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.

Background: Recently, numerous foundation models pretrained on extensive data have demonstrated efficacy in disease prediction using Electronic Health Records (EHRs). However, there remains some unanswered questions on how to best utilize such models especially with very small fine-tuning cohorts. Methods: We utilized Med-BERT, an EHR-specific foundation model, and reformulated the disease binary prediction task into a token prediction task and a next visit mask token prediction task to align with Med-BERT's pretraining task format in order to improve the accuracy of pancreatic cancer (PaCa) prediction in both few-shot and fully supervised settings. Results: The reformulation of the task into a token prediction task, referred to as Med-BERT-Sum, demonstrates slightly superior performance in both few-shot scenarios and larger data samples. Furthermore, reformulating the prediction task as a Next Visit Mask Token Prediction task (Med-BERT-Mask) significantly outperforms the conventional Binary Classification (BC) prediction task (Med-BERT-BC) by 3% to 7% in few-shot scenarios with data sizes ranging from 10 to 500 samples. These findings highlight that aligning the downstream task with Med-BERT's pretraining objectives substantially enhances the model's predictive capabilities, thereby improving its effectiveness in predicting both rare and common diseases. Conclusion: Reformatting disease prediction tasks to align with the pretraining of foundation models enhances prediction accuracy, leading to earlier detection and timely intervention. This approach improves treatment effectiveness, survival rates, and overall patient outcomes for PaCa and potentially other cancers.

Knowledge sharing is crucial in healthcare, especially when leveraging data from multiple clinical sites to address data scarcity, reduce costs, and enable timely interventions. Transfer learning can facilitate cross-site knowledge transfer, but a major challenge is heterogeneity in clinical concepts across different sites. Large Language Models (LLMs) show significant potential of capturing the semantic meaning of clinical concepts and reducing heterogeneity. This study analyzed electronic health records from two large healthcare systems to assess the impact of semantic embeddings from LLMs on local, shared, and transfer learning models. Results indicate that domain-specific LLMs, such as Med-BERT, consistently outperform in local and direct transfer scenarios, while generic models like OpenAI embeddings require fine-tuning for optimal performance. However, excessive tuning of models with biomedical embeddings may reduce effectiveness, emphasizing the need for balance. This study highlights the importance of domain-specific embeddings and careful model tuning for effective knowledge transfer in healthcare.

BERT-based models for Electronic Health Records (EHR) have surged in popularity following the release of BEHRT and Med-BERT. Subsequent models have largely built on these foundations despite the fundamental design choices of these pioneering models remaining underexplored. To address this issue, we introduce CORE-BEHRT, a Carefully Optimized and Rigorously Evaluated BEHRT. Through incremental optimization, we isolate the sources of improvement for key design choices, giving us insights into the effect of data representation and individual technical components on performance. Evaluating this across a set of generic tasks (death, pain treatment, and general infection), we showed that improving data representation can increase the average downstream performance from 0.785 to 0.797 AUROC, primarily when including medication and timestamps. Improving the architecture and training protocol on top of this increased average downstream performance to 0.801 AUROC. We then demonstrated the consistency of our optimization through a rigorous evaluation across 25 diverse clinical prediction tasks. We observed significant performance increases in 17 out of 25 tasks and improvements in 24 tasks, highlighting the generalizability of our findings. Our findings provide a strong foundation for future work and aim to increase the trustworthiness of BERT-based EHR models.