent if either the initial outcome regression or PS estimator is consistent, whereas other estimators are inconsistent if the initial estimator is not consistent. In simulations with near-positivity violations, CTMLE performs well relative to other estimators by adaptively estimating the PS. Conclusion: Each of the DR estimators was consistent, and TMLE and CTMLE had the smallest mean squared error in simulations. (C) 2013 Elsevier Inc. All rights reserved.