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PERRY: Policy Evaluation with Confidence Intervals using Auxiliary Data

arXiv:2507.20068v2 Announce Type: replace Abstract: Off-policy evaluation (OPE) methods estimate the value of a new reinforcement learning (RL) policy prior to deployment. Recent advances have shown that leveraging auxiliary datasets, such as those synthesized by generative models, can improve the accuracy of OPE methods. Unfortunately, such auxiliary datasets may also be biased, and existing methods for using data augmentation within OPE lack principled uncertainty quantification. In high stakes domains like healthcare, reliable uncertainty estimates are important for ensuring safe and informed deployment of RL policies. In this work, we propose two methods to construct valid confidence intervals for OPE with data augmentation. The first provides a confidence interval over $V^{\pi}(s)$, the policy value conditioned on an initial state $s$. To do so we introduce a new conformal prediction method suitable for Markov Decision Processes (MDPs) with continuous state spaces, extending prior work to higher-dimensional settings. Second, we consider the more common task of estimating the average policy performance over all initial states, $V^{\pi}$; we introduce a method that draws on ideas from doubly robust estimation and prediction powered inference. Across simulators spanning inventory management, robotics, healthcare, and a real healthcare dataset from MIMIC-IV, we find that our methods can effectively leverage auxiliary data and consistently produce confidence intervals that cover the ground truth policy values, unlike previously proposed methods. Our work enables a future in which OPE can provide rigorous uncertainty estimates for high-stakes domains.

Machine Learning-Guided Discovery of Bacterial-Selective Membrane-Active Compounds Reveals Mechanistic Bias in Antibiotic Training Datasets

The rise of antibiotic resistance necessitates the discovery of antibacterial compounds with novel mechanisms of action (MoAs). Recent machine learning approaches have shown promise in antibacterial compound discovery, but often identify derivatives of known antibiotic classes rather than mechanistically novel compounds. Previous approaches applied Tanimoto similarity filters at the end of screening pipelines, but this method has substantial drawbacks: Tanimoto similarity can be misleading in chemical space, and post-hoc filtering does not influence what activity models learn to prioritize. Here, we present a machine learning pipeline that addresses chemical novelty upfront by employing an XGBoost-based MoA classifier to explicitly prioritize compounds predicted to have mechanisms distinct from known antibiotic classes, combined with graph neural networks for antibacterial activity and toxicity prediction. Applied to the Zinc20 database, our approach successfully identified non-toxic antibacterial compounds structurally distinct from known antibiotics. Notably, the majority of these hits exhibited membrane-targeting activity with selectivity for bacterial cells over mammalian cells, suggesting potential for next-generation membrane-active antibiotics. However, we did not identify compounds with novel protein targets. Systematic analysis revealed that this limitation stems from mechanistic bias in training data rather than model architecture. Specifically, our activity model learned to preferentially score compounds similar to specific groups in the training data, thus overrepresenting certain MoA classes including membrane-active compounds. Even substantial model architecture and training data enhancements did not overcome this constraint. Our findings demonstrate that the primary bottleneck for discovering mechanistically novel antibiotics is the scarcity of diverse, mechanistically-annotated training data. This work provides both a methodological framework for mechanism-aware screening and critical insights into data requirements for genuinely novel antibiotic discovery.