Biomedical KGs

Understanding mechanistic relationships among genes and their impacts on biological pathways is essential for elucidating disease mechanisms and advancing precision medicine. Despite the availability of extensive molecular interaction and pathway data in public databases, integrating heterogeneous knowledge sources and enabling interpretable multi-step reasoning across biological networks remain challenging. We present GIP-RAG (Gene Interaction Prediction through Retrieval-Augmented Generation), a computational framework that combines biomedical knowledge graphs with large language models (LLMs) to infer and interpret gene interactions. The framework constructs a unified gene interaction knowledge graph by integrating curated data from KEGG, WikiPathways, SIGNOR, Pathway Commons, and PubChem. Given user-specified genes, a query-driven module retrieves relevant subgraphs, which are incorporated into structured prompts to guide LLM-based stepwise reasoning. This enables identification of direct and indirect regulatory relationships and generation of mechanistic explanations supported by biological evidence. Beyond pairwise interactions, GIP-RAG includes a pathway-level functional impact module that simulates propagation of gene perturbations through signaling networks and evaluates potential pathway state changes. Evaluation across diverse biological scenarios demonstrates that the framework generates consistent, interpretable, and evidence-supported insights into gene regulatory mechanisms. Overall, GIP-RAG provides a general and interpretable approach for integrating knowledge graphs with retrieval-augmented LLMs to support mechanistic reasoning in complex molecular systems.

Alkaptonuria (AKU) is an ultra-rare autosomal recessive metabolic disorder caused by mutations in the HGD (Homogentisate 1,2-Dioxygenase) gene, leading to a pathological accumulation of homogentisic acid (HGA) in body fluids and tissues. This leads to systemic manifestations, including premature spondyloarthropathy, renal and prostatic stones, and cardiovascular complications. Being ultra-rare, the amount of data related to the disease is limited, both in terms of clinical data and literature. Knowledge graphs (KGs) can help connect the limited knowledge about the disease (basic mechanisms, manifestations and existing therapies) with other knowledge; however, AKU is frequently underrepresented or entirely absent in existing biomedical KGs. In this work, we apply a text-mining methodology based on PubTator3 for large-scale extraction of biomedical relations. We construct two KGs of different sizes, validate them using existing biochemical knowledge and use them to extract genes, diseases and therapies possibly related to AKU. This computational framework reveals the systemic interactions of the disease, its comorbidities, and potential therapeutic targets, demonstrating the efficacy of our approach in analyzing rare metabolic disorders.

Biomedical knowledge is fragmented across siloed databases -- Reactome for pathways, STRING for protein interactions, ClinicalTrials.gov for study registries, DrugBank for drug vocabularies, DGIdb for drug-gene interactions, SIDER for side effects. We present three open-source biomedical knowledge graphs -- Pathways KG (118,686 nodes, 834,785 edges from 5 sources), Clinical Trials KG (7,774,446 nodes, 26,973,997 edges from 5 sources), and Drug Interactions KG (32,726 nodes, 191,970 edges from 3 sources) -- built on Samyama, a high-performance graph database written in Rust. Our contributions are threefold. First, we describe a reproducible ETL pattern for constructing large-scale KGs from heterogeneous public data sources, with cross-source deduplication, batch loading (Python Cypher and Rust native loaders), and portable snapshot export. Second, we demonstrate cross-KG federation: loading all three snapshots into a single graph tenant enables property-based joins across datasets. Third, we introduce schema-driven MCP server generation for LLM agent access, evaluated on a new BiomedQA benchmark (40 pharmacology questions): domain-specific MCP tools achieve 98% accuracy vs. 85% for schema-aware text-to-Cypher and 75% for standalone GPT-4o, with zero schema errors. All data sources are open-license. The combined federated graph (7.9M nodes, 28M edges) loads in approximately 3 minutes on commodity cloud hardware, with single-KG queries completing in 80-100ms and cross-KG federation joins in 1-4s

