Bayesian fusion forests for heterogeneous treatment effects on survival from randomised and real-world data

We develop the Bayesian fusion forest, a nonparametric framework to estimate heterogeneous treatment effects on survival outcomes by combining a randomised controlled trial and real-world data. The framework relaxes the unconfoundedness assumption on the real-world data by assuming instead that the treatment effect transports across the two sources. Our method opens up right- and interval-censored outcomes to data fusion. We model the survival time with an accelerated failure time decomposition into a shared baseline prognosis, a source-specific deviation, a treatment effect, and a confounding function. The confounding function absorbs the confounding bias in the real-world data. Each component receives a Bayesian tree ensemble prior. The shared baseline prognosis borrows strength across sources, while the deviation captures between-source heterogeneity. A hierarchical Dirichlet process mixture models the error distribution nonparametrically. A simulation study shows efficiency gains over a trial-only analysis across varying levels of confounding and between-source heterogeneity. We combine the ACTG 175 trial with the Multicenter AIDS Cohort Study to estimate the effect of combination antiretroviral therapy for HIV. The fusion identifies a benefit for nearly every patient whereas the trial alone is inconclusive.

Optimizing Clinical Trial Protocols Using EHR-Derived Heterogeneous Treatment Effects

Traditional randomized trials often obscure clinically meaningful heterogeneity in treatment response by focusing on average effects. Leveraging real-world data to emulate clinical trials and estimate heterogeneous treatment effects (HTEs) offers a promising path toward more precise and efficient trial design. In this study, we emulate the DAPA-HF trial using electronic health records from the Mayo Clinic Cloud (MCC) to investigate whether HTE-guided stratification can identify patient subgroups with distinct treatment responses to dapagliflozin versus placebo in patients with heart failure with reduced ejection fraction. All-cause mortality was evaluated using Cox proportional hazards models, with HTEs estimated using a Meta-S learner and subgroups defined using a decision tree-based thresholding approach. In the overall cohort of the emulation, no significant treatment difference was observed (HR, 1.681; 95% CI, 0.828-3.413; p = 0.1507). However, compared with the overall emulated cohort, in which dapagliflozin showed no statistically significant survival benefit, HTE-driven stratification identified subgroups with significant and directionally distinct treatment effects. The beneficial (low-HTE) subgroup showed a significant survival benefit from dapagliflozin (HR = 0.203, 95% CI, 0.087-0.476, p = 0.0002), whereas the harmful (high-HTE) subgroup showed a significant harmful association with markedly increased mortality risk (HR = 6.680, 95% CI, 2.759-16.171, p < 0.0001). These findings indicate that HTE-guided stratification can uncover clinically meaningful beneficial and harmful treatment-effect patterns that are masked in the full-cohort emulation.