Multi-Agent Reasoning for Cardiovascular Imaging Phenotype Analysis

Identifying associations between imaging phenotypes, disease risk factors, and clinical outcomes is essential for understanding disease mechanisms. However, traditional approaches rely on human-driven hypothesis testing and selection of association factors, often overlooking complex, non-linear dependencies among imaging phenotypes and other multi-modal data. To address this, we introduce Multi-agent Exploratory Synergy for the Heart (MESHAgents): a framework that leverages large language models as agents to dynamically elicit, surface, and decide confounders and phenotypes in association studies. Specifically, we orchestrate a multi-disciplinary team of AI agents, which spontaneously generate and converge on insights through iterative, self-organizing reasoning. The framework dynamically synthesizes statistical correlations with multi-expert consensus, providing an automated pipeline for phenome-wide association studies (PheWAS). We demonstrate the system's capabilities through a population-based study of imaging phenotypes of the heart and aorta. MESHAgents autonomously uncovered correlations between imaging phenotypes and a wide range of non-imaging factors, identifying additional confounder variables beyond standard demographic factors. Validation on diagnosis tasks reveals that MESHAgents-discovered phenotypes achieve performance comparable to expert-selected phenotypes, with mean AUC differences as small as $-0.004_{\pm0.010}$ on disease classification tasks. Notably, the recall score improves for 6 out of 9 disease types. Our framework provides clinically relevant imaging phenotypes with transparent reasoning, offering a scalable alternative to expert-driven methods.