Exploring the Latent Structure of AMD Severity Using Retinal Foundation Models

Abstract

Retinal foundation models have demonstrated strong performance across a wide range of ophthalmic tasks, yet relatively little is known about how disease-related information is represented within their learned embeddings and whether this distribution influences downstream prediction performance. In this work, we use Age-related Macular Degeneration (AMD) as a case study to investigate how disease severity is represented within the embedding space of RET-CLIP, a retinal vision-language foundation model, using bilateral fundus images from the AREDS dataset, benchmarked against non-retinal encoders. We first characterize the distribution of AMD severity within the learned representation space and then evaluate how this structure influences classification performance across three clinically relevant task formulations of increasing granularity. Finally, we analyze the most influential latent dimensions combining feature attribution, statistical phenotype association, and qualitative image analyses. Our results show that RET-CLIP represents AMD severity as a continuous spectrum rather than a set of discrete categories, with healthy and advanced disease stages exhibiting clearer separation than intermediate ones. This organization was reflected in downstream performance, which decreased from a balanced accuracy of 0.844 and 0.814 for binary AMD and Late-AMD detection respectively to 0.446 for six-class grading. Furthermore, the most influential latent dimensions were statistically associated to distinct retinal phenotypes, including drusen accumulation, pigmentary alterations, and advanced retinal lesions. These findings suggest that the structure of retinal foundation-model representations influences the difficulty of clinically relevant prediction tasks and demonstrate the potential of representation-level analysis for understanding disease organization and improving interpretability.