Protocol for evaluating ChatGPT in biomedical association generation and verification using a RAG-enabled, cross-model majority voting workflow
Authors: Ahmed Abdeen Hamed, Luis M. Rocha
Organizations: Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA · School of Systems Science & Industrial Engineering, Binghamton University, Binghamton, NY 13902, USA · Universidade Catόlica Portuguesa, Catόlica Biomedical Research Centre, Lisbon, Portugal
Abstract
We present a protocol to evaluate ChatGPT's ability to generate disease-centric biomedical associations. It outlines how we generate the associations, validate the biological entities using biomedical ontologies, and verify associations using literature. The protocol includes a self-consistency strategy to assess generative reliability across ChatGPT models. To address ontology exact-match limitations, we provide a use case performing semantic verification through a workflow enabled by Retrieval-Augmented Generation (RAG) powered by open-source large language models (LLMs). This enables LLMs to establish truth over content generated by other LLMs and expose hallucination.
Retrieval-augmented generation evaluation checks whether model claims are factually grounded in retrieved documents. It does not check whether retrieved evidence is attributed to the correct entity. A clinical RAG response can pass every automated check (zero hallucinations, near-perfect faithfulness, real citations) while presenting drug Y's clinical evidence as evidence about queried drug X. We term this deceptive grounding (DG): a failure invisible to faithfulness, hallucination, and citation checks because every claim is sourced from a real document, about the wrong entity. Using a controlled factorial benchmark across 13 models, we find DG rates spanning 8-87% at peak adversarial conditions. Medical and biomedical fine-tuned models reach up to 86.7%; domain specialization amplifies the failure rather than mitigating it. A controlled ablation identifies the mechanism: removing entity-specific clinical evidence from retrieved documents eliminates entity-attribution failure entirely, shifting all failures to confabulation. The two failure modes respond to the same trigger, taking different paths. Production measurement across 740 drug-disease pairs finds 7.8% overall DG in a deployed RAG system, rising to 13.6% for recently approved drugs. Entity-attribution verification (checking that cited evidence applies to the queried entity) detects DG at 97.0% precision and 98.7% DG recall (IPW-adjusted human gold standard); no existing framework implements it.
Millions of clinicians use ChatGPT to support clinical care, but evaluations of the most common use cases in model-clinician conversations are limited. We introduce HealthBench Professional, an open benchmark for evaluating large language models on real tasks that clinicians bring to ChatGPT in the course of their work. The benchmark is organized around three common use cases central to clinical practice: care consult, writing and documentation, and medical research. Each example includes a physician-authored conversation with ChatGPT for Clinicians and is scored via rubrics written and iteratively adjudicated by three or more physicians across three phases. HealthBench Professional examples were carefully selected for quality, representativeness, and difficulty for OpenAI's current frontier models, to enable continued measurement of progress. Difficult examples for recent OpenAI models were enriched by roughly 3.5 times relative to the candidate pool of 15,079 examples. Additionally, about one-third of examples involve physicians conducting deliberate adversarial testing of models. As a strong baseline, we also collected human physician responses for all tasks (unbounded time, specialist-matched, web access). The best scoring system, GPT-5.4 in ChatGPT for Clinicians, outperforms base GPT-5.4, all other models, and human physicians. We hope HealthBench Professional provides the healthcare AI community a measure to track frontier model progress in real-world clinical tasks and build systems that clinicians can trust to improve care.
While interpretable prototype networks offer compelling case-based reasoning for clinical diagnostics, their raw continuous outputs lack the semantic structure required for medical documentation. Bridging this gap via standard Retrieval-Augmented Generation (RAG) routinely triggers ``retrieval sycophancy,'' where Large Language Models (LLMs) hallucinate post-hoc rationalizations to align with visual predictions. We introduce ProtoMedAgent, a framework that formalizes multimodal clinical reporting as an iterative, zero-gradient test-time optimization problem over a strict neuro-symbolic bottleneck. Operating on a frozen prototype backbone, we distill latent visual and tabular features into a discrete semantic memory. Online generation is strictly constrained by exact set-theoretic differentials and a reflective Scribe-Critic loop, mathematically precluding unsupported narrative claims. To safely bound data disclosure, we introduce a semantic privacy gate governed by k-anonymity and ℓ-diversity. Evaluated on a 4,160-patient clinical cohort, ProtoMedAgent achieves 91.2% Comparison Set Faithfulness where it fundamentally outperforms standard RAG (46.2%). ProtoMedAgent additionally leverages a binding ℓ-diversity phase transition to systematically reduce artifact-level membership inference risks by an absolute 9.8%.