Observing the unobserved confounding through its effects: toward randomized trial-like estimates from real-world survival data

Background: Randomized controlled trials (RCTs) are costly, time-consuming, and often infeasible, while treatment-effect estimation from observational data is limited by unobserved confounding. Methods: We developed a three-step framework to address unobserved confounding in observational survival data. First, we infer a latent prognostic factor (U) from restricted mean survival time (RMST) discrepancies between patients with similar observed factors, the same treatment, and divergent outcomes, leveraging the idea that the aggregate effect of unmeasured factors can be inferred even if individual factors cannot. Second, we balance U with observed baseline covariates using prognostic matching, entropy balancing, or inverse probability of treatment weighting. Third, we apply multivariable survival analysis to estimate hazard ratios (HRs). We evaluated the framework in three observational cohorts with RCT benchmarks, two RCT cohorts, and six multicenter observational cohorts. Results: In three observational cohorts (nine comparisons), balancing U improved agreement with trial HRs in all cases; in the strongest settings, it reduced absolute log-HR error by approximately ten-fold versus using observed covariates alone (mean reduction 0.344; p=0.001). In two RCT cohorts, U was balanced across arms (most SMDs <0.1) and adjustment had minimal impact on log-HRs (mean absolute change 0.08). Across six multicenter cohorts, balancing U within centers reduced cross-center dispersion in chemotherapy log-HR estimates (mean reduction 0.147; p=0.016); when populations were directly balanced across centers to account for case-mix differences, cross-center survival differences were narrowed in 75%-100% of comparisons. Conclusions: Inferring and balancing a latent prognostic signal may reduce unobserved confounding and improve treatment-effect estimation from real-world data.