Assessment of Baseline Ultrawidefield Fluorescein Angiographic Quantitative Leakage Parameters with Ultrawidefield Fundus Features and Clinical Parameters in Diabetic Retinopathy in Protocol AA

Purpose: Evaluate quantitative leakage parameters on ultrawidefield fluorescein angiography (UWF-FA) images and explore their association with Diabetic Retinopathy Severity Scale (DRSS), predominantly peripheral lesions (PPLs), visual acuity, and clinical characteristics. Design: A post hoc analysis of baseline UWF-FA images in the DRCR Retina Network observational study Protocol AA. Participants: A total of 575 eyes from 384 adults across 38 sites in the United States and Canada with gradable UWF-FA. Methods: A machine learning-enhanced feature extraction platform provided initial leakage segmentation of UWF-FA images sequentially reviewed and corrected by 2 certified readers for segmentation accuracy. Ultrawidefield fluorescein angiography leakage was measured in 5 retinal zones: panretinal (entire retina), central macular (3-disc diameter fovea-centered circle), posterior pole (6-disc diameter fovea-centered circle), peripheral (outside 6-disc diameter circle), and widefield far peripheral (outside 9-disc diameter circle); associations with clinical factors were evaluated with marginal beta regression models. Main Outcome Measures: Ultrawidefield fluorescein angiography leakage index, calculated as the area with leakage divided by the analyzable retinal area. Results: The mean quantitative leakage index was 3.5% for panretinal, 6.6% for macular, 4.8% for posterior pole, 3.3% for peripheral, and 2.8% for widefield far peripheral retinal zones. Panretinal leakage was associated with DRSS (mean 2.2% for no to mild nonproliferative diabetic retinopathy [NPDR], 3.4% for moderate NPDR, 4.2% for moderately severe NPDR, 4.8% for severe NPDR, and 5.1% for proliferative diabetic retinopathy; P < 0.001), hemoglobin A1C (HbA1c) (3.2% for HbA1c < 8% vs. 3.8% for HbA1c ≥ 8%; P = 0.01 for continuous HbA1c), visual acuity (3.3% for 20/25 or better vs. 4.7% for 20/32 or worse; continuous P < 0.001), and UWF-FA-PPL types of intraretinal microvascular abnormality (4.3% vs. 3.3%; P = 0.005) or new vessels elsewhere (5.7% vs. 3.4%; P = 0.003). Diabetic retinopathy severity was also statistically significant for leakage within all retinal zones (P < 0.001); eyes with noncentral diabetic macular edema (DME) versus no DME had higher mean leakage in the central macular (11.2% vs. 5.9%; P = 0.005) and posterior pole regions (9.2% vs. 4.2%; P = 0.002). Conclusions: Quantitative UWF-FA leakage analysis identified associations between leakage and DRSS, visual acuity, and presence of DME. In the future, quantitative UWF-FA leakage parameters may be explored as potential biomarkers for disease progression risk. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.