Biomedical KGs

Extracting multi-step explanations from knowledge graphs poses a combinatorial challenge requiring both heuristic guidance (as candidates proliferate with depth) and credit assignment (as path quality emerges over extended sequences). Frontier LLMs, strong on knowledge/reasoning benchmarks, offer a compelling source of such heuristics, yet their knowledge comes sans guarantees and compositional performance degrades as chains lengthen. We thus present TESSERA, a 3-part neuro-symbolic framework that uses LLMs in a circumscribed role: for local discriminative judgement rather than autonomous multi-step generation; the knowledge graph then defines the hypothesis space enforcing hard structural constraints, and MCTS coordinates the long-horizon search with principled credit assignment via backpropagation. LLMs perform dual roles as a prior policy biasing exploration and a comparative state evaluator supplying reward signals. Evaluation on drug mechanism elucidation across two complementary knowledge graphs demonstrates fidelity to curated biology while surfacing coherent alternative mechanisms, with ablations confirming discriminative contribution from both LLM components. Beyond its current application, our framework offers a general paradigm for compositional reasoning over structured knowledge.

Epilepsy diagnosis and treatment require evidence-intensive reasoning across heterogeneous clinical knowledge, including biosignal patterns, genetic mechanisms, pharmacogenomics, treatment strategies, and patient outcomes. In this work, we present \textsc{EpiGraph}, a large-scale epilepsy knowledge graph and benchmark for evaluating knowledge-augmented clinical reasoning. \textsc{EpiGraph} integrates 48,166 peer-reviewed papers and seven clinical resources into a heterogeneous graph containing 24,324 entities and 32,009 evidence-grounded triplets across five clinical layers. Built upon this graph, \textsc{EpiBench} defines five clinically motivated tasks spanning clinical decision-making, EEG report generation, pharmacogenomic precision medicine, treatment recommendation, and deep research planning. We evaluate six LLMs under both standard and Graph-RAG settings. Results show that integrating \textsc{EpiGraph} consistently improves performance across all tasks, with the largest gains observed in pharmacogenomic reasoning (+30--41%). Our findings demonstrate that structured epilepsy knowledge substantially enhances evidence-grounded clinical reasoning and provides a practical benchmark framework for evaluating knowledge-augmented LLMs in real-world neurological settings. Our code is available at: https://github.com/LabRAI/EEG-KG.

Zero-shot single-cell cell-type annotation aims to determine a cell's type from a given set of expressed genes without any training. Existing knowledge-graph-based RAG approaches retrieve evidence by expanding from source entities and relying on iterative LLM reasoning. However, in this setting each query contains tens to hundreds of genes, where no single gene is decisive and the label emerges only from their collective co-occurrence. Such hyper-entity queries fundamentally challenge local, entity-wise exploration strategies, which reason from individual genes, leading to poor scalability and substantial LLM cost. We propose GATHER (Graph-Aware Traversal with Hyper-Entity Retrieval), a convergence-centric retriever tailored to hyper-entity queries. It performs global multi-source graph traversal and identifies topological convergence points -- nodes jointly reachable from many input genes. These convergence nodes act as high-information hyper-entities that capture entity synergy. By incorporating node- and path-importance scoring, GATHER selects informative evidence entirely without LLM involvement during retrieval. Instantiated on a self-constructed cell-centric biological knowledge graph (VCKG), GATHER outperforms strong KG-RAG baselines (ToG, ToG-2, RoG, PoG) on two datasets (Immune and Lung), achieving the highest exact-match accuracy (27.45% and 59.64%) with only a single LLM call per sample, compared to 2--61 calls for KG-RAG baselines. Our results demonstrate that convergence nodes compress multi-entity signals into compact, high-information evidence that conveys more per item than multi-hop paths, providing an efficient global alternative to local entity-wise reasoning.

