GraphDx: A Cost-Aware Knowledge-Enhanced Multi-Agent Framework for Sequential Diagnosis

Real-world clinical diagnosis is a complex process in which the doctor is required to obtain information from both interaction with the patient and conducting medical exams. Additionally, the doctor needs to adapt to different patient personas, as well as noisy and incomplete information that can happen at any time during the process. However, existing benchmarks for medical LLMs and methods for automatic diagnosis largely simplify this process by reducing it to single-turn question answering, noise-free conversations, or sequential exam making, etc., ignoring the interactive and uncertain nature of clinical diagnosis. In this paper, we aim to address this gap by formalizing clinical diagnosis as a Partially Observable Markov Decision Process (POMDP) with three action types: questioning the patient, ordering medical exams as tool calls, and issuing a diagnosis. We also introduce a systematic noise model comprising seven patient noise types and three exam noise types. Using our proposed environment, we train an effective diagnosis agent, MedExAgent, through a two-stage pipeline that first performs supervised finetuning on synthetic conversations structured after the Calgary-Cambridge model for clinical interviews, and then applies DAPO to optimize a composite reward capturing diagnostic accuracy, tool call quality, and exam cost including financial cost and patient discomfort. Through extensive experiments and ablation studies, we demonstrate that MedExAgent achieves diagnostic performance comparable to larger models while maintaining cost-efficient examination strategies.

There is growing interest in using machine learning (ML) to support clinical diagnosis, but most approaches rely on static, fully observed datasets and fail to reflect the sequential, resource-aware reasoning clinicians use in practice. Diagnosis remains complex and error prone, especially in high-pressure or resource-limited settings, underscoring the need for frameworks that help clinicians make timely and cost-effective decisions. We propose ACTMED (Adaptive Clinical Test selection via Model-based Experimental Design), a diagnostic framework that integrates Bayesian Experimental Design (BED) with large language models (LLMs) to better emulate real-world diagnostic reasoning. At each step, ACTMED selects the test expected to yield the greatest reduction in diagnostic uncertainty for a given patient. LLMs act as flexible simulators, generating plausible patient state distributions and supporting belief updates without requiring structured, task-specific training data. Clinicians can remain in the loop; reviewing test suggestions, interpreting intermediate outputs, and applying clinical judgment throughout. We evaluate ACTMED on real-world datasets and show it can optimize test selection to improve diagnostic accuracy, interpretability, and resource use. This represents a step toward transparent, adaptive, and clinician-aligned diagnostic systems that generalize across settings with reduced reliance on domain-specific data.

While Large Language Models (LLMs) have demonstrated potential in healthcare, they often struggle with the complex, non-linear reasoning required for accurate clinical diagnosis. Existing methods typically rely on static, linear mappings from symptoms to diagnoses, failing to capture the iterative, hypothesis-driven reasoning inherent in human clinicians. To bridge this gap, we introduce ClinicalAgents, a novel multi-agent framework designed to simulate the cognitive workflow of expert clinicians. Unlike rigid sequential chains, ClinicalAgents employs a dynamic orchestration mechanism modeled as a Monte Carlo Tree Search (MCTS) process. This allows an orchestrator to iteratively generate hypotheses, actively verify evidence, and trigger backtracking when critical information is missing. The foundation of this framework is a Dual-Memory architecture: a mutable working memory that maintains the evolving patient state for context-aware reasoning, and a static experience memory that retrieves clinical guidelines and historical cases via an active feedback loop. Extensive experiments demonstrate that ClinicalAgents achieves the best performance among evaluated baselines, significantly enhancing both diagnostic accuracy and explainability compared to strong single-agent and multi-agent baselines. Our code is released at https://github.com/ZhuohanGe/ClinicalAgents-Code.