Improving the Efficiency of Subgroup Analysis in Randomized Controlled Trials with TMLE
Authors: Sky Qiu, Nerissa Nance, Rachael Phillips et al.
Summary
arXiv:2605. 15483v1 Announce Type: cross Abstract: Subgroup analyses within randomized controlled trials are often underpowered due to limited sample sizes.
Relevance
Read next because Improving the Efficiency of Subgroup Analysis in Randomized Controlled Trials with TMLE overlaps with clean result "Language-mismatch LoRA SFT on Qwen2.5-7B leaks the trained completion language into bystander directives the model was never trained on, absent under same-language SFT (LOW confidence)", clean result "Only continuous soft prefixes hit both EM axes at once on Qwen-2.5-7B-Instruct: discrete prompt searches split between the alignment objective and the distributional objective, and both discretizations of the soft prefix collapse (MODERATE confidence)", clean result "Training one persona to emit a [ZLT] marker without bystanders adopting it has a one-cell-wide LR x epochs window on Qwen2.5-7B-Instruct (LOW confidence)". Matching terms: rect, under, eval, source, rate, control, without. Source: arxiv stat.ML (Machine Learning).
Threat model
Potential threat/caveat for clean result "Language-mismatch LoRA SFT on Qwen2.5-7B leaks the trained completion language into bystander directives the model was never trained on, absent under same-language SFT (LOW confidence)": this item discusses bias, evaluation.
Abstract
arXiv:2605.15483v1 Announce Type: cross Abstract: Subgroup analyses within randomized controlled trials are often underpowered due to limited sample sizes. We address this challenge by leveraging trial participants outside the subgroup of interest to augment estimation within the subgroup. Specifically, we study two Targeted Maximum Likelihood Estimators (TMLEs) that borrow information from non-subgroup participants within the same trial: a TMLE with pooled regression (TMLE-PR) and an Adaptive Targeted Maximum Likelihood Estimator (A-TMLE). Both estimators enable information sharing without relying on any external real-world data, thereby capitalizing on key strengths of the trial: most importantly, the protection against bias afforded by the randomized treatment, but also harmonized data collection, and consistent treatment and outcome definitions. The general strategy proposed here directly advances the priorities of key regulatory agencies, including the FDA, by improving the precision of subgroup-specific treatment effect estimates without introducing external sources of bias, thereby facilitating rigorous inference to support equitable labeling, access, and post-market evaluation. In a case study based on analysis of data from a cardiovascular outcome trial (LEADER, NCT01179048), we estimate the risk reduction of major adverse cardiac events (MACE) under liraglutide treatment among Black and Asian subgroups -- each comprising less than 10% of the trial population -- using the proposed estimators that borrow information from the remainder of the trial. Using A-TMLE, in particular, we find estimated absolute MACE risk reductions of 1.6, 1.5, and 1.5 percentage points among Asian participants and 2.1, 2.0, and 2.1 percentage points among Black participants at 365, 540, and 730 days, respectively, with 95% confidence intervals excluding the null at each time point.