Biomedical KGs

Drug discovery for neurological disease has traditionally centered on the molecules altered by disease. But the molecules that cause pathology are not necessarily the best points from which to reverse it. Here, we ask which otherwise unaltered molecular control points can be engaged to restore pathological neural circuits toward functional states. We present CircuitATLAS, a provenance-grounded systems-neuroscience knowledge graph and agentic framework for target discovery in circuitopathies. It structures literature-derived relationships across diseases, phenotypes, electrophysiology, circuits, brain regions, cell types and molecular effectors, while deliberately excluding direct disease-gene and disease-protein edges to reduce shortcut reasoning. The graph contains 3.83 million nodes and 7.66 million edges, including 5.31 million LLM-extracted relations, and incorporates structured datasets such as the Human Cell Atlas and new multimodal in vivo measurements. We then introduce an agentic workflow that reasons from measurable disease phenotypes through their circuit and cellular substrates to molecular interventions, therapeutic feasibility and clinical constraints. Finally, we introduce a human-governed in vivo lab-in-the-loop linking hypothesis generation to experimental iteration. Within this framework an agent nominated ATP1A3, the neuronal alpha3 Na+/K+-ATPase, as a control point on cortical excitability; interneuron-restricted expression of ATP1A3 abolished the beta- and gamma-band response to a focal 4-aminopyridine challenge in vivo, and the validated target was then carried into a structure-guided small-molecule campaign terminating in a defined assay to resolve the direction of modulation. CircuitATLAS thus provides a framework for discovering therapeutics based not only on what is molecularly disrupted in disease, but on what can be controlled to restore circuit function.

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.

Cold-start drug-drug interaction (DDI) prediction tests whether models can identify clinically significant interactions for drugs without training-time interaction history. Existing benchmarks mostly report aggregate edge-prediction scores, leaving a key evaluation question unanswered: when models receive molecular, textual, or knowledge-graph (KG) evidence, do they actually use the evidence that pharmacologically supports the interaction? We introduce ColdDDI, a reconstructible diagnostic benchmark built from DrugBank 5.1.13, with 1,900 approved small-molecule drugs and 565,731 positive DDI pairs. ColdDDI evaluates pairs with zero, one, or two unseen drugs. It also annotates each interaction by whether it changes drug exposure or drug effect, and by whether the biomedical knowledge graph contains shared enzymes, transporters, or targets that can plausibly mediate the interaction. These annotations separate evidence availability from predictive dependence. We evaluate eight conventional DDI methods and 13 LLMs; for open-weight LLMs, we test five prompt patterns and use masking, drug replacement, and channel-sensitivity metrics to probe knowledge utilization. ColdDDI exposes that, in the hardest split where both drugs are unseen, the main performance divide is mediator availability. A fine-tuned 1B LLM recovers 89-93% of interactions with a shared enzyme, transporter, or target, but only 40-62% without such a mediator. More importantly, KG-provided evidence is not always used; several KG-augmented baselines change little when the shared mediator is masked or disrupted, whereas fine-tuned LLMs respond strongly to this intervention. Thus, ColdDDI evaluates knowledge utilization rather than knowledge access alone, showing where cold-start DDI models rely on mechanistic evidence and where they fail despite receiving it. Code is available at https://github.com/0217ljh/ColdDDI-NeurIPS2026.

Rare-disease diagnosis is a long-tail reasoning problem: phenotypes are incomplete, individual disorders are sparsely documented, and relevant evidence is distributed across ontologies, gene annotations, and biomedical text. Language models consequently favor common conditions, miss rare candidates, or produce plausible but invalid names. We introduce RareDx, which couples controlled evidence use with knowledge-graph-grounded policy optimization. RareDx-Harness normalizes heterogeneous records into one ranked-diagnosis task and compares direct inference, static retrieval, adaptive tools, and structured phenotype-gene-disease reasoning over a shared knowledge layer. The training pipeline combines Top-10 post-training with RareDx-KGPO, our knowledge-graph-grounded policy optimization method. Its reward projects predictions into a canonical disease graph and integrates curated graded relevance, ontology proximity, biomedical similarity, and phenotype consistency. Vocabulary and output-budget constraints prevent dense partial credit from rewarding fabricated or overlong differentials. Across eight benchmarks, the complete RareDx system centered on Qwen3.5-9B reaches 38.34 macro Hit@10, 1.60 points above GPT-5.5 under the archived protocol; a disjoint validation-selection audit retains a 6.80-point routing gain over Direct on held-out cases. The 27B system reaches 23.53/36.56/40.76 at Hit@1/5/10. Controlled ablations show that retrieval is not uniformly helpful and that controlled routing is central to the gain. These results indicate that structured medical knowledge can turn a compact model into a competitive diagnostic ranker across heterogeneous long-tail settings in clinical practice.

