Among 444 eyes with MP-1 grading available at baseline and enrolled in the prospective ProgStar Study, a total of 359 eyes with a mean sensitivity grading available at both baseline and month 12 were included in the main analysis.
The Nidek MP-1 microperimeter was used to determine light sensitivity at each of 68 retinal locations of a modified Humphrey 10-2 test grid by iteratively adjusting the light intensity until the dimmest visible stimulus was found. Test locations with 0 dB (ie, sites seeing only the brightest stimulus or not seeing any stimuli) were defined as deep scotomas (DS), and test locations with more than 0 dB but less than 12 dB were defined as relative scotomas. In the example of a left eye of a patient with ABCA4-related Stargardt disease who underwent 3 examinations every 6 months, the mean sensitivity in decibels (mean of all 68 sensitivity values) is displayed in the top left corner and the number of DS is shown in the top right corner.
For this analysis, we required use of the follow-up function and good or fair pattern placement on both study visits, reducing the number of included eyes to 106. The test grid was divided into 3 regions: the central or foveal 4 points that were 1.7° away from the center of the grid (red overlay), the 12 perifoveal points were at a distance of 3.5° to 4.7° away and were grouped as the inner ring (yellow overlay), and the remainder of the test locations 5.6° to 10.1° from the grid center were grouped as the outer ring (light blue overlay). The numbers show the count of deep scotomas (DS) and the mean sensitivity of all test locations. All measurements are indicated in decibels (red for the mean sensitivity in the foveal region, yellow for the inner ring, and light blue for the outer ring).
eFigure 1. Bland-Altman Plot of Yearly Change in Sensitivity in Dependence of Average of Mean Sensitivity From Baseline and Month 12
eFigure 2. Spaghetti and Scatterplots Summarizing Mean Sensitivity Measurements
eTable 1. Baseline Characteristics of Eligible Subjects/Eyes by Inclusion in the Analysis
eTable 2. Changes in Macular Sensitivity by Baseline Mean Sensitivity
eTable 3. Factors Associated With Changes in Location Specific MP Parameters From Baseline to One Year In 106 Eyes Where the Follow-Up Function Was Used at One Year and the Tests Were Done With Good to Fair Pattern Placement at Both Visits
eTable 4. Factors Associated With Changes in the MP Parameters From Baseline to One Year
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Schönbach EM, Strauss RW, Muñoz B, et al. Longitudinal Microperimetric Changes of Macular Sensitivity in Stargardt Disease After 12 Months: ProgStar Report No. 13. JAMA Ophthalmol. 2020;138(7):772–779. doi:10.1001/jamaophthalmol.2020.1735
How does light sensitivity of the posterior pole change over time in patients with Stargardt disease?
In this cohort study of 359 eyes with ABCA4-related Stargardt disease, microperimetric mean sensitivity (−0.68 dB per year) and deep scotoma points (1.56 points per year) showed a statistically significant and clinically meaningful change after 12 months.
These results suggest that microperimetric mean sensitivity and deep scotoma points may serve as useful end points for clinical trials investigating emerging treatments for Stargardt disease.
Functional end points for clinical trials investigating the efficacy of emerging treatments for Stargardt disease type 1 (STGD1) are needed.
To assess the yearly rate of change of macular function in patients with STGD1 using microperimetry.
Design, Setting, and Participants
This multicenter prospective cohort study was conducted in an international selection of tertiary referral centers from October 21, 2013, to February 15, 2017. The study included participants with ABCA4-related STGD1 who were enrolled in the Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study at baseline. Data were analyzed from February 16, 2017, to December 1, 2019.
ABCA4-related STGD1 with a minimum lesion size on fundus autofluorescence and a minimum visual acuity.
Main Outcomes and Measures
Changes in overall macular sensitivity (MS), deep scotoma count, number of points that tested normal, and location-specific sensitivity changes.
