Policy Iteration with Human Feedback: Bringing Post-Training RL to In-context Learning

Generative pretraining established reusable task representations; later work on language-based task conditioning and in-context learning showed that a fixed model could adapt its behavior from instructions and demonstrations. Policy Iteration with Human Feedback (PIHF) builds on this development and the recurrent evaluate-and-improve structure of generalized policy iteration. PIHF uses a pretrained language model as its execution substrate and moves persistent revision to a versioned natural-language policy and tool set. A language-model critic and clinical expert review complete-panel reasoning and tool-use trajectories to localize recurrent failures and form candidate revisions; the expert may reinterpret the evidence and retains authority over admission and rollback, while Recall@1 and Recall@5 validate outcomes after candidate execution. Across cumulative ablations and ultra-rare-disease benchmarks, a PIHF-derived policy improved Recall@1 in one proprietary executor and three open-weight executors spanning 3 to 49 billion active parameters. Gains were 32.7 percentage points for GPT-5.4 and 31.1 points for Qwen3.6-35B, a difference of 1.7 points. These results support the feasibility of using pretrained language models as fixed-weight execution substrates for expert-guided policy development in rare-disease diagnosis.

LiteOdyssey: A Lightweight Reasoning AI Agent for Interpretable Rare-Disease Diagnosis

Most medical AI systems improve by scaling additional machinery: more fine-tuning data, more agents, and/or larger retrieval databases. In rare-disease diagnosis, however, such scaling can produce systems that are difficult to deploy, audit, and maintain. We asked whether state-of-the-art diagnostic performance could instead be achieved by extending the reasoning chain of a single AI agent: guiding it with a diagnostic policy, developed through human-AI collaboration and augmenting with freely available biomedical tools. We introduce LiteOdyssey, a lightweight rare-disease diagnostic framework that guides reasoning language model through a clinical genetics workflow. This framework was developed through Policy Iteration with Human Feedback (PIHF) and uses dynamic access to public biomedical tools. On two challenging benchmarks that provide only patient clinical features, LiteOdyssey achieved state-of-the-art performance, with an overall disease Recall@1 of 59.3% over the combined 1,243 cases of LIRICAL (n = 370) and the PhenoPacket Store (n = 873). Both benchmarks have a high proportion of ultra-rare disease (a prevalence below 1 in 1,000,000, with ultra-rare shares of approximately 45% and 52.8%, respectively). On the more difficult PhenoPacket subset, where causal diseases were not mapped to Orphanet in our rarity-mapping pipeline, LiteOdyssey achieved 60.7% Recall@1, compared with 10.7% for the same baseline model (GPT-5.4) without tools. This performance was achieved without fine-tuning, multi-agent ensembles, or a large case-retrieval database. Gains were also observed in the following: on cases never seen during development, on a private cohort of real-world rare disease patients, and on a smaller open-weights model. LiteOdyssey suggests a path toward rare-disease AI systems that are accurate, easier to deploy, and more transparent for physician review.