# RareDx: Controlled Knowledge Integration and Graph-Grounded Policy Optimization for Rare-Disease Diagnosis

arXiv: https://arxiv.org/abs/2609.35549 · HTML: https://mlsanity.com/paper/2609.35549/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 13 of its 37 references that are in the map.
- First posted on arXiv 28 Sep 2026.

## Builds on (most cited first, 13 of 13)

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- [Domain-Specific Language Model Pretraining for Biomedical Natural Language Processing](https://mlsanity.com/paper/2007.15779/) (2020)
- [On-Policy Distillation of Language Models: Learning from Self-Generated Mistakes](https://mlsanity.com/paper/2306.13649/) (2023)
- [Multi-Agent Collaboration Mechanisms: A Survey of LLMs](https://mlsanity.com/paper/2501.06322/) (2025)
- [MedCPT: Contrastive Pre-trained Transformers with Large-scale PubMed Search Logs for Zero-shot Biomedical Information Retrieval](https://mlsanity.com/paper/2307.00589/) (2023)
- [An Agentic System for Rare Disease Diagnosis with Traceable Reasoning](https://mlsanity.com/paper/2506.20430/) (2025)
- [RareBench: Can LLMs Serve as Rare Diseases Specialists?](https://mlsanity.com/paper/2402.06341/) (2024)
- [Accelerating Scientific Discovery with Autonomous Goal-evolving Agents](https://mlsanity.com/paper/2512.21782/) (2025)
- [Geneverse: A collection of Open-source Multimodal Large Language Models for Genomic and Proteomic Research](https://mlsanity.com/paper/2406.15534/) (2024)
- [TeamPath: Building MultiModal Pathology Experts with Reasoning AI Copilots](https://mlsanity.com/paper/2511.17652/) (2025)
- [Occamy-1.0: Open Pareto-frontier 35B Intelligence for Co-work](https://mlsanity.com/paper/2609.11977/) (2026)
- [A Versatile AI Agent for Rare Disease Diagnosis and Risk Gene Prioritization](https://mlsanity.com/paper/2605.06226/) (2026)

## Abstract (arXiv)

Rare-disease diagnosis is a long-tail reasoning problem: phenotypes are incomplete, individual disorders are sparsely documented, and relevant evidence is distributed across ontologies, gene annotations, and biomedical text. Language models consequently favor common conditions, miss rare candidates, or produce plausible but invalid names. We introduce RareDx, which couples controlled evidence use with knowledge-graph-grounded policy optimization. RareDx-Harness normalizes heterogeneous records into one ranked-diagnosis task and compares direct inference, static retrieval, adaptive tools, and structured phenotype-gene-disease reasoning over a shared knowledge layer. The training pipeline combines Top-10 post-training with RareDx-KGPO, our knowledge-graph-grounded policy optimization method. Its reward projects predictions into a canonical disease graph and integrates curated graded relevance, ontology proximity, biomedical similarity, and phenotype consistency. Vocabulary and output-budget constraints prevent dense partial credit from rewarding fabricated or overlong differentials. Across eight benchmarks, the complete RareDx system centered on Qwen3.5-9B reaches 38.34 macro Hit@10, 1.60 points above GPT-5.5 under the archived protocol; a disjoint validation-selection audit retains a 6.80-point routing gain over Direct on held-out cases. The 27B system reaches 23.53/36.56/40.76 at Hit@1/5/10. Controlled ablations show that retrieval is not uniformly helpful and that controlled routing is central to the gain. These results indicate that structured medical knowledge can turn a compact model into a competitive diagnostic ranker across heterogeneous long-tail settings in clinical practice.