Dominic Okonkwo | Searcharxiv

arXiv2026

HypoKG: Evidence-Disciplined Biomedical Hypothesis Generation Beyond Endpoint Knowledge

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.

cs.CL↗

arXiv2026

Capabilities of Claude Fable 5 on Biomedical Challenge Problems

Frontier language models are increasingly evaluated on biomedical benchmarks, but two problems undermine most published evaluations: legacy benchmarks are near-saturated, and open-ended responses are graded by other language models. We evaluate Claude Fable 5, Anthropic's most capable publicly available model, across eight biomedical benchmarks, four text and four multimodal, using deterministic scoring against fixed answer keys throughout. We include two Claude predecessors and GPT-5 as baselines. Refusal is tracked as a distinct outcome in every result table. That decision produces the paper's central finding. Fable 5 refuses between 8.0% and 99.4% of questions depending on the benchmark, a pattern absent in both predecessors and in GPT-5. Once refused items are excluded from the denominator, Fable 5's accuracy exceeds or meets every other model on every benchmark in this study. We identify two distinguishable refusal patterns: one concentrating in basic-science and mechanism content across MedQA and MedXpertQA MM, confirmed independently on two benchmarks using each benchmark's own category labels; and a separate disease-domain pattern on RareBench, where inborn metabolic disease presentations are refused near-universally while adult-onset autoimmune presentations are not. The primary constraint on Fable 5's biomedical usefulness is willingness to engage, not capability once it does.

cs.CL↗