Multi-Modal Explainable Medical AI Assistant for Trustworthy Human-AI Collaboration

Generalist Medical AI (GMAI) systems have demonstrated expert-level performance in biomedical perception tasks, yet their clinical utility remains limited by inadequate multi-modal explainability and suboptimal prognostic capabilities. Here, we present XMedGPT, a clinician-centric, multi-modal AI assistant that integrates textual and visual interpretability to support transparent and trustworthy medical decision-making. XMedGPT not only produces accurate diagnostic and descriptive outputs, but also grounds referenced anatomical sites within medical images, bridging critical gaps in interpretability and enhancing clinician usability. To support real-world deployment, we introduce a reliability indexing mechanism that quantifies uncertainty through consistency-based assessment via interactive question-answering. We validate XMedGPT across four pillars: multi-modal interpretability, uncertainty quantification, and prognostic modeling, and rigorous benchmarking. The model achieves an IoU of 0.703 across 141 anatomical regions, and a Kendall's tau-b of 0.479, demonstrating strong alignment between visual rationales and clinical outcomes. For uncertainty estimation, it attains an AUC of 0.862 on visual question answering and 0.764 on radiology report generation. In survival and recurrence prediction for lung and glioma cancers, it surpasses prior leading models by 26.9%, and outperforms GPT-4o by 25.0%. Rigorous benchmarking across 347 datasets covers 40 imaging modalities and external validation spans 4 anatomical systems confirming exceptional generalizability, with performance gains surpassing existing GMAI by 20.7% for in-domain evaluation and 16.7% on 11,530 in-house data evaluation. Together, XMedGPT represents a significant leap forward in clinician-centric AI integration, offering trustworthy and scalable support for diverse healthcare applications.