Inverse Probability of Treatment Weighting and Confounder Missingness in Electronic Health Record-based Analyses: A Comparison of Approaches Using Plasmode Simulation

Electronic health record (EHR) data represent a critical resource for comparative effectiveness research, allowing investigators to study intervention effects in real-world settings with large patient samples. However, high levels of missingness in confounder variables is common, challenging the perceived validity of EHR-based investigations. METHODS: We investigated performance of multiple imputation and propensity score (PS) calibration when conducting inverse probability of treatment weights (IPTW)-based comparative effectiveness research using EHR data with missingness in confounder variables and outcome misclassification. Our motivating example compared effectiveness of immunotherapy versus chemotherapy treatment of advanced bladder cancer with missingness in a key prognostic variable. We captured complexity in EHR data structures using a plasmode simulation approach to spike investigator-defined effects into resamples of a cohort of 4361 patients from a nationwide deidentified EHR-derived database. We characterized statistical properties of IPTW hazard ratio estimates when using multiple imputation or PS calibration missingness approaches. RESULTS: Multiple imputation and PS calibration performed similarly, maintaining ≤0.05 absolute bias in the marginal hazard ratio even when ≥50% of subjects had missing at random or missing not at random confounder data. Multiple imputation required greater computational resources, taking nearly 40 times as long as PS calibration to complete. Outcome misclassification minimally increased bias of both methods. CONCLUSION: Our results support multiple imputation and PS calibration approaches to missingness in missing completely at random or missing at random confounder variables in EHR-based IPTW comparative effectiveness analyses, even with missingness ≥50%. PS calibration represents a computationally efficient alternative to multiple imputation.