Teaching agentic AI to generalize expert diagnostic reasoning in rare diseases
Rare disease diagnosis depends on expert reasoning that is scarce and difficult to transfer. Large language models rank the correct disease first in only 35.4% of benchmark cases and often rely on learned phenotype-disease associations rather than reusable diagnostic reasoning strategies. We developed liteOdyssey through Policy Iteration with Human Feedback, a process in which model failures and expert corrections are iteratively consolidated into a clinician-gated, natural-language policy executed by a language model. Across 1,243 public benchmark cases spanning 722 rare diseases, liteOdyssey ranked the correct disease first in 59.3% of cases versus 26.5% without the policy, with comparable gains in cases involving diseases excluded from policy development. The same policy transferred across model families and sizes without retraining. Adaptation of the policy to the Undiagnosed Diseases Network (UDN) improved diagnostic accuracy among 515 UDN patients, with gains confirmed by blinded physician adjudication. These results show that expert reasoning can be externalized into an inspectable and revisable natural-language policy that generalizes across rare diseases, transfers across model backbones, and adapts to a real-world patient cohort.