Among the 359 eyes from 200 patients (87 [43.5%] men; mean [SD] age, 33.3 [15.2] years) who underwent microperimetry examination graded at baseline and month 12, the mean (SD) yearly change in MS was −0.68 (2.04) dB (95% CI, −0.89 to −0.47 dB; P < .001), and deep scotoma points increased by a mean (SD) of 1.56 (5.74) points per year. The points with sensitivity of 12 dB or higher decreased in sensitivity by a mean (SD) of −3.01 (9.84) dB (95% CI, −4.03 to −1.99 dB; P < .001). The mean (SD) yearly change in MS was not significantly different between the eyes with a grading of good or fair pattern placement at both visits (−0.67 [2.1] dB) and the eyes with a poor pattern placement during at least 1 visit (−0.64 [2.2] dB) (P = .91).
Conclusions and Relevance
This study showed that MS and the number of deep scotoma points had measurably changed after follow-up of approximately 1 year. Microperimetry may serve as a useful functional outcome parameter for clinical trials aimed at slowing the progression of STGD1.
Stargardt disease type 1 (STGD1) is caused by pathogenic mutations in the ABCA4 gene (OMIM 601691) and leads to atrophic-appearing macular lesions and variable loss of best-corrected visual acuity (BCVA),1 often from 20/20 to 20/400 or worse.2 BCVA remains the most commonly used functional end point in clinical trials for various retinal diseases. However, the Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study recently showed that BCVA is unlikely to be a sensitive outcome measure in STGD1 except in certain subgroups because of the slow rate of BCVA loss.2,3 Conventional perimetry may not be appropriate for conditions that affect the fovea and lead to eccentric fixation.4 Fundus-controlled (micro)perimetry allows precise functional analysis of the macula by displaying stimuli in preplanned retinal areas.5 The MP-1 microperimeter is reliable for testing of macular function in STGD1.6 Point-by-point retest limits were determined to be ±4.2 dB and independent of the magnitude of overall measured sensitivity.6 We assessed longitudinal changes in microperimetric sensitivity during a 12-month period and their association with various parameters in patients with STGD1.
This international, multicenter, prospective cohort study was conducted in an international selection of tertiary referral centers from October 21, 2013, to February 15, 2017, and included participants with ABCA4-related STGD1 who were enrolled in the Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study7 at baseline. The Western Institutional Review Board and all local US and European institutional review boards granted approval. All patients provided written informed consent and received a financial incentive to attend follow-up.
Inclusion criteria were a minimum lesion size on fundus autofluorescence and a minimum visual acuity. The detailed enrollment count and baseline characteristics are presented in eTable 1 in the Supplement and Figure 1. Cases with substantial changes in MS (mean of all 68 test locations) were reviewed by one of us (E.M.S.), and a subset was excluded for technical reasons (Figure 1).
For 3 study visits 6 months apart, the Nidek MP-1 microperimeter (Nidek Co Ltd) was used to test sensitivity at 68 test locations in a custom Humphrey 10-2 pattern (Figure 2) using white, size 3 stimuli (0.43° in arc; comparable to Goldmann size III) with a duration of 200 milliseconds on a white background and a 4-2 strategy under mesopic conditions. Only eyes with adequate pupillary dilation (as determined by the local principal investigator [D.G.B., E.Z., J.S.S., H.P.N.S., and others]) were tested. A training examination preceded microperimetry testing at the baseline visit.
The standard test pattern had the central 4 points at 1.7° from the anatomical fovea, which were grouped as foveal; the 12 perifoveal points were at a distance of 3.5° to 4.7° from the center of the grid and were grouped as the inner ring; and the remainder of the test locations 5.6° to 10.1° from the center were the outer ring (Figure 3). To ensure anatomically identical follow-up, all sites were asked to link all follow-up visits using the built-in follow-up function. In cases of relocation of the preferred retinal locus, technicians were asked to create a new baseline at follow-up. The sensitivity at each retinal location was determined by iteratively adjusting the light intensity until the dimmest visible stimulus was found for all 68 test locations. The sensitivity for each test location was determined on a scale of 0 to 20 dB. Test locations with a sensitivity of 0 dB (seen or not seen) were defined as deep scotomas, and test locations with a sensitivity of more than 0 dB but less than 12 dB were defined as relative scotomas. The ProgStar protocol did not include the testing of individuals with normal vision, but based on the literature,8,9 loci with 12-dB or higher sensitivity were considered to be normal.10 All examinations were performed monocularly while the patent’s contralateral eye was patched.