We introduce DoAtlas-2, a foundation for self-evolving causal biomedical discovery that organizes knowledge around causal mechanisms and advances through external evidence from human populations. DoAtlas-2 integrates 771 research resources covering more than 720,000 participants in 48 countries, from longitudinal clinical phenotypes, medical imaging, and continuous physiological signals to eight molecular layers, together with an evidence network of approximately 4.7 million literature-derived records over 93,566 concepts and 149,383 candidate causal relations. DoAtlas-2 autonomously formulates research questions from evidence gaps and unresolved mechanisms, prespecifies their causal designs, and generates validated analyses. Supporting, challenging, and unresolved results continuously revise mechanistic interpretations, the causal evidence state, and the discovery frontier, so that DoAtlas-2 self-evolves within a closed loop of hypothesis generation, empirical testing, and renewed discovery. DoAtlas-2 has systematically evaluated 2,031 research questions. In the Human Phenotype Project (HPP), it formulated 4,014 candidate pathway questions across vascular, early-glycemic, and hepatic-metabolic systems, and screening of the first 1,079 yielded statistical support for 756. Representative studies identify blood pressure as a convergence node linking adiposity, hepatic, and lipid phenotypes to vascular outcomes, and show that an adiposity-inflammation-blood-pressure pathway is largely attenuated by joint adjustment for body mass index (BMI) and smoking. The discovered vascular network constitutes a completely interpretable predictive foundation, admitting exact attribution of every prediction and closed-form mediation effects. DoAtlas-2 thereby unifies causal mechanism discovery, population-evidence testing, and interpretable prediction within one continuously evolving foundation.

Multi-source knowledge graphs (KGs) need query mechanisms that expose reliability and exploit domain structure. This paper presents TCMaster, a property-graph query substrate for confidence-aware traversal and workload-guided physical design over Traditional Chinese Medicine KGs. TCMaster integrates pharmacopoeias, prescriptions, molecular databases, and LLM-extracted micro-semantics into a KG with approximately 221K entities and 723K base edges. It annotates edges with provenance-level confidence, rewrites Cypher queries with confidence predicates, ranks multi-hop paths under PRODUCT, MIN, or weighted-average policies, and uses ontology skew through direction selection, herb-attribute bitmaps, and materialized shortcut edges. On Neo4j, direction selection improves attribute lookup by a factor of 1.47, shortcuts accelerate high-fanout target counting by a factor of 4.42, confidence filtering removes 39.3 percent of low-quality heterogeneous paths, and KG retrieval improves TCMbench QA accuracy by 20.0 percentage points.

Biomedical knowledge graphs combine ontology-derived hierarchies with transversal associations among heterogeneous entities such as phenotypes, diseases, genes, proteins, and patients. This hybrid structure raises the question of whether hyperbolic embeddings, which naturally capture tree-like organization, remain useful beyond purely hierarchical graphs. We present a preliminary study of hyperbolic graph representation learning for Mendelian-disease differential diagnosis on a patient-integrated biomedical graph. Experiments on isolated ontology subgraphs show that hyperbolic models achieve strong performance in substantially lower dimensions than Euclidean baselines. We then evaluate the models on a link-prediction task that ranks candidate diseases for each patient. Results suggest that hyperbolic embeddings can exploit biomedical hierarchical structure while supporting diagnostic reasoning over heterogeneous patient-level graphs.

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.

Path-finding over knowledge graphs has become an effective way to ground LLM reasoning on multi-hop questions. However, biomedical QA introduces two distinct challenges that general-domain methods are not designed for: (i) queries do not expose intermediate reasoning and can be answered through multiple valid pathways, and (ii) biomedical knowledge graphs are densely connected, so path-finding methods easily take wrong turns. To address these challenges, we propose AdaPath, a path-finding framework that retrieves query-adaptive meta-paths from Path-Bank, which captures both query semantics and biomedical knowledge graph structure. AdaPath provides the missing cues in biomedical queries while effectively pruning dense knowledge graph neighborhoods during multi-hop reasoning. We further release BioStrat-QA, a biomedical KGQA benchmark that stratifies multi-hop queries by how much intermediate reasoning they expose. Across biomedical KGQA benchmarks, AdaPath consistently outperforms baselines, sustaining meaningful path-finding even when multi-hop queries expose less surface information. The source code is available at https://github.com/Jun-Hyeong-Kim/AdaPath.

