Unified Multiparadigm Fusion Intelligence for Rare Disease Diagnosis

Abstract

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 DeepRare, frontier LLMs including GPT 5.5, and specialized tools like PhenoBrain and LIRICAL under stringent anti-leakage protocols. A randomized, crossover clinician-AI validation demonstrated that FusionRare elevates the true diagnostic rank in 45% of decisions, improves physician confidence in 62%, and reduces time to diagnosis by 21%. These findings indicate that reconciling these orthogonal AI paradigms significantly enhances diagnostic capabilities, bridging the gap between computational benchmarks and actionable clinical reliability. More broadly, this work provides a replicable framework for deploying trustworthy diagnostic AI across complex, high-stakes, and underserved medical domains.