Model Structure Uncertainty in the Characterization and Growth of Geographic Atrophy

Abstract

Purpose: To identify the most suitable model for assessing the rate of growth of total geographic atrophy (GA) by analysis of model structure uncertainty. Methods: Model structure uncertainty refers to unexplained variability arising from the choice of mathematical model and represents an example of epistemic uncertainty. In this study, we quantified this uncertainty to help identify a model most representative of GA progression. Fundus autofluorescence (FAF) images and GA progression data (i.e., total GA area estimation at each presentation) were acquired using Spectralis HRA+OCT instrumentation and RegionFinder software. Six regression models were evaluated. Models were compared using various statistical tests, [i.e., coefficient of determination (r2), uncertainty metric (U), and test of significance for the correlation coefficient, r], as well as adherence to expected physical and clinical assumptions of GA growth. Results: Analysis was carried out for 81 GA-affected eyes, 531 FAF images (range: 3-17 images per eye), over median of 57 months (IQR: 42, 74), with a mean baseline lesion size of 2.62 ± 4.49 mm2 (range: 0.11-20.69 mm2). The linear model proved to be the most representative of total GA growth, with lowest average uncertainty (original scale: U = 0.025, square root scale: U = 0.014), high average r2 (original scale: 0.92, square root scale: 0.93), and applicability of the model was supported by a high correlation coefficient, r, with statistical significance (P = 0.01). Conclusions: Statistical analysis of uncertainty suggests that the linear model provides an effective and practical representation of the rate and progression of total GA growth based on data from patient presentations in clinical settings. Translational Relevance: Identification of correct model structure to characterize rate of growth of total GA in the retina using FAF images provides an objective metric for comparing interventions and charting GA progression in clinical presentations.