Biomedical knowledge graphs (KGs) accelerate drug discovery, but standard pipelines assume query molecules already exist as graph entities, leaving unregistered molecules disconnected. We address this cold-start challenge, termed the out-of-graph molecule problem, by introducing MolBioKG. This two-layer system grounds unseen molecules in biomedical evidence via multi-resolution structural anchoring. It connects an index of 2.74 million molecules (represented by scaffolds, fragments, functional groups, and fingerprints) to a 9.6-million-edge KG. Given only a SMILES string, MolBioKG retrieves structurally related graph entities and traverses their biomedical neighborhoods without task-specific training. It features two inference mechanisms: static multi-anchor retrieval using Reciprocal Rank Fusion, and Adapt-KG, a tool-using LLM policy for adaptive traversal. Evaluated across in-graph link recovery, complex multi-hop reasoning, and out-of-graph generalization, MolBioKG outperforms strong baselines. Notably, it raises Hits@10 from 0.585 to 0.876 in multi-hop reasoning and out-of-graph target recall from 0.145 to 0.269, all while ensuring predictions retain traceable structural anchors and source-attributed KG evidence.

Inadequate target--disease linkage accounts for 40--50% of PhaseII efficacy failures, so anticipating which programmes will advance would let sponsors back the hypotheses most likely to reach patients. What a programme can be judged on is the evidence that supported its linkage \emph{when it entered the clinic}. No existing biomedical knowledge graph allows that evidence profile to be assembled as of a past date. We present the Temporal Heterogeneous Biomedical Knowledge Graph (THBKG), which describes and predicts therapeutic target--disease links through time: 110,396 entities and 11.1M edges across nineteen relation types, each edge carrying the year its evidence changed, so a pair's profile can be recovered as it stood when its own decision fell due. On this graph we define a decision-aligned benchmark that predicts, for a target--disease pair entering PhaseII, whether it advances to Phase~III on evidence datable before that decision. Graph propagation over the THBKG outranks every direct-evidence reference scored under the same decision-aligned protocol, reaching a relative success of 4.3--4.5 at the top ten pairs per therapeutic area. The gain concentrates on the 72.8% of pairs with no direct target--disease evidence at their decision point, where a direct-edge model has nothing to read: the encoders still rank five- to sixfold above chance, recovering the signal by propagating over the intervening biology. Adapting a path-based explainer to the decision-time subgraph decomposes each prediction into the evidence landscape behind the hypothesis for explainable prediction. We release the THBKG as a continually updated substrate for studying therapeutic target hypotheses by retrospective validation.

The rapid growth of biomedical knowledge has made the validation of automatically generated biological annotations a major bottleneck in biomedical curation. While computational methods can rapidly produce large numbers of candidate annotations, determining which are biologically valid still requires costly expert review. Prioritizing these candidates before manual curation has therefore become a fundamental challenge. Machine learning techniques can support this process by exploiting biomedical knowledge graphs (bioKGs), which capture biological entities and their functional associations. In this work, we propose a framework that leverages bioKGs to estimate the plausibility of candidate annotations and guide expert curation. Starting from knowledge graph embeddings, we train relation-specific binary classifiers using a community-based negative sampling strategy to obtain reliable confidence estimates. We then introduce a family of plausibility measures that combine classifier confidence, classifier reliability, and the semantic context provided by alternative relationships involving the same pair of biological entities. Unlike conventional confidence estimation, the proposed approach explicitly accounts for multiple biologically meaningful relations that may coexist between the same entities. Experimental results on five large bioKGs demonstrate that the proposed negative sampling strategy consistently improves classifier robustness, increasing balanced accuracy by an average of 5.8%. Moreover, the plausibility measures outperform classifier confidence alone, enabling more effective prioritization of candidate annotations for expert review. Overall, our results show that the use of bioKGs improves the efficiency of AI-assisted biomedical curation while preserving expert control over the final annotation assessment.

Designing microbial strains that produce high-value chemicals at commercially viable titers remains a central challenge in metabolic engineering. Existing computational approaches either rely on stoichiometric constraint-based models that cannot learn from experimental data, or apply tabular machine learning to hand-crafted features that discard the relational structure of biological knowledge. We present Canopy, a heterogeneous graph foundation model that integrates ten public and proprietary data sources into a unified knowledge graph (KG) of 6.9M nodes across 13 types and 34 edge types, covering genes, proteins, metabolites, reactions, pathways, strains, and fermentation experiments. Node features are encoded through domain-specific foundation models (ESM-2 for protein sequences, MoLFormer for chemical SMILES, and PubMedBERT for biomedical text), yielding a multi-modal representation within a single graph. We pretrain a Heterogeneous Graph Transformer (HGT) augmented with SignNet positional encodings, Jumping Knowledge aggregation, and virtual nodes using four self-supervised objectives (link prediction, masked node modelling, distance prediction, and contrastive experiment clustering), balanced via learned homoscedastic uncertainty weighting. On the downstream task of fermentation titer prediction, frozen Canopy embeddings achieve $R^{2} = 0.41$ with a lightweight probe, outperforming tabular baselines (best $R^{2} = 0.24$) and homogeneous GNN variants.

