Estimating the causal effects of multiple intermittent treatments with application to COVID-19.

To draw real-world evidence about the comparative effectiveness of multiple time-varying treatments on patient survival, we develop a joint marginal structural survival model and a novel weighting strategy to account for time-varying confounding and censoring. Our methods formulate complex longitudinal treatments with multiple start/stop switches as the recurrent events with discontinuous intervals of treatment eligibility. We derive the weights in continuous time to handle a complex longitudinal data set without the need to discretise or artificially align the measurement times. We further use machine learning models designed for censored survival data with time-varying covariates and the kernel function estimator of the baseline intensity to efficiently estimate the continuous-time weights. Our simulations demonstrate that the proposed methods provide better bias reduction and nominal coverage probability when analysing observational longitudinal survival data with irregularly spaced time intervals, compared to conventional methods that require aligned measurement time points. We apply the proposed methods to a large-scale COVID-19 data set to estimate the causal effects of several COVID-19 treatments on the composite of in-hospital mortality and intensive care unit (ICU) admission relative to findings from randomised trials.