Pitfalls and Solutions in Clone-Censor-Weight for Target Trial Emulation: Insights from Review, Simulation, and Real-World Analyses

Background: The clone-censor-weight (CCW) method is increasingly finding application in target trial emulation to compare treatment strategies involving grace periods. However, its performance has not been systematically evaluated against the ground truth. Many studies utilising CCW ignore time-varying covariates and informative pre-existing censoring. Heavy-tailed inverse probability of censoring weights (IPCW) may yield biased estimates and under-coverage. Methods: Simulation Part 1 evaluated the bias, root mean squared error, and coverage probability of CCW analysis under correctly specified and misspecified IPCW models across scenarios with or without time-varying covariates and informative pre-existing censoring. Part 2 varied the confounding strength, assessing whether inference failures could be detected using an IPCW tail-heaviness index (a weighted Hill estimator-derived Pareto-type tail index) and the estimator's standard deviation, the target of bootstrap standard error. Results: Under correct specification, all bias estimates were below 0.005; coverage approached the nominal level of 0.95 with increasing sample size. Omitting the time-varying covariate or mishandling pre-existing censoring yielded bias up to 0.069 and coverage substantially below 0.95. Under strong confounding, confidence intervals failed to attain nominal coverage, even with correct specification and large sample sizes, when the oracle tail-heaviness index was <=1. When the index was >1, the coverage approached 0.95 as the estimator's standard deviation decreased. Conclusions: CCW analysis yields accurate estimates and confidence intervals with nominal coverage when implemented correctly, and confounding is not excessively strong. Investigators should account for time-varying covariates and pre-existing censoring and evaluate the tail behaviour of IPCW distribution and estimator's bootstrap standard error.