Improving large language model applications in biomedicine with retrieval-augmented generation: a systematic review, meta-analysis, and clinical development guidelines

OBJECTIVE: The objectives of this study are to synthesize findings from recent research of retrieval-augmented generation (RAG) and large language models (LLMs) in biomedicine and provide clinical development guidelines to improve effectiveness. MATERIALS AND METHODS: We conducted a systematic literature review and a meta-analysis. The report was created in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 analysis. Searches were performed in 3 databases (PubMed, Embase, PsycINFO) using terms related to "retrieval augmented generation" and "large language model," for articles published in 2023 and 2024. We selected studies that compared baseline LLM performance with RAG performance. We developed a random-effect meta-analysis model, using odds ratio as the effect size. RESULTS: Among 335 studies, 20 were included in this literature review. The pooled effect size was 1.35, with a 95% confidence interval of 1.19-1.53, indicating a statistically significant effect (P = .001). We reported clinical tasks, baseline LLMs, retrieval sources and strategies, as well as evaluation methods. DISCUSSION: Building on our literature review, we developed Guidelines for Unified Implementation and Development of Enhanced LLM Applications with RAG in Clinical Settings to inform clinical applications using RAG. CONCLUSION: Overall, RAG implementation showed a 1.35 odds ratio increase in performance compared to baseline LLMs. Future research should focus on (1) system-level enhancement: the combination of RAG and agent, (2) knowledge-level enhancement: deep integration of knowledge into LLM, and (3) integration-level enhancement: integrating RAG systems within electronic health records.