Accurate protein-protein interaction (PPI) prediction is central to functional genomics, disease mechanism discovery, and drug development. A difficult setting arises when candidate interactions include proteins that have no observed PPI edges during training, where models relying on network topology alone often lose useful context. This paper presents \method, a multimodal representation framework for cold-start PPI prediction. \method\ combines region-aware protein sequence encoding with four protein-centered biomedical knowledge graphs, including protein-drug, protein-disease, protein-miRNA, and protein-lncRNA associations. The sequence branch extracts contextual representations from structurally informed sequence regions, while graph attention encoders learn modality-specific protein embeddings from sparse biomedical associations. A bridge reconstruction objective regularizes graph learning by recovering shared protein-entity associations, and a pair-level gating module adaptively integrates sequence and graph evidence for each candidate protein pair. Experiments on two benchmark datasets under novel-old and novel-novel cold-start settings show that \method\ consistently outperforms competitive sequence, network, and knowledge-graph baselines across ACC, F1, AUC, AUPR, and MCC.

Patients increasingly seek medication information online, yet safety knowledge for psychiatric drugs is split between regulatory adverse-event records, which are authoritative but abstract, and patient narratives, which are experience-near but unvalidated. Integrating them without conflating evidence and anecdote is especially consequential in psychiatry, where poorly contextualised information can amplify fear, nocebo responses, and non-adherence. Here we develop a provenance-aware, knowledge-graph-based multi-agent framework unifying 466,525 Reddit posts, 60,782 WebMD reviews, and twenty years of U.S. FDA Adverse Event Reporting System records for nine antidepressants. A large-language-model entity-recognition pipeline benchmarked against physician annotations reached highest F1 scores of 0.969 for medications and 0.973 for conditions. The two community platforms were far more concordant with each other (overlap up to a Jaccard similarity of 0.905) than with regulatory reports, indicating that patient-generated data form a partly independent safety signal. For sertraline, many adverse events appeared in community sources hundreds of days before the corresponding FDA date. A Neo4j knowledge graph grounded in ATC-N, ICD-10, and MedDRA vocabularies preserves provenance, keeping every claim traceable and regulatory facts distinct from patient experience. These results establish source-aware integration as a route to more auditable psychiatric medication information, with usefulness and patient benefit to be tested prospectively.

A recent Nature Medicine study reports that general-purpose frontier LLMs outperform specialized retrieval-augmented clinical tools on medical benchmarks, and that retrieval can hurt strong models. We ask the natural follow-up: does structured knowledge-graph (KG) grounding change this, and when does grounding help at all? We contribute two results. First, a reproduction: the study's headline HealthBench score (~88) is the Consensus variant, not full HealthBench, where frontier models and ideal completions both score ~46-47 under a physician-calibrated grader (agreement 82.5%); we reproduce GPT-5.2 Consensus =90.9 and flag a score-deflating grader bug. Second, a knowledge-boundary result. Using a graph+vector engine (samyama-graph) over the public biomedical KG PrimeKG, neither naive triple retrieval nor an agentic natural-language-to-Cypher loop (82% successful queries) improves MedQA across a weak-to-strong model ladder (all |Delta| <= 3.4). On a synthetic counterfactual KG, and on a hybrid benchmark mixing known and novel facts, the identical pipeline lifts out-of-training accuracy from chance to ~100% (+68 to +79) while adding nothing on known facts (a no-LLM arm answers both). Across three regimes (no-knowledge, graph-aided, hybrid), grounding helps only insofar as the decisive fact lies outside the model's training -- public-KG facts are redundant, private and novel data are where it pays -- matching the study's institutional-data caveat.

