Fundus Refraction Offset as an Individualized Myopia Biomarker

Importance: As on-axis metrics, spherical equivalent refraction (SER) and axial length (AL) are limited in capturing individual-level differences in posterior segment anatomy. Objective: To propose a fundus-level metric-fundus refraction offset (FRO)-and investigate its association with ocular parameters derived from optical coherence tomography (OCT). Design, Setting, and Participants: This cross-sectional, population-based study used data from 45 180 healthy eyes in the UK Biobank (2009-2010). Fundus photographs from a random subset (70%) were used to train a deep learning model to predict SER, with the goal of developing a model that learned to capture the nonpathological variations in fundus appearance from -15.50 D to 9.25 D. The trained model was applied to the remaining subset (internal unseen set) to derive FRO for each eye. FRO was also computed for an external dataset (the Caledonian cohort, 2023-2024) with enhanced depth imaging OCT and AL data for 152 right eyes. Data were analyzed from July to November 2024. Exposure: FRO, defined as the error in fundus-predicted SER. A more negative FRO indicated a more myopic-looking fundus than typical for an eye with the same SER. Main Outcomes and Measures: The association between FRO and macular thickness (MT) was tested using linear mixed-effects regression in the internal unseen set, controlling for SER, age, sex, and race. In the external dataset, the associations of FRO with choroidal area, choroidal vascularity index (CVI), and MT were examined using linear fixed-effects regression, controlling for SER (and subsequently AL) and other aforementioned covariates. Results: High-quality OCT data were available from 9524 eyes in the internal unseen set and 152 eyes in the external dataset among individuals with a mean (SD) age of 54.5 (8.2) years and 19.3 (3.8) years, respectively. In the internal unseen set, a more negative FRO was independently associated with lower MT (β, 0.64; 95% CI, 0.37-0.90; P < .001). A similar association was observed in the external dataset-whether adjusted for SER (β, 2.45; 95% CI, 0.64-4.26; P = .008) or AL (β, 2.09; 95% CI, 0.28-3.91; P = .02). Additionally, CVI decreased as FRO became more negative-both in the SER-adjusted (β, 0.01; 95% CI, 0.01-0.02; P < .001) and AL-adjusted (β, 0.01, 95% CI, 0.004-0.02; P = .001) analyses. Conclusion and Relevance: In this study, FRO reflected the individual-level mismatch between SER (or AL) and the anatomical severity of ametropia. This may have prognostic relevance for personalized risk prediction of myopia and its complications.