Medication errors pose a significant threat to patient safety, making pharmacist verification (PV) a critical, yet heavily burdened, final safeguard. The direct application of Large Language Models (LLMs) to this zero-tolerance domain is untenable due to their inherent factual unreliability, lack of traceability, and weakness in complex reasoning. To address these challenges, we introduce PharmGraph-Auditor, a novel system designed for safe and evidence-grounded prescription auditing. The core of our system is a trustworthy Hybrid Pharmaceutical Knowledge Base (HPKB), implemented under the Virtual Knowledge Graph (VKG) paradigm. This architecture strategically unifies a relational component for set constraint satisfaction and a graph component for topological reasoning via a rigorous mapping layer. To construct this HPKB, we propose the Iterative Schema Refinement (ISR) algorithm, a framework that enables the co-evolution of both graph and relational schemas from medical texts. For auditing, we introduce the KB-grounded Chain of Verification (CoV), a new reasoning paradigm that transforms the LLM from an unreliable generator into a transparent reasoning engine. CoV decomposes the audit task into a sequence of verifiable queries against the HPKB, generating hybrid query plans to retrieve evidence from the most appropriate data store. Experimental results demonstrate robust knowledge extraction capabilities and show promises of using PharmGraph-Auditor to enable pharmacists to achieve safer and faster prescription verification.

The contributions of model complexity, data volume, and feature modalities to knowledge graph-based drug repurposing remain poorly quantified under rigorous temporal validation. We constructed a pharmacology knowledge graph from ChEMBL 36 comprising 5,348 entities including 3,127 drugs, 1,156 proteins, and 1,065 indications. A strict temporal split was enforced with training data up to 2022 and testing data from 2023 to 2025, together with biologically verified hard negatives mined from failed assays and clinical trials. We benchmarked five knowledge graph embedding models and a standard graph neural network with 3.44 million parameters that incorporates drug chemical structure using a graph attention encoder and ESM-2 protein embeddings. Scaling experiments ranging from 0.78 to 9.75 million parameters and from 25 to 100 percent of the data, together with feature ablation studies, were used to isolate the contributions of model capacity, graph density, and node feature modalities. Removing the graph attention based drug structure encoder and retaining only topological embeddings combined with ESM-2 protein features improved drug protein PR-AUC from 0.5631 to 0.5785 while reducing VRAM usage from 5.30 GB to 353 MB. Replacing the drug encoder with Morgan fingerprints further degraded performance, indicating that explicit chemical structure representations can be detrimental for predicting pharmacological network interactions. Increasing model size beyond 2.44 million parameters yielded diminishing returns, whereas increasing training data consistently improved performance. External validation confirmed 6 of the top 14 novel predictions as established therapeutic indications. These results show that drug pharmacological behavior can be accurately predicted using target-centric information and drug network topology alone, without requiring explicit chemical structure representations.

The rapid growth of biomedical evidence makes it difficult to translate biomarker mechanisms into actionable drug combination hypotheses. We present CoDHy, an interactive AI co-scientist for biomarker-guided hypothesis generation in oncology. CoDHy constructs task-specific knowledge graphs from curated databases and biomedical literature, then combines graph embeddings with agent-based reasoning to generate, validate, and rank evidence-grounded drug combinations. Through a web interface, researchers specify the biomarker, cancer context, and literature scope; inspect supporting evidence and intermediate results; and iteratively refine the generated hypotheses. The demonstration presents CoDHy's end-to-end workflow and shows how researchers can interactively explore and compare mechanistically supported drug combinations while remaining in control of hypothesis prioritization.

Understanding disease-gene associations is essential for unravelling disease mechanisms and advancing diagnostics and therapeutics. Traditional approaches based on manual curation and literature review are labour-intensive and not scalable, prompting the use of machine learning on large biomedical data. In particular, graph neural networks (GNNs) have shown promise for modelling complex biological relationships. To address limitations in existing models, we propose GLaDiGAtor (Graph Learning-bAsed DIsease-Gene AssociaTiOn pRediction), a novel GNN framework with an encoder-decoder architecture for disease-gene association prediction. GLaDiGAtor constructs a heterogeneous biological graph integrating gene-gene, disease-disease, and gene-disease interactions from curated databases, and enriches each node with contextual features from well-known language models (ProtT5 for protein sequences and BioBERT for disease text). In evaluations, our model achieves superior predictive accuracy and generalisation, outperforming 14 existing methods. Literature-supported case studies confirm the biological relevance of high-confidence novel predictions, highlighting GLaDiGAtor's potential to discover candidate disease genes. These results underscore the power of graph convolutional networks in biomedical informatics and may ultimately facilitate drug discovery by revealing new gene-disease links. The source code and processed datasets are publicly available at https://github.com/HUBioDataLab/GLaDiGAtor.

