MedHopQA: A Disease-Centered Multi-Hop Reasoning Benchmark and Evaluation Framework for LLM-Based Biomedical Question Answering
Authors: Rezarta Islamaj, Robert Leaman, Joey Chan, Nicholas Wan, Qiao Jin, Natalie Xie, John Wilbur, Shubo Tian, +8 more
Organizations: National Library of Medicine, Division of Intramural Research, Bethesda, MD, US · University of Illinois at Urbana-Champaign, Department of Computer Science, Urbana, IL, US · University of Michigan Medical School, Ann Arbor, Michigan, US
Evaluating large language models (LLMs) in the biomedical domain requires benchmarks that can distinguish reasoning from pattern matching and remain discriminative as model capabilities improve. Existing biomedical question answering (QA) benchmarks are limited in this respect. Multiple-choice formats can allow models to succeed through answer elimination rather than inference, while widely circulated exam-style datasets are increasingly vulnerable to performance saturation and training data contamination. Multi-hop reasoning, defined as the ability to integrate information across multiple sources to derive an answer, is central to clinically meaningful tasks such as diagnostic support, literature-based discovery, and hypothesis generation, yet remains underrepresented in current biomedical QA benchmarks. MedHopQA is a disease-centered multi-hop reasoning benchmark consisting of 1,000 expert-curated question-answer pairs introduced as a shared task at BioCreative IX. Each question requires synthesis of information across two distinct Wikipedia articles, and answers are provided in an open-ended free-text format. Gold annotations are augmented with ontology-grounded synonym sets from MONDO, NCBI Gene, and NCBI Taxonomy to support both lexical and concept-level evaluation. MedHopQA was constructed through a structured process combining human annotation, triage, iterative verification, and LLM-as-a-judge validation. To reduce leaderboard gaming and contamination risk, the 1,000 scored questions are embedded within a publicly downloadable set of 10,000 questions, with answers withheld, on a CodaBench leaderboard. MedHopQA provides both a benchmark and a reusable framework for constructing future biomedical QA datasets that prioritize compositional reasoning, saturation resistance, and contamination resistance as core design constraints.
Multi-hop question answering (QA) remains a significant challenge in the biomedical domain, requiring systems to integrate information across multiple sources to answer complex questions. To address this problem, the BioCreative IX MedHopQA shared task was designed to benchmark in multi-hop reasoning for large language models (LLMs). We developed a novel dataset of 1,000 challenging QA pairs spanning diseases, genes, and chemicals, with particular emphasis on rare diseases. Each question was constructed to require two-hop reasoning through the integration of information from two distinct Wikipedia pages. The challenge attracted 48 submissions from 13 teams. Systems were evaluated using both surface string comparison and conceptual accuracy (MedCPT score). The results showed a substantial performance gap between baseline LLMs and enhanced systems. The top-ranked submission achieved an 89.30% F1 score on the MedCPT metric and an 87.30% exact match (EM) score, compared with 67.40% and 60.20%, respectively, for the zero-shot baseline. A central finding of the challenge was that retrieval-augmented generation (RAG) and related retrieval-based strategies were critical for strong performance. In addition, concept-level evaluation improved answer assessment when correct responses differed in surface form. The MedHopQA dataset is publicly available to support continued progress in this important area. Challenge materials: https://www.ncbi.nlm.nih.gov/research/bionlp/medhopqa and benchmark https://www.codabench.org/competitions/7609/
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.
Biomedical question answering with large language models is commonly evaluated using answer accuracy, but answer accuracy alone does not indicate whether a model can produce parseable outputs, follow structured reliability instructions, recognize weak answer spaces, or avoid confident incorrect commitments. This paper presents HypothesisMed, an inference-time reliability pipeline for biomedical multiple-choice question answering. It combines direct, chain-of-thought, HypothesisMed-v3 prompting, and answer fusion. The final answer is selected by fusion, while HypothesisMed-v3 supplies SPACE labels and confidence information. SPACE labels mark the answer space as VALID, INCOMPLETE, or CONTRADICTED. We evaluate Qwen2.5-7B, Phi-4-mini, DeepSeek-R1-32B, and BioMistral-7B on MedQA, MedMCQA, and PubMedQA using 1,000 examples per dataset. The pipeline improves weighted accuracy over each model's best direct or chain-of-thought baseline while increasing parse and SPACE coverage. We also scale evaluation to Qwen2.5-7B and Phi-4-mini using 10,183 examples per model. Fusion improves Phi-4-mini accuracy from 0.4296 to 0.5192, while Qwen2.5-7B chain-of-thought remains slightly higher in answer accuracy. However, Qwen2.5-7B fusion achieves complete parse and SPACE coverage with much lower false commitment. A 12,000-example SPACE stress test shows answer-space diagnosis remains difficult, with SPACE accuracy of 0.3074 for Qwen2.5-7B and 0.4168 for Phi-4-mini. These results show that answer accuracy, parseability, structured reliability reporting, calibration behavior, and false-commitment behavior are separable capabilities. The main contribution is not a universal state-of-the-art claim, but a reproducible inference-time framework for evaluating biomedical question answering models as auditable workflow components under structured reliability constraints.