Revealing Interconnections between Diseases: from Statistical Methods to Large Language Models

Identifying disease interconnections through manual analysis of large-scale clinical data is labor-intensive, subjective, and prone to expert disagreement. While machine learning (ML) shows promise, three critical challenges remain: (1) selecting optimal methods from the vast ML landscape, (2) determining whether real-world clinical data (e.g., electronic health records, EHRs) or structured disease descriptions yield more reliable insights, (3) the lack of "ground truth," as some disease interconnections remain unexplored in medicine. Large language models (LLMs) demonstrate broad utility, yet they often lack specialized medical knowledge. Our framework integrates the following: (i) a statistical co-occurrence analysis and a masked language modeling (MLM) approach using real clinical data; (ii) domain-specific BERT variants (Med-BERT and BioClinicalBERT); (iii) a general-purpose BERT and document retrieval; and (iv) four LLMs (Mistral, DeepSeek, Qwen, and Y andexGPT). Our graph-based comparison of the obtained interconnection matrices shows that the LLM-based approach produces interconnections with the lowest diversity of ICD code connections to different diseases compared to other methods, including text-based and domain-based approaches. This suggests an important implication: LLMs have limited potential for discovering new interconnections. In the absence of ground truth databases for medical interconnections between ICD codes, our results constitute a valuable medical disease ontology that can serve as a founda-tional resource for future clinical research and artificial intelligence applications in healthcare. Electronic health records (EHRs) provide a valuable resource for studying disease progression and relationships between diagnoses. Machine learning (ML) can help discover hidden patterns in medical data, but many existing models are hard to interpret. In particular, it is not always clear whether large language models (LLMs) make predictions based on meaningful medical knowledge or simply rely on textual similarities between diagnosis descriptions (Cui et al., 2025). This is especially critical in healthcare, where model decisions must align with established medical knowledge and pathophysiological mechanisms. We also analyze and compare the obtained results and summarize it into medical disease ontology.