A Novel Digital Twin Strategy to Examine the Implications of Randomized Control Trials for Real-World Populations

medRxiv [Preprint]. 2024 Mar 26:2024.03.25.24304868. doi: 10.1101/2024.03.25.24304868.

Abstract

Randomized clinical trials (RCTs) are essential to guide medical practice; however, their generalizability to a given population is often uncertain. We developed a statistically informed Generative Adversarial Network (GAN) model, RCT-Twin-GAN, that leverages relationships between covariates and outcomes and generates a digital twin of an RCT (RCT-Twin) conditioned on covariate distributions from a second patient population. We used RCT-Twin-GAN to reproduce treatment effect outcomes of the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial, which tested the same intervention but had different treatment effect results. To demonstrate treatment effect estimates of each RCT conditioned on the other RCT patient population, we evaluated the cardiovascular event-free survival of SPRINT digital twins conditioned on the ACCORD cohort and vice versa (SPRINT-conditioned ACCORD twins). The conditioned digital twins were balanced by the intervention arm (mean absolute standardized mean difference (MASMD) of covariates between treatment arms 0.019 (SD 0.018), and the conditioned covariates of the SPRINT-Twin on ACCORD were more similar to ACCORD than a sprint (MASMD 0.0082 SD 0.016 vs. 0.46 SD 0.20). Most importantly, across iterations, SPRINT conditioned ACCORD-Twin datasets reproduced the overall non-significant effect size seen in ACCORD (5-year cardiovascular outcome hazard ratio (95% confidence interval) of 0.88 (0.73-1.06) in ACCORD vs median 0.87 (0.68-1.13) in the SPRINT conditioned ACCORD-Twin), while the ACCORD conditioned SPRINT-Twins reproduced the significant effect size seen in SPRINT (0.75 (0.64-0.89) vs median 0.79 (0.72-0.86)) in ACCORD conditioned SPRINT-Twin). Finally, we describe the translation of this approach to real-world populations by conditioning the trials on an electronic health record population. Therefore, RCT-Twin-GAN simulates the direct translation of RCT-derived treatment effects across various patient populations with varying covariate distributions.

Publication types

  • Preprint