Precision Drug Repurposing (PDR): Patient-level modeling and prediction combining foundational knowledge graph with...

Drug repurposing accelerates therapeutic development by finding new indications for approved drugs. However, accounting for individual patient differences is challenging. This study introduces a Precision Drug Repurposing (PDR) framework at single-patient resolution, integrating individual-level data with a foundational biomedical knowledge graph to enable personalized drug discovery.

We developed a framework integrating patient-specific data from the UK Biobank (Polygenic Risk Scores, biomarker expressions, and medical history) with a comprehensive biomedical knowledge graph (61,146 entities, 1,246,726 relations). Using Alzheimer's Disease as a case study, we compared three diverse patient-specific models with a foundational model through standard link prediction metrics. We evaluated top predicted candidate drugs using patient medication history and literature review.

Our framework maintained the robust prediction capabilities of the foundational model. The integration of patient data, particularly Polygenic Risk Scores (PRS), significantly influenced drug prioritization (Cohen's d = 1.05 for scoring differences). Ablation studies demonstrated PRS's crucial role, with effect size decreasing to 0.77 upon removal. Each patient model identified novel drug candidates that were missed by the foundational model but showed therapeutic relevance when evaluated using patient's own medication history. These candidates were further supported by aligned literature evidence with the patient-level genetic risk profiles based on PRS.

This exploratory study demonstrates a promising approach to precision drug repurposing by integrating patient-specific data with a foundational knowledge graph.