Unified Multiparadigm Fusion Intelligence for Rare Disease Diagnosis

Jian Yang, Peiling Liu, Songda Li, Yu Cao, Yuqing Feng +8

Rare diseases (RDs) affect an estimated 300 million people globally, leaving patients to navigate a protracted diagnostic odyssey constrained by clinical scarcity and fragmented medical knowledge. Artificial intelligence (AI) has progressively advanced RD diagnostics, from symbolic methods and deep learning to large language model (LLM)-based systems. However, each paradigm carries structural limitations: symbolic methods are bounded by knowledge completeness, neural models sacrifice interpretability, and LLM-based systems are vulnerable to evaluation biases like data leakage. In this study, we introduce FusionRare, a unified multiparadigm fusion framework integrating knowledge-driven symbolic reasoning, deep-learning pattern recognition, case-based patient retrieval, and LLM-based heuristic inference via statistical meta-aggregation and knowledge-enhanced agentic reflection. Evaluated on 2,528 strictly isolated clinical cases, FusionRare achieves state-of-the-art RD prioritization, attaining a macro-averaged Recall @1 of 51% for phenotype-only diagnosis and 79% for phenotype-genotype joint analysis. These results represent decisive advantages over the advanced agentic system…