Building evidence-based knowledge bases from full-text literature for disease-specific biomedical reasoning

Large language models (LLMs) can generate biomedical hypotheses, but it remains unclear whether they truly reason from scientific evidence or simply produce convincing-sounding ideas. To study this, we combine three major biological databases: the Kyoto Encyclopedia of Genes and Genomes (KEGG), Rhea, and UniProt, into a unified biochemical knowledge graph and construct a benchmark of 550 paths connecting enzyme sources to rare disease endpoints, yielding 13,200 hypotheses from six LLMs under four conditions varying the biological information each model receives: source enzyme only, full biological path, or source and disease endpoint only. Hypotheses are scored using an expert-derived five-criterion rubric on a 1-5 scale per criterion. We find that models given both the source and disease endpoint often produce the highest-scoring hypotheses, showing that LLMs can generate compelling ideas from minimal information. However, these hypotheses are less grounded in the evidence. In contrast, models given the full biological path generate hypotheses more consistent with known mechanistic relationships. We call this evidence-disciplined reasoning. To confirm this effect, we shuffled intermediate path steps while keeping endpoints fixed. Evidence grounding dropped significantly (delta = -0.793, p < 0.001), confirming models genuinely used path structure during reasoning. Our findings show that knowledge graphs support hypothesis generation in two ways: they identify biological endpoint pairs absent from the literature, and their mechanistic paths guide how LLMs reason between them.

Post-discharge risk prediction from electronic health records (EHRs) is difficult because many dependencies that link discharge-time observations to downstream complications, such as comorbidity cascades and drug-disease interactions, are absent from the record. External medical knowledge graphs (KGs) can supply these missing dependencies, but tracing them demands three properties: KG exploration must remain cost-bounded, retrieved evidence must be differentiated by source quality, and the resulting rationale must be citable for retrospective review. Large language models (LLMs) can plan and verify over structured evidence, making them natural candidates for KG reasoning, but existing LLM-based methods do not satisfy these three properties jointly. In this paper, we propose BAR, a Budget-Aware LLM Reasoning framework over medical KGs with three contributions. First, BAR refines the raw KG into disease-specific evidence graphs whose edges carry support scores and provenance records, turning the KG into a quality-annotated reasoning space rather than a static feature source. Second, an LLM then reasons over this graph through a plan-navigate-verify loop that decomposes the question into steps, retrieves evidence under a patient-specific budget, and revises when verification fails. Third, a reasoning policy is trained with a reward that compares predictions with and without acquired evidence, combined with acquisition cost and citation-integrity terms. Across 8 diseases and 3 prediction horizons on MIMIC-III and MIMIC-IV, BAR improves AUPRC by 3.4 points over the strongest baseline, raises citation precision from 59.8% to 77.9%, and consumes only 62-65% of the budget cap.

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.