Deep Kernel Learning for Stratifying Glaucoma Trajectories
Authors: Bruce Rushing, Angela Danquah, Alireza Namazi, Arjun Dirghangi, Heman Shakeri
Organizations: Research Computing, University of Virginia · School of Data Science, University of Virginia · School of Medicine, University of Virginia
Abstract
Effectively stratifying patient risk in chronic diseases like glaucoma is a major clinical challenge. Clinicians need tools to identify patients at high risk of progression from sparse and irregularly-sampled electronic health records (EHRs). We propose a novel deep kernel learning (DKL) architecture that leverages a Gaussian Process (GP) backend. The GP's kernel is defined by a transformer-based feature extractor applied to clinical-BERT embeddings to model glaucoma patient trajectories from multimodal EHR data. Our method successfully identifies three clinically distinct patient subgroups. Crucially, the model learns to decouple disease progression from current severity, identifying a high-risk group with a worsening trajectory despite having better average visual acuity than a second, stably poor group. This reveals that the model learns to identify progression risk rather than just the current disease state. This ability to stratify patients based on their risk trajectory progression offers a powerful tool for clinical decision support, enabling targeted interventions for high-risk individuals and improving the management of glaucoma care.
Glaucoma is a leading cause of irreversible blindness worldwide, yet most automated diagnosis systems rely on opaque deep-learning models that offer little clinical interpretability. We present GlaKG, a biomarker-centric fundus knowledge graph that integrates structural biomarkers, clinically grounded rules, and image features to produce traceable reasoning for glaucoma diagnosis and risk stratification. GlaKG encodes six entity types (Fundus Image, Optic Disc, Neural Rim, Pathology, Diagnosis, Risk Level), eight relation types, and 11 clinically validated rules into a unified graph, so that every prediction is accompanied by an explicit reasoning chain linking biomarker evidence to activated clinical rules. To keep knowledge-based reasoning strictly separate from label information, we adopt a post-processing fusion framework that combines ResNet50 image embeddings with a normalized KG reasoning-chain score via a tunable weight alpha, with all fitting confined to the training split. On a publicly available, AI-annotated fundus dataset, GlaKG reaches F1 = 0.9953 for binary glaucoma classification and 0.930 accuracy with 0.922 weighted F1 for four-class risk stratification; we report openly that the dataset's biomarker annotations are highly label-correlated, and therefore frame these figures as an upper bound attainable with clean structured biomarkers rather than as leakage-free image-only performance. Feature-importance analysis shows KG-derived and biomarker features contributing near-equally (51.1% vs. 48.9%), and the reasoning chain flags borderline cases by exposing low chain scores rather than failing silently. GlaKG's central contribution is therefore a clinically auditable reasoning framework that complements raw predictive performance by explicitly exposing the biomarker evidence and rule activations behind each decision.
Glaucoma is a leading cause of irreversible blindness worldwide, and early detection from fundus images is critical for effective disease management. While deep learning has achieved promising performance in fundus image analysis, most existing methods rely on single time-point images and fail to capture longitudinal structural and vascular changes associated with disease progression. Sequential fundus images acquired during clinical follow-up provide valuable temporal information; however, current sequential models often struggle to detect subtle early progression signals and commonly depend on fixed-length inputs or diagnostic cues from already glaucomatous images, limiting their clinical utility for early prediction. To address these limitations, we propose DiffSight-Former, a framework for glaucoma progression prediction from sequential fundus images. It incorporates a time-variant feature extraction module based on a fundus-specific foundation model to obtain robust anatomical representations. A multi-structure difference modeling module is introduced to quantify progression-related changes in the optic disc/cup region and retinal vasculature. These representations are integrated with temporal interval embeddings and processed by a time-aware Transformer to model disease progression and estimate the probability of future glaucoma onset. Experiments were conducted on two longitudinal datasets, SIGF (405 sequences) and GRAPE (263 sequences). On SIGF, DiffSight-Former achieved an AUC of 91.54% and a sensitivity of 92.16% for progression prediction. On GRAPE, it achieved an average accuracy of 87.48% across three clinical visual-field progression criteria. Compared with existing approaches, DiffSight-Former demonstrates strong performance and robustness across different temporal settings, highlighting its potential for longitudinal glaucoma monitoring and early risk prediction.
We evaluated whether a glaucoma risk assessment (GRA) model trained on All of Us national data can identify patients at high probability of glaucoma using only systemic electronic health records (EHR) at an independent institution. In this cross-sectional study, 20,636 Stanford patients seen from November 2013 to January 2024 were included (15% with glaucoma). A pretrained GRA model was fine-tuned on the Stanford cohort and tested on a held-out set using demographics, systemic diagnoses, medications, laboratory results, and physical examination measurements as inputs. The best model achieved AUROC 0.883 and PPV 0.657. Calibration was consistent with clinical risk: the highest prediction decile showed the greatest glaucoma diagnosis rate (65.7%) and treatment rate (57.0%). Performance improved with more trainable layers up to 15 and with additional data. An EHR-only GRA model may enable scalable and accessible pre-screening without specialized imaging.