Biomedical question answering (QA) increasingly requires reasoning over interacting entities, where supporting evidence is scattered across biomedical knowledge graphs, literature documents, and web-accessible resources. However, existing biomedical QA benchmarks mainly focus on exam-style knowledge, literature comprehension, or short-range multi-hop inference, leaving source-conditioned graph reasoning and evidence topology construction underexplored. To fill this gap, we introduce BioMedHop, a multi-source graph-grounded benchmark for evaluating biomedical reasoning over structured evidence topologies. BioMedHop contains 10,045 instances across KG, document, web, and hybrid evidence settings, covering shared-neighbor matching, intersection reasoning, path-based reasoning, and counting, with option-based, open-ended, and numeric count renderings. To support this benchmark, we further propose BioWeave, a source-aware reasoning framework that retrieves biomedical KG paths, gathers supporting clues from documents and web sources, assembles them into a unified evidence graph, and verifies answers through entity-level evidence support. Comprehensive experiments show that BioWeave achieves the best overall performance among compared methods on BioMedHop, outperforming the strong hybrid baseline ToG-2 by 10.5% in the overall average. Moreover, BioWeave consistently improves different LLM backbones and enables smaller models, such as Qwen3-4B, to achieve reasoning performance comparable to GPT-4-Turbo.

Historical medical archives and traditional medicines hold immense potential for drug discovery and remain a primary source for current drug development. However, pre-ontological prose and idiosyncratic taxonomies prevent the standardization and medical modernization of the data for use in current biomedical pipelines. Furthermore, no existing LLM agent system, whether tool-calling, retrieval-augmented, or agentic deep-research, can convert such text into verifiable drug-discovery leads at scale. We close this gap with DeepRoot, a multi-agent LLM system that jointly builds and utilizes a verified knowledge graph, showing that grounding and reasoning -- often conflated -- are separable axes the system can compose for therapeutic reasoning. Applied to the Shen Nong Ben Cao Jing, DeepRoot recovers $10$ of $21$ held-out compound-disease treatment pairs at R@$20$ ($47.6\%$ vs $4.8\%$ for a raw corpus LLM and $\sim\!2.4\%$ random) and dominates an LLM-as-judge audit for reasoning quality over baseline LLMs and LLMs with direct tool-call access to the same APIs DeepRoot itself queries. Tool-using LLMs hallucinate evidence on $87\%$ of claims, versus 7-10% for DeepRoot. Graph-only inference hallucinates $0\%$ but ranks lowest on reasoning coherence; DeepRoot KG+LLM is the only condition to win on both axes, pointing toward a route for systematic mining and repurposing of historical medical knowledge.

Knowledge graphs (KGs) have emerged as a promising solution for integrating and reasoning over complex biomedical and clinical data in healthcare. By representing structured relationships among entities such as diseases, drugs, symptoms, and patient records, KGs provide a semantic backbone for decision-making, prediction, recommendation, and personalized care. Recent advances have demonstrated their utility across diverse medical applications--including clinical decision support systems, disease and treatment outcome prediction, health recommender systems, precision medicine, and medical question answering--where KGs often enhance interpretability, semantic coherence, and patient-specific reasoning. In parallel, a growing body of work focuses on medical KG generation itself, proposing frameworks that construct graphs from EHRs, clinical narratives, biomedical literature, and web resources using ontologies, semantic web technologies, deep-learning-based information extraction, and hybrid neuro-symbolic pipelines. Despite this progress, significant challenges remain, including limited and fragmented knowledge coverage, difficulties in aligning heterogeneous data sources, the fragility of current reasoning and representation-learning methods on dense multi-relational graphs, and unresolved issues related to privacy, bias, and accountability. This survey reviews and categorizes current research on KGs in medicine along both application-oriented and methodology-oriented dimensions, discusses their benefits and technical foundations, and outlines key limitations and open research directions. By analyzing trends, architectures, and evaluation practices, this work aims to guide future developments in KG-driven medical AI systems and support their safe and effective integration into healthcare environments.

Predicting the effect of an unseen gene knockout perturbation on transcriptomic gene expression remains a highly challenging problem for virtual cell models. Recent progress has been made by leveraging biological knowledge graphs to provide a notion of similar perturbation, allowing for improved extrapolation beyond the set of training perturbations. In this work, we demonstrate that the simplest model to leverage these assumptions - a K-nearest neighbour from the knowledge graph - achieves highly competitive performance on this task, and that this can be improved further using LLMs optimised via reinforcement learning (RL) for predictive performance. Specifically, we find that the K-nearest neighbour approach beats almost all methods on out-of-distribution perturbation prediction, and when a reasoning LLM is trained via RL to make changes to the neighbourhood, it obtains equivalent performance to current state of the art methods on the cell lines from Replogle et al. (2022). We also demonstrate that the RL training improves the LLM's performance on the downstream task of differential expression prediction, despite not being trained on this directly. Overall, these findings demonstrate the efficacy of knowledge graphs as model priors, and show early signs that RL can refine LLMs into generalizable tools for predicting complex biological responses.

