M2G-LLM: Enhancing Clinical Prediction via Multimodal Graph Reasoning and LLM Context Injection

Clinical questions often depend on linking a patient's multimodal evidence to external biomedical knowledge, yet existing predictive systems rarely represent such links explicitly, so they can neither be traced to their evidence sources nor removed to measure their contributions. We present MM-KG (Multimodal Knowledge Graph), which represents heterogeneous, multimodal patient observations and biomedical concepts as separate layers in one typed graph, joined by explicit alignment edges. First, modality-specific harmonizers convert EHR text, imaging, genomic, and biospecimen data into typed observations mapped to UMLS concepts, which a route-prioritized aligner links to a biomedical knowledge graph. Query-conditioned retrieval then selects a compact subgraph for downstream use by a large language model or a graph neural network. We build MM-KGs for MIMIC-IV and ADNI, and evaluate them with a 2x2 design that separates patient evidence, biomedical knowledge, and their interaction. On questions that require both sources, neither source alone performs far above chance, whereas their combination yields a drug-controlled AUROC interaction of +0.194 on MIMIC and +0.299 on ADNI. On held-out five-candidate ranking, MM-KG outperforms MindMap by +0.131 Hits@1 and leads an adapted GraphCare on the items that require consulting the patient, and deleting the single answer-bearing relation from the retrieved packet returns Hits@1 to the no-knowledge baseline. Finally, query-conditioned retrieval reaches 0.731 AUROC with 6.8x less context than the strongest generic policy, whereas static knowledge graph context gives no consistent gain on ordinary outcome prediction. Knowledge graphs thus benefit clinical LLMs not as background context but as explicit links between multimodal patient evidence and the relation a question requires, and MM-KG makes these links retrievable, traceable, and testable.

Building effective clinical decision support systems requires the synthesis of complex heterogeneous multimodal data. Such modalities include temporal electronic health records data, medical images, radiology reports, and clinical notes. Large language model (LLM)-based agents have shown impressive performance in various healthcare tasks, especially those involving textual modalities. Considering the fragmentation of healthcare data across hospital systems, collaborative agent frameworks present a promising direction to mitigate data sharing challenges. However, the effectiveness of LLM agents for multimodal clinical risk prediction remains largely unexamined. In this work, we conduct a systematic evaluation of LLM-based agents for clinical prediction tasks using large-scale real-world data. We assess performance in unimodal and multimodal settings and quantify performance gaps between single agent and multi-agent systems. Our findings highlight that single agent frameworks outperform naive multi-agent systems, are better at handling multimodal data, and are better calibrated. This underscores a critical need for improving multi-agent collaboration to better handle heterogeneous inputs. By open-sourcing our code and evaluation framework, this work offers a new benchmark to support future developments relating to agentic systems in healthcare.

Recent advances in large language models (LLMs) have opened new avenues for multimodal reasoning. Yet, most existing methods still rely on pretrained vision-language models (VLMs) to encode image-text pairs in isolation, ignoring the relational structure that real-world multimodal data naturally form. This motivates reasoning on multimodal graphs (MMGs), where each node has textual and visual attributes and edges provide structural cues. Enabling LLM-based reasoning on such heterogeneous multimodal signals while preserving graph topology introduces two key challenges: resolving weak cross-modal consistency and handling heterogeneous modality preference. To address this, we propose Mario, a unified framework that simultaneously resolves the two above challenges and enables effective LLM-based reasoning over MMGs. Mario consists of two innovative stages. Firstly, a graph-conditioned VLM design that jointly refines textual and visual features through fine-grained cross-modal contrastive learning guided by graph topology. Secondly, a modality-adaptive graph instruction tuning mechanism that organizes aligned multimodal features into graph-aware instruction views and employs a learnable router to surface, for each node and its neighborhood, the most informative modality configuration to the LLM. Extensive experiments across diverse MMG benchmarks demonstrate that Mario consistently outperforms state-of-the-art graph models in both supervised and zero-shot scenarios for node classification and link prediction. The code will be made available at https://github.com/sunyuanfu/Mario.