Background: Clinical named entity recognition tools commonly map free text to Unified Medical Language System (UMLS) Concept Unique Identifiers (CUIs). For many downstream tasks, however, the clinically meaningful unit is not a single CUI but a concept set comprising related synonyms, subtypes, and associated concepts. Constructing these sets is labour-intensive, inconsistently performed, and poorly supported by existing tools. Methods We present CUICurate, a graph-based retrieval-augmented generation (GraphRAG) framework for automated UMLS concept set curation. A UMLS knowledge graph (KG) was constructed and embedded for semantic retrieval. Candidate CUIs were retrieved using graph-based expansion and then filtered and classified using large language models (GPT-5 and Qwen3-32B). The framework was evaluated on five lexically heterogeneous clinical concepts against a manually curated concept sets and gold-standard concept sets. Results CUICurate produced substantially larger and more complete concept sets than the manual benchmarks. A single retrieval configuration across concepts achieved high recall of definitive concepts with manageable candidate sets. GPT-5 outperformed manual curation for all concepts and retained at least 95% of definitive gold-standard CUIs, while Qwen3-32B achieved comparable but slightly lower performance. Many missed concepts were not observed in 10,000 MIMIC-III notes. CUICurate infrastructure and end-to-end processing was inexpensive and stable across runs. Conclusions CUICurate offers a scalable, reproducible and cost-efficient approach for generating clinician-reviewable UMLS concept sets tailored to clinical natural language processing and phenotyping applications.

Adverse Drug Reactions (ADRs) are a leading cause of morbidity and mortality. Existing prediction methods rely mainly on chemical similarity, machine learning on structured databases, or isolated target profiles, but often fail to integrate heterogeneous, partly unstructured evidence effectively. We present a knowledge graph-based framework that unifies diverse sources, drug-target data (ChEMBL), clinical trial literature (PubMed), trial metadata (ClinicalTrials.gov), and post-marketing safety reports (FAERS) into a single evidence-weighted bipartite network of drugs and medical conditions. Applied to 400 protein kinase inhibitors, the resulting network enables contextual comparison of efficacy (HR, PFS, OS), phenotypic and target similarity, and ADR prediction via target-to-adverse-event correlations. A non-small cell lung cancer case study correctly highlights established and candidate drugs, target communities (ERbB, ALK, VEGF), and tolerability differences. Designed as an orthogonal, extensible analysis and search tool rather than a replacement for current models, the framework excels at revealing complex patterns, supporting hypothesis generation, and enhancing pharmacovigilance. Code and data are publicly available at https://github.com/davidjackson99/PKI_KG.

Understanding biomedical experiments provides a foundation for downstream tasks, e.g., laboratory automation, and facilitates effective cross-disciplinary communication. Two challenges, High Information Density (HID) and Multi-Step Reasoning (MSR), pose unique difficulties for precise experimental understanding. Extracting structured knowledge, e.g., Knowledge Graphs (KGs), is an effective approach to address the HID and MSR. However, existing biomedical datasets for structured knowledge information extraction are limited to a general or coarse-grained level, hindering fine-grained experimental understanding. To address this gap, we introduce Biomedical Protocol Information Extraction Dataset (BioPIE), a dataset providing procedure-centric KGs that capture entities, actions, and relations at a scale sufficient for reasoning across biomedical protocols. We evaluate information extraction methods on BioPIE and implement a question answering system leveraging the dataset for validation, demonstrating improved understanding performance on test sets as well as on the HID and MSR question sets.

Medical deep learning models depend heavily on domain-specific knowledge to perform well on knowledge-intensive clinical tasks. Prior work has primarily leveraged unimodal knowledge graphs, such as the Unified Medical Language System (UMLS), to enhance model performance. However, integrating multimodal medical knowledge graphs remains largely underexplored, mainly due to the lack of resources linking imaging data with clinical concepts. To address this gap, we propose MEDMKG, a Medical Multimodal Knowledge Graph that unifies visual and textual medical information through a multi-stage construction pipeline. MEDMKG fuses the rich multimodal data from MIMIC-CXR with the structured clinical knowledge from UMLS, utilizing both rule-based tools and large language models for accurate concept extraction and relationship modeling. To ensure graph quality and compactness, we introduce Neighbor-aware Filtering (NaF), a novel filtering algorithm tailored for multimodal knowledge graphs. We evaluate MEDMKG across three tasks under two experimental settings, benchmarking twenty-four baseline methods and four state-of-the-art vision-language backbones on six datasets. Results show that MEDMKG not only improves performance in downstream medical tasks but also offers a strong foundation for developing adaptive and robust strategies for multimodal knowledge integration in medical artificial intelligence.