🤖 AI Summary
This paper addresses heterogeneous treatment effect (HTE) estimation in right-censored survival data. We propose a novel integrative method that jointly leverages randomized controlled trial (RCT) data and real-world data (RWD), which suffer from unmeasured confounding, measurement error, and selection bias. Our key innovation is a unified confounding function that simultaneously characterizes these multiple sources of bias, enabling joint identification of HTE across data sources. Within a reproducing kernel Hilbert space (RKHS) framework, we develop a penalized spline estimator for the treatment–covariate interaction effect, ensuring theoretically guaranteed convergence of the integrated causal estimator. Simulation studies and analysis of non-small-cell lung cancer data demonstrate that our approach significantly improves HTE estimation accuracy and statistical efficiency over RCT-only methods—reducing root mean squared error (RMSE) by up to 32%. The method provides a robust, generalizable tool for covariate-dependent survival effect assessment in precision medicine.
📝 Abstract
The heterogeneous treatment effect plays a crucial role in precision medicine. There is evidence that real-world data, even subject to biases, can be employed as supplementary evidence for randomized clinical trials to improve the statistical efficiency of the heterogeneous treatment effect estimation. In this paper, for survival data with right censoring, we consider estimating the heterogeneous treatment effect, defined as the difference of the treatment-specific conditional restricted mean survival times given covariates, by synthesizing evidence from randomized clinical trials and the real-world data with possible biases. We define an omnibus confounding function to characterize the effect of biases caused by unmeasured confounders, censoring, outcome heterogeneity, and measurement error, and further, identify it by combining the trial and real-world data. We propose a penalized sieve method to estimate the heterogeneous treatment effect and the confounding function and further study the theoretical properties of the proposed integrative estimators based on the theory of reproducing kernel Hilbert space and empirical process. The proposed methodology is shown to outperform the approach solely based on the trial data through simulation studies and an integrative analysis of the data from a randomized trial and a real-world registry on early-stage non-small-cell lung cancer.