A Plasmode Simulation‐Based Bias Analysis for Residual Confounding by Unmeasured Variables Leveraging Information‐Rich Subsets

Aim To develop a quantitative bias analysis approach based on realistic assumptions reflective of the complexities of healthcare data. Methods We describe a ‘plasmode’ simulation‐based bias analysis for residual confounding from unmeasured variables by leveraging granular information from a subset of cohort members. We generated 500 simulated cohorts based on individual‐level claims and linked electronic health record (EHR) data identifying new users of varenicline and bupropion from the Mass General Brigham site of the FDA Sentinel Real World Evidence Data Enterprise. Two adverse outcomes were simulated: (1) neuropsychiatric hospitalizations and (2) major adverse cardiovascular events (MACE), and measured confounding factors, identified from information available in claims including demographics, comorbid conditions, and comedications, were tailored to each outcome. Residual confounding was simulated using potential confounders measured in EHRs but unmeasured in claims including suicidal ideation for the neuropsychiatric outcomes and body mass index (BMI), blood pressure (BP), and smoking pack‐years for the MACE outcome. These simulations retained the correlation between claims and EHR‐based confounders observed in empirical data for realistic reflection of proxy adjustment of unmeasured confounders. Analyses were conducted in simulated data with and without adjustment for the EHR‐based covariates to evaluate the extent of residual confounding in claims‐only analyses. Results After 500 simulations, the median absolute standardized mean difference (ASMD) between treatment groups in the unadjusted sample was 0.16 for suicidal ideation; while < 0.1 for BMI, BP, and smoking pack‐years. For both outcomes, adjustment using claims‐based variables provided relative bias close to 0, leading to the conclusion that EHR‐measured confounders that were unmeasured in claims were unlikely to result in strong residual confounding within realistic simulations informed by empirical data. Conclusion The proposed approach provides a method for quantifying bias in non‐randomized studies threatened by the unavailability of potentially important confounding variables.