Causal machine learning methods and use of sample splitting in settings with high-dimensional confounding

Observational epidemiological studies commonly seek to estimate the causal effect of an exposure on an outcome. Adjustment for potential confounding bias in modern studies is challenging due to the presence of high-dimensional confounding, which occurs when there are many confounders relative to sample size or complex relationships between continuous confounders and exposure and outcome. Despite recent advances, limited evaluation, and guidance are available on the implementation of doubly robust methods, Augmented Inverse Probability Weighting (AIPW) and Targeted Maximum Likelihood Estimation (TMLE), with data-adaptive approaches and cross-fitting in realistic settings where high-dimensional confounding is present. Motivated by an early-life cohort study, we conducted an extensive simulation study to compare the relative performance of AIPW and TMLE using data-adaptive approaches in estimating the average causal effect (ACE). We evaluated the benefits of using cross-fitting with a varying number of folds, as well as the impact of using a reduced versus full (larger, more diverse) library in the Super Learner ensemble learning approach used for implementation. We found that AIPW and TMLE performed similarly in most cases for estimating the ACE, but TMLE was more stable. Cross-fitting improved the performance of both methods, but was more important for estimation of standard error and coverage than for point estimates, with the number of folds a less important consideration. Using a full Super Learner library was important to reduce bias and variance in complex scenarios typical of modern health research studies.