Pathology is the cornerstone of modern medicine, where accurate decision-making relies heavily on evidence-based practices. While artificial intelligence (AI) has the potential to transform clinical workflows, the intersection of AI and evidence-based medicine remains under-explored, with primitive attempts restricted to text-only general medicine. In this work, we present PathPocket, a multimodal AI agentic co-pilot designed specifically for evidence grounded pathology. We construct the most comprehensive pathology evidence corpus to date, encompassing approximately 110,472 public and authorized documents structured across a rigorous hierarchy of evidence from clinical guideline to expert opinion. From this meticulously graded foundation, we build a large-scale multimodal pathology hypergraph containing over 4.55 million entities and 7.10 million relations. Serving as a robust knowledge engine, this hypergraph provides traceable evidence for a collaborative multi-agent reasoning framework integrating input understanding, evidence retrieval, filtering, and diagnosis generation. This enables PathPocket to seamlessly resolve a wide spectrum of clinical tasks, ranging from text-only queries to complex multimodal diagnostics involving region-of-interest (ROI) and gigapixel whole-slide images (WSIs). We rigorously evaluate the system on a multidimensional benchmark of over 200,000 real-world cases, where it significantly outperforms existing state-of-the-arts. Crucially, extensive user studies demonstrate that PathPocket substantially improves the diagnostic accuracy and confidence of pathologists. By directly grounding pathology interpretations in verifiable literature, PathPocket offers a practical and scalable solution for the future of evidence grounded computational pathology.

Graph neural networks (GNNs) applied to drug-drug interaction (DDI) prediction rely exclusively on molecular structure encoded as SMILES-derived graphs. Prior work in this series demonstrated that model performance is bounded by the structural information content of training labels -- an Information Ceiling -- that architectural refinements alone cannot overcome. The present study investigates whether pharmacogenomic prior knowledge from the PharmGKB database partially closes this ceiling by providing metabolic pathway context that is independent of, and complementary to, molecular structure. Cytochrome P450 (CYP) enzyme substrate, inhibitor, and inducer annotations for four clinically relevant isoforms (CYP2D6, CYP3A4, CYP2C19, CYP2C9) are extracted and incorporated as a 12-dimensional feature vector concatenated to the molecular embedding prior to interaction prediction. Experiments are conducted under both pair-level and drug-level data splits to quantify generalization to unseen drugs. Results indicate that knowledge graph (KG) augmentation substantially improves DDI type classification under pair-level split conditions (F1-macro: 0.532 vs. 0.241 baseline), while binary interaction detection and drug-level generalization remain bounded by the Information Ceiling (AUC inflation: 0.224 vs. 0.250 baseline). Mechanistic validation on strictly held-out compounds confirms that augmentation preferentially improves CYP2C9-mediated interaction prediction, with probabilities increasing from 0.033-0.117 (baseline) to 0.560-0.586 (KG-augmented). An extension to single-molecule toxicity prediction on the Tox21 benchmark confirms that the effect is contingent on pharmacogenomic annotation coverage. These findings motivate the multimodal framework proposed for the subsequent study in this series.

Systematic characterization of drug-disease relationships is essential for drug discovery and repurposing, yet is hindered by the heterogeneity and rapid growth of biomedical literature. Existing datasets rely on labor-intensive curation and are often incomplete, while LLM-only approaches suffer from hallucination and weak evidence grounding. We introduce UniD$^3$, a unified framework that integrates Large Language Models with Knowledge Graph-enhanced Retrieval-Augmented Generation (KG-RAG) to extract, organize, and validate drug-disease knowledge across Drug-Disease Matching (DDM), Drug Effectiveness Assessment (DEA), and Drug-Target Analysis (DTA). UniD$^3$ processes 157,849 PubMed articles with Llama 3.3-70B and constructs knowledge graphs via a dual-stage strategy combining paper-level extraction with KG-level consolidation centered on drug and disease entities. These graphs support KG-RAG-based generation of structured datasets, evaluated through external benchmarks, fuzzy matching with curated resources, and clinician review. UniD$^3$ produces six knowledge graphs and large-scale datasets, including 28,915 DDM, 15,042 DEA, and over 4,000 DTA QA pairs. External validation shows strong performance (F1: 0.85-0.87 for DDM/DEA; 0.82 for DTA), with clinician review confirming high reliability (AUROC = 0.90). KG-RAG-augmented models outperform standalone LLMs, and the UniD$^3$ chatbot enables interpretable, citation-supported exploration of drug-disease relationships. UniD$^3$ provides a scalable, extensible framework for transforming unstructured biomedical literature into high-quality, structured drug-disease knowledge, supporting AI-driven discovery, repurposing, and precision medicine.

