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 (<i>p</i> ≤ 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.