Can Broad Biomedical Knowledge be Contextualized into Scenario-Grounded Propositions?

Translational medicine turns underspecified development goals into evidence synthesis that must combine literature, trials, patents, and quantitative multi-omics analysis while preserving identifiers, uncertainty, and retrievable provenance. General-purpose foundation models and off-the-shelf tool-augmented or multi-agent systems are not built for this: they tend to produce single-shot answers or run open-endedly, and fall short on the auditable, scenario-specific workflows that heterogeneous biomedical sources demand. This paper introduces Ingenix BioResearcher, a scenario-guided multi-agent system that maps queries to versioned research playbooks, delegates to specialized subagents over 30+ tools and machine-learning endpoints, mixes structured database access with sandboxed code for genome-scale analyses, and applies claim-level multi-model reconciliation before editorial assembly. We evaluate BioResearcher across unit-level capabilities, open-ended biomedical reasoning, and end-to-end clinical discovery. It leads evaluated baselines on 109 single-step tests (83.49% pass rate; 0.892 average score), achieves strong biomedical benchmark performance (89.33% on BixBench-Verified-50 and the top 0.758 mean score on BaisBench Scientific Discovery), and leads on a 30-query clinical end-to-end benchmark with the highest positive hit rate (74.7% $\pm$ 3.3%) and negative clear rate (96.8% $\pm$ 0.2%). These results show broad, competitive performance across unit-level, open-ended, and end-to-end clinical evaluations.

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.

Current AI-powered research systems adopt a direct search-then-summarize paradigm that treats hypotheses as end products of scientific discovery. We argue this leaves a critical gap: hypotheses can serve a far more powerful role as organizational instruments that structure the research process itself. We propose the Hypothesis-Driven Deep Research (HDRI) methodology - the first framework using hypotheses to organize general-purpose deep research across arbitrary domains, rather than merely validating claims within specific domains. This transforms research from reactive information retrieval into proactive, verifiable, and iterative knowledge discovery. HDRI is formalized with six core principles and an eight-stage pipeline. A central innovation is the gap-driven iterative research mechanism - a closed-loop quality assurance system that automatically identifies informational and logical gaps, triggering targeted supplementary investigation. We further introduce a fact reasoning framework with traceable reasoning chains and quantified confidence propagation, a subject locking mechanism to prevent entity confusion, and a multi-dimensional quality assessment scheme. The methodology is realized in the INFOMINER system. Experiments demonstrate improvements of 22.4% in fact density, 90% subject matching accuracy, 0.92 multi-source verification confidence, and 14% completeness gain from gap-driven supplementation. Five case studies validate its practical applicability, achieving an average quality rating of 4.46/5.0.