Biological systems are governed by structured molecular interactions, where pathways, regulatory circuits, and functional gene relationships shape cellular behavior and disease progression. Much of this knowledge is naturally represented as graphs. However, most biomedical AI models cannot directly use graph-encoded biological knowledge and instead require compressed low-dimensional representations, which can lose important structure and reduce performance, especially in limited-sample clinical studies. Here, we introduce Graph-in-Graph (GiG), a knowledge graph-modulated deep learning framework for data-efficient clinical prediction. GiG represents each patient as a standalone modular graph, in which curated biological knowledge graphs define edges and patient-specific measurements, such as gene expression, define node features. This design allows multiple biological knowledge graphs to be integrated while preserving gene-gene interactions and pathway topology during patient-level representation learning. Across cohorts comprising nearly 9,700 patients and five clinical tasks, including liquid biopsy cancer detection, prostate cancer diagnosis, and 32-class pan-cancer classification, GiG consistently outperforms traditional and state-of-the-art methods, with the largest gains in limited-sample settings. On the challenging prostate cancer diagnosis task, GiG improves macro-F1 by up to 49 percentage points relative to competing methods. Control experiments replacing real pathway graphs with random topologies confirm that these gains arise from biologically grounded knowledge graph structure rather than graph modeling alone. These findings show that knowledge graph-modulated deep learning can improve robustness, interpretability, and sample efficiency in clinical data analysis, and provide a principled framework for integrating biological knowledge graphs into predictive modeling.

Biomedical knowledge graphs (KGs) treat disease associations as static facts, but temporal information is crucial for clinical reasoning, e.g., a symptom diagnostic of one disease at age 3 may imply a different disease at age 13. Existing KGs such as PrimeKG, Hetionet, and iKraph do not encode when a finding becomes clinically relevant over the course of a disease. This limits their usefulness for longitudinal clinical reasoning and retrieval augmentation. We introduce ChronoMedKG, a temporal biomedical knowledge graph that contains 460,497 evidence-linked triples (filtered from 13M raw extractions) covering 13,431 diseases. Each association is tied to temporal components like onset window or progression stage, which are backed by PMID-traceable evidence and a multi-signal credibility score. The graph is constructed through a disease-autonomous multi-agent pipeline in which multiple frontier LLMs independently extract knowledge from PubMed and PMC literature. Only those relations are kept that are supported by multi-model consensus, survive credibility filtering, as well as ontology alignment. ChronoMedKG scored 92.7% agreement against Orphadata and adds temporal grounding for 6,250 diseases absent from HPOA, Orphadata, and Phenopackets, including 1,657 Orphanet-coded rare diseases. We further introduce ChronoTQA, a benchmark of 3,341 questions across eight task types (six temporal plus two static controls), with a 12-question supplementary probe. Frontier LLMs lose roughly 30 points moving from static to temporal questions; ChronoMedKG retrieval rescues 47-65% of their long-tail failures, against 17-29% for HPOA-RAG. As such, ChronoMedKG provides a crucial temporal axis for retrieval-augmented clinical systems that was previously absent.

Large language models (LLMs) are increasingly used in the mental health domain, yet it remains unclear how well they capture related biomedical knowledge and how reliably they apply it to clinically salient structured judgments. Here, we present a knowledge-graph (KG)-grounded benchmark for assessing LLMs on mental-health entity recognition, relation judgment, and two-hop reasoning. The benchmark is derived from PrimeKG and comprises nine task families with KG-supported answers and controlled negative options. Experiments across 15 closed- and open-source LLMs reveal a persistent recognition-to-judgment gap: leading models achieve near-ceiling performance on entity typing and on the small relation-typing subset, yet they still struggle with relation prediction and two-hop reasoning. Additionally, short KG-derived snippets benefit some models but degrade performance for others. Moreover, output-format reliability can substantially influence measured performance under constrained multiple-choice settings, highlighting the critical role of response validity in benchmark-based evaluation. MHGraphBench should therefore be interpreted as evaluating agreement with a curated mental-health slice of PrimeKG under a constrained multiple-choice interface, rather than as a direct assessment of real-world clinical safety.

