Reproducibility of Measurements of Retinal Structural Parameters Using Optical Coherence Tomography in Stargardt Disease

Abstract

Purpose: To assess the reproducibility of retinal measurements from optical coherence tomography (OCT) in ABCA4-related Stargardt disease (STGD1).

Methods: The international multicenter Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study enrolled 259 STGD1 patients. OCT images were graded by the study reading center (RC). Semiautomatic segmentation with manual adjustments was used to segment the layers of retinal pigmentation epithelium, outer segments, inner segments (ISs), outer nuclear layer (ONL), inner retina, and the total retina (TR). The images were overlaid to the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. For each layer, the thickness and the intact area of the ETDRS central subfield, inner ring, and outer ring were recorded, respectively. A different set of RC graders regraded 30 independent ProgStar images to evaluate measurement reproducibility. Reproducibility was assessed graphically and using statistics including intraclass correlation (ICC) and relative absolute difference (RAD).

Results: Across all layers, measurements of the ETDRS central subfield had low ICC and/or large RAD. The outer-ring region was not fully captured in some images. For inner ring, good reproducibility was observed for intact area in the IS (ICC = 0.99, RAD = 4%), thicknesses of the ONL (ICC = 0.93, RAD = 6%), and TR (ICC = 0.99, RAD = 1%).

Conclusions: STGD1's complex morphology made outer retina segmentation challenging. Measurements of the inner ring, including the intact area of IS (i.e., the ellipsoid zone [EZ]) and ONL and TR thicknesses, had good reproducibility and showed anatomical impairment.

Translational relevance: ONL and TR thicknesses and the EZ intact area in the ETDRS inner ring hold potential as structural endpoints for STGD1 trials. Structure-function relationships need to be further established.

Keywords: inherited retinal degeneration; outcome measures; reliability; repeatability; structure parameters.

Figure 1

ETDRS grid: the central subfield is the circle in the center with a diameter of 1 mm. The inner ring consists of the four subfields surrounding the central circle, and the middle circle has a diameter of 3 mm. The outer ring consists of the four subfields surrounding the inner ring, and the outer circle has a diameter of 6 mm.

Figure 2

Retinal boundaries and layers in SD-OCT segmentation adopted in the ProgStar study. (A) An example of segmentation in a normal eye. Note, the photoreceptor segment layer, namely, outer (purple) is snapped to the RPE cell layer, and inner (green) boundary to denote no thickness due to subretinal fluid/subretinal hyperreflective materials. (B) An example of segmentation in a Stargardt patient eye. Note relevant boundaries are snapped together at locations where IS/OS junction is not present, subretinal fluid/subretinal hyperreflective materials are present, and/or RPE is atrophied. ILM, inner limiting membrane; OPL, outer plexiform layer; ELM, external limiting membrane; IS/OS junction, inner segment-outer segment junction, called ellipsoid zone (EZ); RPE, retinal pigment epithelium.

Figure 3

Bland-Altman Plots for thickness and intact area of retinal layers of (A) RPE, (B) outer segment, (C) inner segment, (D) outer nuclear layer, (E) inner retina, and (F) the total retina in the ETDRS center and inner ring and outer ring regions. In each plot, the darkened line is the mean of the difference of two gradings (grading 2 – grading 1), the lighter lines are the 95% upper and lower limits of the mean difference, and the dotted line is for difference = 0.

Figure 3

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Figure 3

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Figure 4

An example of an unambiguous case in the ProgStar reproducibility study. Screenshots are provided showing the unannotated image and the segmentation from the original grading and regrading, respectively. Agreement on segmentation between the two gradings was good because the morphology was very clear.

Figure 5

Example of an ambiguous case in the ProgStar reproducibility study where determination of the RPE-atrophy transition thresholds was different in the two gradings. Screenshots are provided showing the unannotated image and the segmentation from the original grading and regrading, respectively. Note RPE is the layer between the green and brown lines. RPE absence is denoted in the central A-scans where the green line is absent, as it is overlapping with the brown line corresponding with Bruch's membrane (the two lines are snapped together, representing zero thickness).

Figure 6

An example of an ambiguous case in the ProgStar reproducibility study where determination of preserved RPE versus debris was different between gradings. Screenshots are provided showing the unannotated image and the segmentation from the original grading and regrading, respectively. Note RPE is the layer between the green and brown lines. RPE absence is denoted in the original grading in the central A-scans where the green line is absent, as it is overlapping with the brown line corresponding with Bruch's membrane (the two lines are snapped together, representing zero thickness). There is also slight disagreement in EZ preservation.

Figure 7

An example of a scan with incomplete scan area that made the ETDRS outer ring region not fully measured. The green covered area is the scanned area, whereas the blue circles are the ETDRS grid.