Background: Randomized clinical trials (RCTs) are designed to produce evidence in selected populations. Assessing their effects in the real-world is essential to change medical practice, however, key populations are historically underrepresented in the RCTs. We define an approach to simulate RCT-based effects in real-world settings using RCT digital twins reflecting the covariate patterns in an electronic health record (EHR).
Methods: We developed a Generative Adversarial Network (GAN) model, RCT-Twin-GAN, which generates a digital twin of an RCT (RCT-Twin) conditioned on covariate distributions from an EHR cohort. We improved upon a traditional tabular conditional GAN, CTGAN, with a loss function adapted for data distributions and by conditioning on multiple discrete and continuous covariates simultaneously. We assessed the similarity between a Heart Failure with preserved Ejection Fraction (HFpEF) RCT (TOPCAT), a Yale HFpEF EHR cohort, and RCT-Twin. We also evaluated cardiovascular event-free survival stratified by Spironolactone (treatment) use.
Results: By applying RCT-Twin-GAN to 3445 TOPCAT participants and conditioning on 3445 Yale EHR HFpEF patients, we generated RCT-Twin datasets between 1141-3445 patients in size, depending on covariate conditioning and model parameters. RCT-Twin randomly allocated spironolactone (S)/ placebo (P) arms like an RCT, was similar to RCT by a multi-dimensional distance metric, and balanced covariates (median absolute standardized mean difference (MASMD) 0.017, IQR 0.0034-0.030). The 5 EHR-conditioned covariates in RCT-Twin were closer to the EHR compared with the RCT (MASMD 0.008 vs 0.63, IQR 0.005-0.018 vs 0.59-1.11). RCT-Twin reproduced the overall effect size seen in TOPCAT (5-year cardiovascular composite outcome odds ratio (95% confidence interval) of 0.89 (0.75-1.06) in RCT vs 0.85 (0.69-1.04) in RCT-Twin).
Conclusions: RCT-Twin-GAN simulates RCT-derived effects in real-world patients by translating these effects to the covariate distributions of EHR patients. This key methodological advance may enable the direct translation of RCT-derived effects into real-world patient populations and may enable causal inference in real-world settings.
Keywords: Electronic Health Records; Generative Adversarial Networks; Randomized Control Trials; Synthetic Cohorts.