Abstract
Externally controlled survival trials are increasingly used when concurrent randomized controls are infeasible, particularly in oncology and rare-disease settings with time-to-event endpoints. We target an average-treatment-effect-on-the-treated (ATT)-type marginal hazard-ratio estimand, comparing treatment with counterfactual control in the treated trial population, and estimate it using inverse-probability-weighted (IPW) Cox regression. Valid inference is challenging because IPW Cox regression depends on the weights through both event contributions and risk-set averages, making flexible machine-learning nuisance estimation difficult to incorporate directly. Building on machine-learning-assisted generalized entropy calibration (MEC) by Lee and Kim (2026), we propose MEC-Cox for ATT-weighted IPW Cox regression. The method begins with normalized source-propensity-score odds weights for external controls and then applies Bregman calibration to balance cross-fitted prognostic summaries between external controls and treated trial patients. The calibration basis may include control-survival predictions, Cox linear predictors, penalized-survival-model predictions, or other prognostic-score summaries. MEC-updated weights therefore play a dual role as source-transport and prognostic-score balancing weights. We establish consistency, characterize a calibration-induced efficiency gain, and develop a stacked sandwich variance estimator. Simulations show that MEC-Cox can reduce bias, increase efficiency, and improve coverage through flexible machine-learning-assisted adjustment.
Explore similar work
May 15, 2026stat.ML
Time-to-event data is widespread across the life sciences and engineering, but it is typically encountered together with censoring, which complicates the application of standard machine learning methods. Deep Cox models have emerged as a popular method for analyzing time-to-event data because they gracefully handle censoring and can be used with unstructured data such as clinical text reports, genomic sequences, and pathology images. However, their predicted survival probabilities are often poorly calibrated, thus limiting their practical utility. In this paper, we propose a novel post hoc calibration method for Deep Cox models that uses isotonic regression to refine predicted survival probabilities without affecting discriminative power. We establish favorable theoretical guarantees, including a double-robustness property and asymptotic calibration. Experiments on synthetic and real-world clinical data demonstrate the empirical effectiveness of our method.
Anchit Jain, Kevin Zhang, Stephen Bates
May 18, 2026cs.LG
Adaptive experimentation enables efficient estimation of causal effects, but existing methods are not designed for survival data with censoring, where event times are only partially observed (e.g., overall survival in cancer trials but with dropout). In this paper, we develop a novel framework for adaptive experimentation to estimate causal effects under right censoring. For this, we derive the semiparametric efficiency bound for the average survival effect curve as a function of the treatment allocation policy and thereby obtain a closed-form efficiency-optimal allocation policy. The policy generalizes classical Neyman allocation to survival settings by prioritizing patient strata where both event and censoring dynamics induce high uncertainty. Building on this, we propose the Adaptive Survival Estimator (ASE), an adaptive framework that learns the allocation policy and estimates the average survival effect curve sequentially. Our framework has three main benefits: (i) it accommodates arbitrary machine learning models for nuisance estimation; (ii) it is guided by a closed-form efficiency-optimal allocation policy; and (iii) it admits strong theoretical guarantees, including asymptotic normality via a martingale central limit theorem. We demonstrate our framework across various numerical experiments to show consistent efficiency gains over uniform randomization and censoring-agnostic baselines.
Yuxin Wang, Dennis Frauen, Jonas Schweisthal +3
Mar 19, 2026cs.LG
Randomized controlled trials (RCTs) are the gold standard for estimating treatment effects, yet they are often underpowered for detecting effect heterogeneity. Large observational studies (OS) can supplement RCTs for conditional average treatment effect (CATE) estimation, but a key barrier is covariate mismatch: the two sources measure different, only partially overlapping, covariates. We propose CALM (Calibrated ALignment under covariate Mismatch), which learns embeddings that map each source's features into a common representation space. OS outcome models are transferred to the RCT embedding space and calibrated using trial data, preserving causal identification from randomization. Finite-sample risk bounds decompose into alignment error, outcome-model complexity, and calibration complexity terms, making explicit when the learned embedding is accurate enough to reduce variance. We instantiate CALM in two forms: a closed-form linear version, CALM-Lin, and a neural representation-learning version, CALM-NN. Across 51 simulation settings, calibration-based linear methods are effectively tied in linear-CATE regimes, while CALM-NN wins all 22 nonlinear-CATE settings by wide margins. Moreover, on two real-data studies CALM-NN delivers the largest gains over the trial-only baseline.
Amir Asiaee, Samhita Pal