Employing General-Purpose and Biomedical Large Language Models with Advanced Prompt Engineering for Pharmacoepidemiologic Study Design

Xinyao Zhang; Nicole Sonne Heckmann; Manuela Del Castillo Suero; Francesco Paolo Speca; Maurizio Sessa

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arXiv · 2604.17988

Employing General-Purpose and Biomedical Large Language Models with Advanced Prompt Engineering for Pharmacoepidemiologic Study Design

Xinyao Zhang·Nicole Sonne Heckmann·Manuela Del Castillo Suero·Francesco Paolo Speca·Maurizio Sessa

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Abstract

Background: The potential of large language models (LLMs) to automate and support pharmacoepidemiologic study design is an emerging area of interest, yet their reliability remains insufficiently characterized. General-purpose LLMs often display inaccuracies, while the comparative performance of specialized biomedical LLMs in this domain remains unknown. Methods: This study evaluated general-purpose LLMs (GPT-4o and DeepSeek-R1) versus biomedically fine-tuned LLMs (QuantFactory/Bio-Medical-Llama-3-8B-GGUF and Irathernotsay/qwen2-1.5B-medical_qa-Finetune) using 46 protocols (2018-2024) from the HMA-EMA Catalogue and Sentinel System. Performance was assessed across relevance, logic of justification, and ontology-code agreement across multiple coding systems using Least-to-Most (LTM) and Active Prompting strategies. Results: GPT-4o and DeepSeek-R1 paired with LTM prompting achieved the highest relevance and logic of justification scores, with GPT-4o-LTM reaching a median relevance score of 4 in 8 of 9 questions for HMA-EMA protocols. Biomedical LLMs showed lower relevance overall and frequently generated insufficient justification. All LLMs demonstrated limited proficiency in ontology-code mapping, although LTM provided the most consistent improvements in reasoning stability. Conclusion: Off-the-shelf general-purpose LLMs currently offer superior support for pharmacoepidemiologic design compared to biomedical LLMs. Prompt strategy strongly influenced LLM performance.

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Xinyao Zhang, Nicole Sonne Heckmann, Manuela Del Castillo Suero, Francesco Paolo Speca, Maurizio Sessa. 2026-04-20. Employing General-Purpose and Biomedical Large Language Models with Advanced Prompt Engineering for Pharmacoepidemiologic Study Design. https://arxiv.org/abs/2604.17988

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