# RareDxR1: Autonomous Medical Reasoning for Rare Disease Diagnosis Beyond Human Annotation

arXiv: https://arxiv.org/abs/2607.00147 · HTML: https://mlsanity.com/paper/2607.00147/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 14 of its 35 references that are in the map.
- First posted on arXiv 30 Jun 2026.

## Placed in

- LLM reasoning / [Clinical and biomedical applications](https://mlsanity.com/lr/clinical-and-biomedical-applications/)

## Builds on (most cited first, 14 of 14)

- [GPT-4 Technical Report](https://mlsanity.com/paper/2303.08774/) (2023)
- [DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models](https://mlsanity.com/paper/2402.03300/) (2024)
- [Qwen3 Technical Report](https://mlsanity.com/paper/2505.09388/) (2025)
- [DeepSeek-R1: Incentivizing Reasoning Capability in LLMs via Reinforcement Learning](https://mlsanity.com/paper/2501.12948/) (2025)
- [DAPO: An Open-Source LLM Reinforcement Learning System at Scale](https://mlsanity.com/paper/2503.14476/) (2025)
- [Large Language Models for Mathematical Reasoning: Progresses and Challenges](https://mlsanity.com/paper/2402.00157/) (2024)
- [HuatuoGPT-o1, Towards Medical Complex Reasoning with LLMs](https://mlsanity.com/paper/2412.18925/) (2024)
- [HuaTuo: Tuning LLaMA Model with Chinese Medical Knowledge](https://mlsanity.com/paper/2304.06975/) (2023)
- [Med-R1: Reinforcement Learning for Generalizable Medical Reasoning in Vision-Language Models](https://mlsanity.com/paper/2503.13939/) (2025)
- [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)
- [Baichuan-M1: Pushing the Medical Capability of Large Language Models](https://mlsanity.com/paper/2502.12671/) (2025)
- [Med-RLVR: Emerging Medical Reasoning from a 3B base model via reinforcement Learning](https://mlsanity.com/paper/2502.19655/) (2025)
- [Integrating Chain-of-Thought and Retrieval Augmented Generation Enhances Rare Disease Diagnosis from Clinical Notes](https://mlsanity.com/paper/2503.12286/) (2025)

## Abstract (arXiv)

Rare disease differential diagnosis is a critical yet arduous clinical task, requiring physicians to identify precise phenotypes from complex, unstructured patient symptoms and execute intricate reasoning within a vast search space. However, existing AI approaches typically rely on pipeline-based phenotype extraction or retrieval-augmented generation, which suffer from critical information loss due to predefined ontologies, retrieval bottlenecks, and a lack of diagnostic logic. To address these challenges, we introduce RareDxR1, an end-to-end reasoning-centric large language model designed for open-domain rare disease diagnosis directly from unstructured clinical notes. We design a progressive end-to-end training framework by synergizing knowledge internalization with autonomous evolutionary learning, thereby bypassing reliance on structured phenotypes and closed-set decision-making. To overcome the limitations of RAG and phenotype restriction, we enabled the deep internalization of fragmented rare-disease knowledge directly into the model's parameters. Moreover, to bridge the gap between model generation and expert reasoning, we propose Reflection-Enhanced Reasoning Sampling (RERS), a strategy that synthesizes expert-level diagnostic trajectories by learning from failures without human annotation. Additionally, we propose a dual-level curriculum reinforcement learning approach for gradually mastering rare disease diagnosis. Experimental results demonstrate that RareDxR1 achieves state-of-the-art accuracy across different benchmarks, marking a significant breakthrough in open-domain rare disease diagnosis. Our code and dataset will be publicly available.