Knowledge graphs automatically constructed from text are increasingly used in real-world applications. However, their inherent noise, fragmentation, and semantic inconsistencies significantly affect the performance of Graph Neural Networks (GNNs) on downstream tasks. Assessing their performance and robustness remains difficult, as it is often unclear whether observed results stem from the learning model or from the quality of the constructed graph itself. In this work, we introduce a dual-purpose benchmark designed to jointly evaluate (i) the performance of GNNs on noisy, text-derived graphs and (ii) the effectiveness of graph construction methods on a downstream task. The benchmark is built in the biomedical domain from a single textual corpus and includes two automatically constructed graphs generated using different extraction methods, alongside a high-quality reference graph curated by experts that serves as an upper performance bound. This design enables controlled comparison of construction methods and systematic evaluation of GNN robustness through semi-supervised node classification. We further provide a standardized, reproducible, and extensible evaluation framework, facilitating the integration of new graph extraction methods and learning models.

Graph Self-Supervised Learning (GSSL) offers a powerful paradigm for learning graph representations without labeled data. However, existing work assumes clean, manually curated graphs. Recent advances in NLP enable the large-scale automatic extraction of knowledge graphs from text, opening new opportunities for GSSL while introducing substantial real-world noise. This type of noise remains largely unexplored, as prior robustness studies typically rely on synthetic perturbations. To address this gap, we present the first comprehensive evaluation of GSSL methods on text-driven graphs for unsupervised term typing. We introduce Noise-Aware Text-Driven Graph GSSL (NATD-GSSL), a unified framework that combines automatic graph construction, graph refinement, and GSSL. Our evaluation follows a dual-graph protocol that contrasts a noisy graph derived from MedMentions with a clean Unified Medical Language System (UMLS) reference graph, aligned through a shared gold standard. Our results reveal variability in robustness across both pretext tasks and Graph Neural Network (GNN) architectures. Relation reconstruction is highly sensitive to noise and benefits from well-defined schemas, whereas feature reconstruction is considerably more robust, achieving performance comparable to clean-graph settings. Contrastive objectives are generally less affected by noise but depend strongly on alignment with downstream tasks. GNN architecture also plays a critical role: bidirectional relational message-passing designs are better suited to noisy, text-driven graphs, while unidirectional relational ones perform best on clean graphs. Overall, NATD-GSSL provides practical guidance for applying GSSL to real-world, noisy graphs and achieves up to a 7% improvement over pretrained language model baselines. All code and benchmarks are publicly available at https://github.com/OthmaneKabal/MC2GAE.

We present a method for finding hierarchy-aware embeddings of knowledge graphs (KGs) using graph neural networks (GNNs) enriched with a semantic loss derived from underlying ontologies. This method yields embeddings that better reflect domain knowledge. To demonstrate their utility, we predict and interpret the effects of gene deletions in the yeast Saccharomyces cerevisiae and learn box embeddings for KGs in the absence of a prediction task. We further show how box embeddings can serve as the basis for evaluating KG revisions. Our yeast KG is constructed from community databases and ontology terms. Low-dimensional box embeddings combined with GNNs are used to predict cell growth for double gene knockouts. Over 10-fold cross validation, these predictions have a mean $R^2$scoreof~0.360, significantly higher than baseline comparisons, demonstrating that high-level qualitative knowledge is informative about experimental outcomes. Incorporating semantic loss terms in the training of the models improves their predictive performance ($R^2$=0.377) by aligning embeddings with ontology structure. This shows that class hierarchies from ontologies can be exploited for quantitative prediction. We also test the trained models on triple gene knockouts, showing they generalise to data beyond those seen in training. Additionally, by identifying co-occurring relations in the yeast KG important for the cell-growth predictions, we construct hypotheses about interacting traits in yeast. A biological experiment validates one such finding, revealing an association between inositol utilisation and osmotic stress resistance, highlighting the model's potential to guide biological discovery.

