Explainable Artificial Intelligence Framework for Predicting Treatment Outcomes in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness, yet current tools for forecasting treatment outcomes remain limited by either the opacity of deep learning or the rigidity of rule-based systems. To address this gap, we propose a hybrid neuro-symbolic and large language model (LLM) framework that combines mechanistic disease knowledge with multimodal ophthalmic data for explainable AMD treatment prognosis. In a pilot cohort of ten surgically managed AMD patients (six men, four women; mean age 67.8 ± 6.3 years), we collected 30 structured clinical documents and 100 paired imaging series (optical coherence tomography, fundus fluorescein angiography, scanning laser ophthalmoscopy, and ocular/superficial B-scan ultrasonography). Texts were semantically annotated and mapped to standardized ontologies, while images underwent rigorous DICOM-based quality control, lesion segmentation, and quantitative biomarker extraction. A domain-specific ophthalmic knowledge graph encoded causal disease and treatment relationships, enabling neuro-symbolic reasoning to constrain and guide neural feature learning. An LLM fine-tuned on ophthalmology literature and electronic health records ingested structured biomarkers and longitudinal clinical narratives through multimodal clinical-profile prompts, producing natural-language risk explanations with explicit evidence citations. On an independent test set, the hybrid model achieved AUROC 0.94 ± 0.03, AUPRC 0.92 ± 0.04, and a Brier score of 0.07, significantly outperforming purely neural and classical Cox regression baselines (p ≤ 0.01). Explainability metrics showed that >85% of predictions were supported by high-confidence knowledge-graph rules, and >90% of generated narratives accurately cited key biomarkers. A detailed case study demonstrated real-time, individualized risk stratification—for example, predicting an >70% probability of requiring three or more anti-VEGF injections within 12 months and a ~45% risk of chronic macular edema if therapy lapsed—with predictions matching the observed clinical course. These results highlight the framework’s ability to integrate multimodal evidence, provide transparent causal reasoning, and support personalized treatment planning. While limited by single-center scope and short-term follow-up, this work establishes a scalable, privacy-aware, and regulator-ready template for explainable, next-generation decision support in AMD management, with potential for expansion to larger, device-diverse cohorts and other complex retinal diseases.