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.

Identifying and making statistical inferences on differential treatment effects (commonly known as subgroup analysis in clinical research) is central to precision health. Subgroup analysis allows practitioners to pinpoint populations for whom a treatment is especially beneficial or protective, thereby advancing targeted interventions. Tree based recursive partitioning methods are widely used for subgroup analysis due to their interpretability. Nevertheless, these approaches encounter significant limitations, including suboptimal partitions induced by greedy heuristics and overfitting from locally estimated splits, especially under limited sample sizes. To address these limitations, we propose a fused optimal causal tree method that leverages mixed integer optimization (MIO) to facilitate precise subgroup identification. Our approach ensures globally optimal partitions and introduces a parameter fusion constraint to facilitate information sharing across related subgroups. This design substantially improves subgroup discovery accuracy and enhances statistical efficiency. We provide theoretical guarantees by rigorously establishing out of sample risk bounds and comparing them with those of classical tree based methods. Empirically, our method consistently outperforms popular baselines in simulations. Finally, we demonstrate its practical utility through a case study on the Health and Aging Brain Study Health Disparities (HABS-HD) dataset, where our approach yields clinically meaningful insights.

Machine learning (ML) models are increasingly used to support clinical decision-making. However, real-world medical datasets are often noisy, incomplete, and imbalanced, leading to performance disparities across patient subgroups. These differences raise fairness concerns, particularly when they reinforce existing disadvantages for marginalized groups. In this work, we analyze several medical prediction tasks and demonstrate how model performance varies with patient characteristics. While ML models may demonstrate good overall performance, we argue that subgroup-level evaluation is essential before integrating them into clinical workflows. By conducting a performance analysis at the subgroup level, differences can be clearly identified-allowing, on the one hand, for performance disparities to be considered in clinical practice, and on the other hand, for these insights to inform the responsible development of more effective models. Thereby, our work contributes to a practical discussion around the subgroup-sensitive development and deployment of medical ML models and the interconnectedness of fairness and transparency.

Machine learning (ML) models may suffer from significant performance disparities between patient groups. Identifying such disparities by monitoring performance at a granular level is crucial for safely deploying ML to each patient. Traditional subgroup analysis based on metadata can expose performance disparities only if the available metadata (e.g., patient sex) sufficiently reflects the main reasons for performance variability, which is not common. Subgroup discovery techniques that identify cohesive subgroups based on learned feature representations appear as a potential solution: They could expose hidden stratifications and provide more granular subgroup performance reports. However, subgroup discovery is challenging to evaluate even as a standalone task, as ground truth stratification labels do not exist in real data. Subgroup discovery has thus neither been applied nor evaluated for the application of subgroup performance monitoring. Here, we apply subgroup discovery for performance monitoring in chest x-ray and skin lesion classification. We propose novel evaluation strategies and show that a simplified subgroup discovery method without access to classification labels or metadata can expose larger performance disparities than traditional metadata-based subgroup analysis. We provide the first compelling evidence that subgroup discovery can serve as an important tool for comprehensive performance validation and monitoring of trustworthy AI in medicine.

Machine learning models are often criticized for their black-box nature, raising concerns about their applicability in critical decision-making scenarios. Consequently, there is a growing demand for interpretable models in such contexts. In this study, we introduce Model-based Deep Rule Forests (mobDRF), an interpretable representation learning algorithm designed to extract transparent models from data. By leveraging IF-THEN rules with multi-level logic expressions, mobDRF enhances the interpretability of existing models without compromising accuracy. We apply mobDRF to identify key risk factors for cognitive decline in an elderly population, demonstrating its effectiveness in subgroup analysis and local model optimization. Our method offers a promising solution for developing trustworthy and interpretable machine learning models, particularly valuable in fields like healthcare, where understanding differential effects across patient subgroups can lead to more personalized and effective treatments.

Coronary artery disease (CAD) is the dominant cause of death and hospitalization across the globe. Atherosclerosis, an inflammatory condition that gradually narrows arteries and has potentially fatal effects, is the most frequent cause of CAD. Nonetheless, the circulation regularly adapts in the presence of atherosclerosis, through the formation of collateral arteries, resulting in significant long-term health benefits. Therefore, timely detection of coronary collateral circulation (CCC) is crucial for CAD personalized medicine. We propose a novel deep learning based method to detect CCC in angiographic images. Our method relies on a convolutional backbone to extract spatial features from each frame of an angiography sequence. The features are then concatenated, and subsequently processed by another convolutional layer that processes embeddings temporally. Due to scarcity of data, we also experiment with pretraining the backbone on coronary artery segmentation, which improves the results consistently. Moreover, we experiment with few-shot learning to further improve performance, given our low data regime. We present our results together with subgroup analyses based on Rentrop grading, collateral flow, and collateral grading, which provide valuable insights into model performance. Overall, the proposed method shows promising results in detecting CCC, and can be further extended to perform landmark based CCC detection and CCC quantification.

Large language models such as ChatGPT are increasingly explored in medical domains. However, the absence of standard guidelines for performance evaluation has led to methodological inconsistencies. This study aims to summarize the available evidence on evaluating ChatGPT's performance in medicine and provide direction for future research. We searched ten medical literature databases on June 15, 2023, using the keyword "ChatGPT". A total of 3520 articles were identified, of which 60 were reviewed and summarized in this paper and 17 were included in the meta-analysis. The analysis showed that ChatGPT displayed an overall integrated accuracy of 56% (95% CI: 51%-60%, I2 = 87%) in addressing medical queries. However, the studies varied in question resource, question-asking process, and evaluation metrics. Moreover, many studies failed to report methodological details, including the version of ChatGPT and whether each question was used independently or repeatedly. Our findings revealed that although ChatGPT demonstrated considerable potential for application in healthcare, the heterogeneity of the studies and insufficient reporting may affect the reliability of these results. Further well-designed studies with comprehensive and transparent reporting are needed to evaluate ChatGPT's performance in medicine.

Before embarking on data collection, researchers typically compute how many individual observations they should do. This is vital for doing studies with sufficient statistical power, and often a cornerstone in study pre-registrations and grant applications. For traditional statistical tests, one would typically determine an acceptable level of statistical power, (gu)estimate effect size, and then use both values to compute the required sample size. However, for analyses that identify subgroups, statistical power is harder to establish. Once sample size reaches a sufficient threshold, effect size is primarily determined by the number of measured features and the underlying subgroup separation. As a consequence, a priory computations of statistical power are notoriously complex. In this tutorial, I will provide a roadmap to determining sample size and effect size for analyses that identify subgroups. First, I introduce a procedure that allows researchers to formalise their expectations about effect sizes in their domain of choice, and use this to compute the minimally required number of measured variables. Next, I outline how to establish the minimum sample size in subgroup analyses. Finally, I use simulations to provide a reference table for the most popular subgroup analyses: k-means, Ward agglomerative hierarchical clustering, c-means fuzzy clustering, latent class analysis, latent profile analysis, and Gaussian mixture modelling. The table shows the minimum numbers of observations per expected subgroup (sample size) and features (measured variables) to achieve acceptable statistical power, and can be readily used in study design.