Gradeability and Reproducibility of Geographic Atrophy Measurement in GATHER-1, a Phase II/III Randomized Interventional Trial

Abstract

Objective: To validate GATHER-1 inclusion criteria and the study's primary anatomic end point by assessing the reproducibility of geographic atrophy (GA) measurements and factors that affect reproducibility.

Design: Post hoc analysis of phase II/III clinical trial.

Subjects: All 286 participants included in the GATHER-1 study.

Methods: For each subject, blue-light fundus autofluorescence (FAF), color fundus photographs, fluorescein angiograms, and OCT scans were obtained on the study eye and fellow eye. Geographic atrophy area and other lesion characteristics were independently graded by 2 experienced primary readers. If the 2 readers differed on gradeability, GA area (> 10%) or other lesion characteristics, the image was graded by an arbitrator whose measurement or characterization was the final grade.

Main outcome measures: The main outcome measures were gradeability and reproducibility of FAF imaging data. Imaging data included lesion area, confluence of GA with peripapillary atrophy (PPA), whether GA involved the foveal centerpoint, and type of hyperautofluorescence pattern.

Results: A total of 2004 images (1002 visits, 286 participants) were analyzed. Gradeability (90.5%) and interreader gradeability concordance (90.2%) were high across all visits. Study eye images were more gradable compared with fellow-eye images. A greater proportion of smaller lesions required arbitration, but interreader reproducibility was consistently high for all images. There was no difference in gradeability, gradeability concordance, or lesion-area concordance for images with PPA-confluent GA compared with those with nonconfluent PPA. Foveal centerpoint-involving lesions had lower gradeability and lesion-area concordance. Images with diffuse patterns of hyperautofluorescence had better gradeability and gradeability concordance than those with nondiffuse patterns but had no difference in lesion-area or lesion-area concordance.

Conclusions: There is high gradeability and excellent reproducibility measures across all images. These data support the validity of conclusions from GATHER-1 and the chosen inclusion criteria and end point.

Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: GATHER-1; Geographic atrophy measurement.

Figure 1

Example fundus autofluorescence images of gradable and ungradable geographic atrophy. A, Gradable image. B, Ungradable image because of indistinct margins around the fovea. C, Ungradable image because of poor image quality. D, Peripapillary atrophy confluent with geographic atrophy. E, Foveal centerpoint involvement. F, Diffuse, trickling, hyperautofluorescent pattern.

Figure 2

Distribution of geographic atrophy size across all gradable images. The blue bars represent the study eyes and the pink bars represent the fellow eyes. Areas of overlap are denoted in purple. Vertical blue lines correspond to the size inclusion criteria used in the study; on initial visit, all study eyes had to be between 2.5 mm² and 17.5 mm².

Figure 3

Bland Altman plot for all images (A) and screening-visit images (B) shows high interreader reproducibility across all image sizes. A, Across all images, the mean difference in lesion size between the 2 readers is 0.129 mm² (solid line), and dashed red lines represent the mean difference +/- coefficient of reproducibility (CR), which was 1.47 mm². The vast majority (97.4%) of all interreader differences lay within the bounds of the CR and therefore are reproducible. B, For screening-visit images, the mean difference in lesion area between the 2 readers is 0.148 mm² (solid line), and the mean differences ± CR (1.32mm²) are −1.17 mm² and 1.47 mm². Once again, 97.7% of all interreader differences lay within the range defined by the CR and, therefore, are reproducible. GA = geographic atrophy.