An AI agent for treatment reasoning over a biomedical tool universe

Shanghua Gao, Ayush Noori, Richard Zhu, Curtis Ginder, Zhenglun Kong, Xiaorui Su, Justin Kauffman, Benjamin S. Glicksberg, Joshua Lampert, Ankit Sakhuja, Ashwin Sawant, ATHENA-R1 Evaluation Consortium, David A. Clifton, Noa Dagan, Ran Balicer, Marinka Zitnik

Treatment reasoning underpins every therapeutic decision, integrating disease context, comorbidities, medications, contraindications, and evolving biomedical knowledge to select an appropriate therapy. It is inherently iterative: candidates are weighed against many constraints, revised as evidence emerges, and grounded in verifiable sources. Here we introduce ATHENA-R1, an AI agent for treatment reasoning across all FDA approved drugs since 1939, trained by reinforcement learning over a universe of 212 biomedical tools. At each step it identifies missing information, selects and runs relevant tools, and incorporates the evidence. To train it without human-annotated traces, we build a two-level self-learning framework: multi-agent systems construct the tools, tasks, and reasoning trajectories for supervised fine-tuning, then reinforcement learning with scientific feedback rewards reasoning quality (evidence gathering, grounded tool use, logical non-redundancy). Across five benchmarks of 3,168 drug reasoning tasks and 456 patient treatment cases, ATHENA-R1 outperforms language models and tool-use systems, reaching 94.7% accuracy on open-ended drug reasoning and 82.9% on treatment reasoning, 17.8 and 10.7 points above GPT-5. In blinded evaluations by experts from 28 rare disease organizations, it is preferred over reference models on all criteria, and physicians rated it favorably on complex hospitalized cardiovascular and infectious-disease cases. Adverse-event hypotheses it generated, tested in electronic health records from 5.4 million patients, reached adjusted odds ratios of 1.48-1.84, with no elevation among negative controls. Because it requires knowing what evidence to seek before concluding, treatment reasoning has long been hard for AI; we show it can be reframed as a learnable process of iterative evidence gathering that reinforcement learning can train AI to perform.