Improved Off-policy Reinforcement Learning in Biological Sequence Design

Designing biological sequences with desired properties is a significant challenge due to the combinatorially vast search space and the high cost of evaluating each candidate sequence. To address these challenges, reinforcement learning (RL) methods, such as GFlowNets, utilize proxy models for rapid reward evaluation and annotated data for policy training. Although these approaches have shown promise in generating diverse and novel sequences, the limited training data relative to the vast search space often leads to the misspecification of proxy for out-ofdistribution inputs. We introduce δ-Conservative Search, a novel off-policy search method for training GFlowNets designed to improve robustness against proxy misspecification. The key idea is to incorporate conservativeness, controlled by parameter δ, to constrain the search to reliable regions. Specifically, we inject noise into high-score offline sequences by randomly masking tokens with a Bernoulli distribution of parameter δ and then denoise masked tokens using the GFlowNet policy. Additionally, δ is adaptively adjusted based on the uncertainty of the proxy model for each data point. This enables the reflection of proxy uncertainty to determine the level of conservativeness. Experimental results demonstrate that our method consistently outperforms existing machine learning methods in discovering high-score sequences across diverse tasks-including DNA, RNA, protein, and peptide design-especially in large-scale scenarios. The code is available at https://github.com/hyeonahkimm/delta cs .