Fairness Definitions and Metrics in Deep Reinforcement Learning for Drug Discovery in Healthcare: A Rapid Evidence Review
Authors: Esmaeil Shakeri, Ronnie de Souza Santos, Behrouz Far
Organizations: Department of Electrical and Software Engineering, Schulich School of Engineering, University of Calgary, Canada
Abstract
Deep reinforcement learning (DRL) is increasingly applied to de novo molecular design, but choices in data, rewards, and evaluation can yield uneven performance across disease areas and chemotypes. Despite this, there is no concise synthesis of how fairness is defined, measured, and tested in DRL-based drug discovery. In this rapid evidence review, we synthesize fairness definitions and metrics for DRL-driven molecule generation in healthcare. We focus on three questions: (i) how dataset composition and split strategies, especially scaffold versus random splits, affect evaluation and distribution shift; (ii) how reward design (e.g., QED, docking, toxicity, synthetic accessibility) can create or mitigate bias, with emphasis on cancer targets; and (iii) which measurable metrics best capture fairness. This includes parity across cancer versus non-cancer indications and across cancer subtypes. It also includes distributional balance in key physicochemical descriptors, scaffold/chemotype diversity, groupwise validity, toxicity, and synthetic accessibility. From 2017 onward, we searched major biomedical, computer science, and engineering literature databases and used arXiv for horizon scanning. Records were screened using PRISMA-style procedures and analyzed via content coding to link reported parity outcomes to dataset and reward choices. Our review provides a concise set of fairness definitions and metrics for DRL molecule generation. It offers practical guidance for reporting distribution parity and outcome parity. It also summarizes how dataset and reward choices relate to observed parity effects and identifies open gaps relevant to trustworthy, cancer-relevant DRL generation.
Developing effective anticancer therapeutics remains challenging due to tumor heterogeneity and the absence of well-defined molecular targets across cancer subtypes. Generative models conditioned on cancer genotypes offer a promising avenue for personalized drug discovery, yet existing approaches lack explicit optimization for simultaneous sensitivity, synthesizability, and mechanistic binding plausibility. We present a latent-space optimization approach for a pretrained genotype-to-drug diffusion model, introducing a learnable perturbation over the molecular latent space optimized via gradient ascent to maximize a composite reward combining predicted drug sensitivity (AUC), drug-likeness (QED), and synthetic accessibility (SAS). Critically, biological realism is enforced by grounding both reward design and evaluation in experimentally-derived cancer cell line data and validated pharmacologic signals, anchoring candidate generation in real-world clinical evidence. Mechanistic consistency plausibility is further assessed by a multi-agent LLM pipeline grounded in the diffusion model's attention mechanism. Experiments across 15 cancer cell lines from three held-out evaluation sets demonstrate consistent and noticeable improvements over competing baselines in sensitivity, drug-likeness, synthesizability, and chemical validity.
Brenda Nogueira, Gisela A. Gonzalez-Montiel, Nitesh V. Chawla +1
Deep reinforcement learning (DRL) has delivered strong results in domains such as Atari and Go, but it still suffers from high sample cost and weak transfer beyond the training setting. A common response is to reuse information from previously trained models through transfer, distillation, ensemble methods, or federated training instead of learning each target task from random initialization. The literature on these mechanisms is fragmented, and published comparisons are hard to interpret because tasks, baselines, and compute budgets differ. This paper presents a PRISMA-guided systematic review of empirical studies on pretrained knowledge reuse in DRL. Starting from 589 records retrieved from IEEE Xplore, the ACM Digital Library, and citation tracing, we screened 570 unique records and assessed 89 full texts. After applying the final eligibility criteria, 15 empirical studies remained in the main synthesis. We analyzed them qualitatively across three factors: source-target similarity, diversity among reused models, and the fairness of comparisons against from-scratch baselines. Three patterns recur across the surviving corpus. First, positive results are concentrated in settings where source and target tasks share substantial structure or where the method includes an explicit gating or alignment mechanism. Second, evidence for ensembles and federated aggregation is promising but sparse and mostly limited to narrow settings. Third, compute-matched comparisons are rare, which weakens claims about efficiency gains over stronger single-agent baselines. The paper contributes a narrower and internally consistent review scope, a study-level synthesis of empirical evidence, and a provisional independence spectrum that should be treated as a hypothesis for future benchmarking rather than a validated metric.
Precision oncology requires predicting which drugs will suppress a specific tumor from its molecular profile, but drug-blind sensitivity prediction has plateaued despite increasingly complex drug representations. Here we show that this stagnation reflects a metric artifact rather than a representational bottleneck. The standard benchmark, global Pearson r, is dominated by between-drug potency differences that a trivial drug-mean predictor captures without any cell-specific learning. Per-drug Pearson r, which isolates within-drug cell ranking, reveals that no drug encoding improves over cell-only features across four independent datasets. A controlled experiment channeling mechanism-of-action identity as either a drug feature or a training-distribution constraint identifies the cause. Supplying MoA as a feature yields negligible benefit, whereas using it to stratify training raises per-drug r substantially for targeted kinase inhibitors, because pan-cancer co-training suppresses pathway-specific sensitivity signals. Mechanism-stratified training and response matching from pilot observations provide two deployable strategies that together recover the principal sources of predictive gain in drug-blind sensitivity prediction.