Human-AI Co-reasoning for Clinical Diagnosis with Evidence-Integrated Language Agent

Large language models (LLMs) are increasingly used for health-related decision support. Yet most evaluations treat diagnosis as a single-shot task with complete information provided upfront, often as a multiple-choice selection. This diverges from clinical practice, where diagnosis is interactive and open-ended, involving sequential hypothesis refinement through targeted questioning. We address this gap. We build MeDxBench, a large-scale benchmark of 4,421 clinical cases across 20 specialties. We further propose MeDxAgent, a multi-agent consultation system for interactive diagnosis, and systematically study its prompt-, flow- and agent-level design choices. MeDxAgent achieves a 10.3% accuracy gain over the baseline on MeDxBench, closing 52.3% of the gap to a full-information oracle. We find that specific design choices: collecting demographics first, passing summarized dialogue for diagnosis, and feeding candidate diagnoses for targeted questioning, improve accuracy, mirroring how physicians reason, though their effect emerges fully only in combination. Code and dataset will be released upon publication.

Clinical diagnosis is a complex reasoning process in which clinicians gather evidence, form hypotheses, and test them against alternative explanations. In medical training, this reasoning is explicitly developed through counterfactual questioning--e.g., asking how a diagnosis would change if a key symptom were absent or altered--to strengthen differential diagnosis skills. As large language model (LLM)-based systems are increasingly used for diagnostic support, ensuring the interpretability of their recommendations becomes critical. However, most existing LLM-based diagnostic agents reason over fixed clinical evidence without explicitly testing how individual findings support or weaken competing diagnoses. In this work, we propose a counterfactual multi-agent diagnostic framework inspired by clinician training that makes hypothesis testing explicit and evidence-grounded. Our framework introduces counterfactual case editing to modify clinical findings and evaluate how these changes affect competing diagnoses. We further define the Counterfactual Probability Gap, a method that quantifies how strongly individual findings support a diagnosis by measuring confidence shifts under these edits. These counterfactual signals guide multi-round specialist discussions, enabling agents to challenge unsupported hypotheses, refine differential diagnoses, and produce more interpretable reasoning trajectories. Across three diagnostic benchmarks and seven LLMs, our method consistently improves diagnostic accuracy over prompting and prior multi-agent baselines, with the largest gains observed in complex and ambiguous cases. Human evaluation further indicates that our framework produces more clinically useful, reliable, and coherent reasoning. These results suggest that incorporating counterfactual evidence verification is an important step toward building reliable AI systems for clinical decision support.

Complex clinical reasoning requires models to update diagnostic hypotheses as new evidence emerges and to coordinate different medical specialities under limited consultation resources. Existing LLM-based clinical reasoning systems typically perform single-pass prediction or rely on fixed multi-agent workflows, making expert participation either static or unnecessarily exhaustive. We propose Sparse Multi-Stage Expert-Agent Routing, a language-based clinical reasoning framework that models diagnosis as a stage-wise routing process. Given progressively available clinical evidence derived from multiple modalities, the framework maintains an evolving case state and adaptively activates a sparse set of medical expert agents, supported by expert-specific memory across stages. To evaluate free-text diagnostic conclusions beyond surface similarity, we further introduce ClinFEScore, a fact-aware semantic evaluation protocol for clinical reasoning outputs. On reconstructed multi-stage cases from MAC and AgentClinic-NEJM, our framework reduces the average number of activated experts from 17.0 to 3.0 whilst maintaining strong fact-level diagnostic quality. On 200 real-world hospital MDT cases, ClinFEScore correlates strongly with clinician judgements (Spearman's $ρ=0.81$; Pearson's $r=0.87$), whilst our method achieves 91.5% clinician-verified diagnostic accuracy with approximately five expert-agent/LLM calls per case. These results support sparse stage-wise coordination as an efficient and clinically relevant approach to LLM-based clinical reasoning.