A Two-Level Clinical Novelty Prioritization Framework for Disease Trajectories Discovered 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.