Representation Learning of Human Disease Mechanisms for a Foundation Model in Rare and Common Diseases
A fundamental challenge in translational medicine is the computational modeling of complex human diseases to accelerate therapeutic development. Representation learning provides a powerful framework to address this, yet creating models that capture deep biological mechanisms remains a critical need. To this end, we propose a novel strategy that partitions the disease landscape into rare and non-rare categories, enabling systematic knowledge repurposing both within and between these groups. Here, we introduce Dis2Vec (Disease to Vector), a representation learning framework designed to operationalize this concept. Dis2Vec generates biologically grounded disease embeddings by learning from human genetic and phenotypic data, forming the foundation for Disease-Disease Association Learning (DDAL) and unsupervised disease clustering. We evaluate Dis2Vec representations in two downstream applications. First, we assess DDAL performance on a transfer learning benchmark designed to predict therapeutic transferability, using real-world drug repurposing investment decisions made in clinical trials. Second, unsupervised clustering analyses reveal shared biological mechanisms across diseases. By modeling the disease landscape in this way, Dis2Vec enhances translational research efficiency across both rare and non-rare diseases, advancing the development of foundational models for therapeutic science. Furthermore, Dis2Vec establishes a biologically grounded disease-representation and benchmarking layer that paves the way for trustworthy agentic biomedical AI systems in rare-disease indication expansion.