Graph-Enhanced Disease Trajectory Discovery and Temporal Endpoint Forecasting from Longitudinal Electronic Health Records

Graph-based analysis of electronic health records (EHRs) yields disease-trajectory catalogs, but structural support does not establish semantic novelty. We present a two-level framework to prioritize 99,527 branching motifs previously discovered by an upstream patient-disjoint, train-only MIMIC-IV v3.1 pipeline and frozen after validation-based catalog selection. The framework separates path-level and node-to-endpoint semantic sparsity from reliability-adjusted clinical priority. Three deterministic textualizations per motif or node-target pair were embedded with BAAI/bge-small-en-v1.5 and calibrated against 166,972 pre-2023 PubMed references using mean top-20 cosine distance. Positive recombination occurred in 8.63% of motifs and had negligible effect on global ranking, whereas specificity and support/GNN reliability terms changed clinical-priority ordering. Robustness analyses across neighbor counts, templates, encoders, generic-label taxonomies, score settings, PrimeKG, and corrected density-based RND showed that broad ordering was more stable than hard top-k membership. A semantic-dose analysis did not support a monotonic relation between score and forecasting benefit after endpoint and token-count adjustment (1.96 days per SD; 95% CI, -0.75 to 4.68). In the frozen catalog-q90 high-semantic subgroup, branch-enhanced forecasting reduced conditional event-time MAE by 20.1 days (95% CI, 13.3-27.0) and sMAPE by 2.37 percentage points (95% CI, 1.81-2.93), while discrimination and endpoint-ranking differences were inconclusive. Corrected RND showed low tail agreement with the primary score (Spearman rho = 0.430; q90 Jaccard = 0.125) despite a similar aggregate timing association. These findings support representation-aware, uncertainty-aware literature-relative prioritization of discovered trajectories rather than causal discovery or clinician-adjudicated novelty.

Learning from Electronic Health Records (EHRs) has gained significant attention due to its potential to improve clinical prediction. However, effective learning remains challenging because EHRs encode heterogeneous, temporally ordered clinical interactions. In particular, EHRs contain: (i) heterogeneous clinical entities, including patients, visits, diagnoses, prescriptions, and procedures, together with their heterogeneous interactions, (ii) longitudinal patient trajectories across hospital visits and (iii) shared statistical dependencies across related clinical prediction tasks. Existing EHR learning methods capture only a subset of these properties. To bridge this gap, we propose Multi-task Graph transformer for Heterogeneous Temporal EHRs (MiGHT-EHR), which jointly models all three within a unified representation learning method. MiGHT-EHR constructs a heterogeneous graph from EHRs in which nodes represent clinical entities and edges connect statistically associated entities identified via normalized point-wise mutual information. Across MIMIC-III and MIMIC-IV datasets, MiGHT-EHR outperforms state-of-the-art methods on average across four tasks: drug recommendation, prediction of length-of-stay, mortality, and readmission, with particularly strong improvements in mortality and readmission prediction. Furthermore, a post-hoc analysis of the learned representations reveals that patient neighborhoods are organized by clinical outcomes, salient medical concepts are recoverable as linear directions in the representation space, and task probabilities are well calibrated. Collectively, these findings demonstrate that MiGHT-EHR representations support diverse prediction tasks while preserving clinically interpretable structure.

The growing adoption of electronic health record (EHR) systems has provided unprecedented opportunities for predictive modeling to guide clinical decision making. Structured EHRs contain longitudinal observations of patients across hospital visits, where each visit is represented by a set of medical codes. While sequence-based, graph-based, and graph-enhanced sequence approaches have been developed to capture rich code interactions over time or within the same visits, they often overlook the inherent heterogeneous roles of medical codes arising from distinct clinical characteristics and contexts. To this end, in this study we propose the Disease Trajectory-aware Transformer for EHR (DT-BEHRT), a graph-enhanced sequential architecture that disentangles disease trajectories by explicitly modeling diagnosis-centric interactions within organ systems and capturing asynchronous progression patterns. To further enhance the representation robustness, we design a tailored pre-training methodology that combines trajectory-level code masking with ontology-informed ancestor prediction, promoting semantic alignment across multiple modeling modules. Extensive experiments on multiple benchmark datasets demonstrate that DT-BEHRT achieves strong predictive performance and provides interpretable patient representations that align with clinicians' disease-centered reasoning. The source code is publicly accessible at https://github.com/GatorAIM/DT-BEHRT.git.