Biomedical knowledge graphs (KGs) are widely used in the life sciences, yet many are derived from unstructured documents and therefore lack schema-level constraints, whereas graphs assembled from structured resources are difficult to harmonize into a unified representation. We present OptimusKG, a multimodal biomedical labeled property graph (LPG) built from structured and semi-structured resources to preserve factual, type-specific metadata across molecular, anatomical, clinical, and environmental domains. OptimusKG contains 190,939 nodes across 10 entity types, 21,818,752 edges across 27 edge types, and 67,070,490 property instances encoding 109,665,797 values across 145 distinct property keys, derived from 18 ontologies and controlled vocabularies. The graph enforces a top-level schema for nodes and edges and retains granular, type-specific properties, cross-references, and provenance. We assessed the validity of OptimusKG by evaluating whether graph relationships are supported by evidence from the scientific literature using a multimodal agent, PaperQA3. PaperQA3 identified supporting evidence for 70.0% of sampled edges, whereas 83.4% of sampled false edges received no supporting evidence. Edges without literature support were concentrated in associations derived from experimental and functional genomics resources, suggesting that OptimusKG captures biomedical knowledge that may precede synthesis in the scientific literature. OptimusKG is distributed as Apache Parquet files, providing a standardized resource for graph-based machine learning, knowledge-grounded retrieval with large language models, and biomedical discovery use cases such as hypothesis generation.

Knowledge graphs (KGs) are increasingly used to support large lan guage model (LLM) reasoning, but standard triplet-based KGs treat each relation as globally valid. In many settings, whether a relation should count as evidence depends on the context. We therefore formulate triplet validity as a triplet-specific function of context and refer to this formulation as a Quantum Knowledge Graph (QKG). We instantiate QKG in medicine using a diabetes-centered PrimeKG subgraph, whose 68,651 context-sensitive relations are further annotated with patient-group-specific constraints. We evaluate it in a reasoner--validator pipeline for medical question answering on a KG-grounded subset of MedReason containing 2,788 questions. With Haiku-4.5 as both the Reasoner and the Validator, KG-backed validation significantly improves over a no-validator baseline ($+0.61$ pp), and QKG with context matching yields the largest gain, outperforming both KG validation without context matching ($+0.79$ pp) and the no-validator baseline ($+1.40$ pp; paired McNemar, all $p<0.05$). Under a stronger validator (Qwen-3.6-Plus), the raw QKG gain over the no-validator baseline grows from $+1.40$ pp to $+5.96$ pp; the context-matching gap is non-significant ($p=0.73$) on the raw set but becomes borderline significant ($p=0.05$) after adjustment for knowledge leakage and suspicious questions, consistent with a benchmark-gold ceiling rather than a QKG limitation. Taken together, the results support the view that the value of a KG in LLM-based clinical reasoning lies not merely in storing medically related facts, but in representing whether those facts are applicable to the specific patient context. For reproducibility and further research, we release the curated QKG datasets and source code.\footnote{https://github.com/HKAI-Sci/QKG}

Drug repurposing is often framed as a candidate identification task, but existing approaches provide limited guidance for distinguishing biologically plausible candidates from historically well-connected ones. Here we introduce DrugKLM, a hybrid framework that integrates biomedical knowledge graph structure with large language model-based mechanistic reasoning to enable mechanistically grounded therapeutic prioritization. Across benchmark datasets, DrugKLM outperforms knowledge graph-only and language model-only baselines, including TxGNN. Beyond improved recall, DrugKLM confidence scores exhibit functional alignment with molecular phenotypes: higher scores are associated with transcriptional signatures linked to improved survival across 12 TCGA cancers. The scoring framework preferentially captures biologically perturbational signals rather than historical indication patterns. Expert curation across five cancers further reveals systematic differences in prioritization behavior, with DrugKLM elevating candidates supported by coherent mechanistic rationale and disease-specific clinical context. Together, these results establish DrugKLM as an evidence-integrative framework that translates heterogeneous biomedical data into mechanistically interpretable and clinically grounded therapeutic hypotheses.

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 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.