Reasoning benchmarks measure clinical performance on clean inputs. We evaluate the step before reasoning: retrieval over real EHR notes, where negation, temporality, and family-versus-patient attribution can flip a correct answer to a wrong one. EpiKG carries an assertion label and a temporality tag with every fact in a patient knowledge graph, then routes retrieval by question intent. ClinicalBench is a 400-question test over 43 MIMIC-IV patients across 9 assertion-sensitive categories. A 7-condition ablation tests each piece of EpiKG across six LLMs (Claude Opus 4.6, GPT-OSS 20B, MedGemma 27B, Gemma 4 31B, MedGemma 1.5 4B, Qwen 3.5 35B). Three physicians blindly adjudicated 100 paired items. The author-blind primary endpoint, leave-author-out paired exact McNemar on 50 unanimous-strict items rated by two external physicians, yields +22.0 percentage points (95 percent Newcombe CI [+5.1, +31.5], p=0.0192). The architectural novelty, intent-aware KG-RAG over a Contriever dense-RAG baseline (C2b to C4g_kw on the change-excluded n=362 endpoint), is +8.84 percentage points (paired McNemar p=1.79e-3); +12.43 percentage points under oracle intent. Sensitivities agree directionally: three-rater physician majority +24.0 percentage points (subject to single-author circularity); deterministic keyword reproducibility proxy +39.5 percentage points. Across the six models, the gain shrinks as the LLM-alone baseline rises (beta=-1.123, r=-0.921, p=0.009). With n=6 this looks more like regression to the mean than encoding substituting for model size. Physician adjudication identified 56 percent of auto-generated reference answers as defective, a methodological finding indicating that NLP-pipeline clinical-QA benchmarks require physician adjudication to be usable. ClinicalBench, the frozen evaluator, three-rater adjudication data, and the EpiKG output stack are publicly released.

Biomedical knowledge graphs underwrite drug repurposing and clinical decision support, yet the upstream ontologies they depend on update on independent cycles that add millions of edges and deprecate hundreds of thousands more between releases. Yet existing continual graph learning has been studied almost exclusively on synthetic random splits of static, generic KGs, a regime that cannot reproduce the asynchronous, structured evolution real biomedical KGs undergo. To this end, we introduce PrimeKG-CL, a CGL benchmark built from nine authoritative biomedical databases (129K+ nodes, 8.1M+ edges, 10 node types, 30 relation types) with two genuine temporal snapshots (June 2021, July 2023; 5.83M edges added, 889K removed, 7.21M persistent), 10 entity-type-grouped tasks, multimodal node features, and a per-task persistent/added/removed test stratification. On three tasks (biomedical relationship prediction, entity classification, KGQA), we evaluate six CL strategies across four KGE decoders, plus LKGE, an LLM-RAG agent, and CMKL. We find that decoder choice and continual learning strategy interact strongly: no single strategy performs best across all decoders, and mismatched combinations can significantly degrade performance. Moreover, only DistMult exhibits a clear separation between persistent and deprecated knowledge, indicating that standard metrics conflate retention of still-valid facts with failure to forget outdated ones; this effect is absent under RotatE. In addition, multimodal features improve entity-level tasks by up to 60%, and a recent CKGE framework (IncDE) failed to scale to our 5.67M-triple base task across five attempts up to 350GB RAM. Data, pipeline, baselines, and the stratified split are released openly. Dataset:huggingface.co/datasets/yradwan147/PrimeKGCL|Code:github.com/yradwan147/primekg-cl-neurips2026

Biomedical knowledge graphs are increasingly large, dynamic, and multimodal, driven by rapid advances in biotechnology such as high-throughput sequencing. Machine learning models can infer previously unobserved biomedical relationships and characterize biomedical entities in these graphs, but existing knowledge graph embedding methods and their continual learning extensions either assume static graph structure or fail to exploit multimodal information under evolving data distributions. They also apply uniform regularization across all model parameters, ignoring that different modalities may exhibit distinct forgetting dynamics as the graph evolves. We propose the Continual Multimodal Knowledge Graph Learner (CMKL), a CL framework for biomedical KGs that natively encodes structure, text, and molecules, fuses them through a Mixture-of-Experts (MoE) router, and protects previously learned knowledge with standard EWC regularization and a K-means-diverse multimodal replay buffer. We evaluate CMKL on a 129K-entity biomedical continual benchmark with 10 tasks. On continual biomedical entity classification, CMKL reaches AP 0.591 versus 0.370 for the strongest structural baseline, a 60% gain that is driven by access to multimodal features and preserved across the sequence with near-zero forgetting (AF 0.008). On continual relationship prediction, CMKL reaches AP $0.062$, matching Naive Sequential and EWC (0.058) within seed noise and outperforming Joint Training (0.047, p=0.045) and LKGE (0.039). A frozen-text ablation reaches AP 0.136, more than double any jointly trained model, yet that signal is unreachable by margin-ranking gradients: the greedy-modality asymmetry lives at the representation level, not the fusion level, and MoE routing manages it by suppressing the unreachable modality without forcing it through a learned bottleneck. Code: github.com/yradwan147/cmkl-neurips2026