KELLM: Knowledge-Enhanced Label-Wise Large Language Model for Safe and Interpretable Drug Recommendation

Abstract

The proliferation of electronic health records (EHRs) and advances in deep learning have enabled personalized drug combination recommendations. However, traditional deep learning models often lack the contextual understanding and medical knowledge integration necessary for accurate predictions. While large language model (LLM)-based approaches address some of these challenges, they still fall short in incorporating critical medical knowledge, addressing comprehensive safety constraints such as multi-disease drug contraindications (MDCs), and providing sufficient interpretability of the causal mechanisms behind their outputs. To overcome these limitations, we propose KELLM, a knowledge-enhanced LLM framework for drug recommendations. By linking medical entities in EHRs to an external medical knowledge graph, inputs are enriched with causal chains, enhancing both prediction accuracy and interpretability. Additionally, we introduce a fine-tuned label-wise LLaMA model designed for multi-label classification, which incorporates safety considerations such as drug-drug interactions (DDIs) and MDCs to ensure clinically accurate and safe recommendations. Experimental results show that KELLM achieves state-of-the-art performance in effectiveness and safety metrics, while also providing evidence-based insights through causal chains that clarify its reasoning process. This establishes a new benchmark for trustworthy, interpretable drug combination recommendations.