DeepImagine: Learning Biomedical Reasoning via Successive Counterfactual Imagining

Abstract: Predicting the outcomes of prospective clinical trials remains a major challenge for LLMs. Prior work has shown that both traditional correlational predictors, such as random forests and logistic regression, and strong commercial LLMs achieve limited performance on this task. In this paper, we propose DeepImagine, a framework for teaching LLMs biomedical reasoning through successive counterfactual imagining. The central idea is to approximate hidden causal mechanisms of clinical trials by training models to infer how observed trial results would change under controlled perturbations of experimental conditions, such as dosage, outcome measures, study arms, geography, and other trial attributes. To support this objective, we construct both natural and approximate counterfactual pairs from real clinical trials with reported outcomes. For settings where strict counterfactual supervision is available, such as paired outcome measures or dose-ranging study arms within the same trial, we train models with supervised fine-tuning. For broader settings where only approximate counterfactual pairs can be retrieved, we optimize models with reinforcement learning using verifiable rewards based on downstream benchmark correctness. We further augment training with synthetic reasoning traces that provide causally plausible explanations for local counterfactual transitions. Using this pipeline, we train LLMs under 10B parameters, including Qwen3.5-9B, and evaluate them on clinical trial outcome prediction. We aim to show that DeepImagine consistently improves over untuned LLMs and traditional correlational baselines. Finally, we aim to show that the learned reasoning trajectories provide interpretable signals about how models represent trial-level mechanisms, suggesting a practical path toward more mechanistic and scientifically useful biomedical LLMs.