The reading center categorized the pattern placement on the fovea as adequate, poor, or cannot grade. When the center of the grid was less than 1° from the anatomical fovea, the pattern placement was considered adequate. Distances from 1° to less than 2° were considered fair. Poor pattern placement means improper grid placement at a distance of more than 2°.
In a previous report,10 eyes that had fair or adequate pattern placement (326 eyes) were included. We found no difference in the mean (SD) change in MS between the eyes whose pattern placement was determined to be good or fair at both visits (−0.67 [2.1] dB, preliminary analysis) and the eyes with poor pattern placement during at least 1 visit (−0.64 [2.2] dB) (P = .91). We therefore decided to report changes irrespective of the quality of the pattern placement as our main analysis.
We also investigated the effect of the use of the follow-up function. A NAVIS software update during study conduct allowed importing single horizontal line optical coherence tomographic images to identify the anatomical fovea for accurate coregistration of the center of the test grid onto the anatomical fovea as previously described.10 Those sites that had not used the tool from the beginning had to create a new baseline for follow-up, resulting in inconsistent use of the follow-up tool. This heterogeneity allowed us to investigate the effect of the function.
Data were analyzed from February 16, 2017, to December 1, 2019. Linear models with generalized estimating equations were used to estimate the associations between the outcome parameters while accounting for between-eye correlations. Aggregated residuals were used for model assessment. If the assumption of a linear association between an independent variable and the outcome variable was not met, piecewise linear models with generalized estimating equations were used where the cutoff value for the final model was determined through iterative model fitting and was the value that yielded the minimum information criteria in the model fit. The rate of progression with each variable was first estimated in a univariate analysis. Multivariate analysis was further run by including variables that were significantly associated with the rate of progression. The study used SAS statistical software, version 9.3 (SAS Institute Inc) for analyses. A 2-sided P < .05 was considered to be statistically significant.
Among the 359 eyes from 200 patients (87 [43.5%] men; mean [SD] age, 33.3 [15.2] years) who underwent an MP-1 examination graded at baseline and month 12, the mean (SD) yearly change in MS was −0.68 (2.04) dB (95% CI, −0.89 to −0.47 dB; P < .001), and deep scotoma points increased by a mean (SD) of 1.56 (5.74) points per year (95% CI, 0.97-2.16 points per year; P < .001). A total of 283 eyes at baseline (78.8%) and 310 eyes at month 12 (86.4%) were found to have good or fair pattern placement.
Of all eyes with both baseline and month 12 data available, the latter were linked to the baseline examination via the follow-up function in 147 eyes. The yearly decrease in mean sensitivity with the use of the follow-up function was larger than that without (−0.87 vs −0.55 dB; P = .25). The relative scotoma (overall median change in scotoma points, 1.00; range, −28 to 38; P = .18) and normal point count (overall median change in normal points, −2.0; range, −49 to 30; P = .89) were not significantly different after 12 months. There was no significant difference in change of MS at month 12 depending on quality of pattern placement; of all eligible and gradable eyes, it was good or fair for both visits in 261 eyes (change in MS, −0.67 dB) and poor for at least 1 visit in 104 eyes (change in MS, −0.64 dB) (P = .91). Therefore, we report the change in MS without use of the follow-up function and regardless of the quality of pattern placement as our main outcome. A total of 359 eyes had an MP-1 examination result graded at both baseline and month 12, and this overall change in MS after 1 year was −0.68 dB (95% CI, −0.89 to −0.47 dB; P < .001), and deep scotoma points increased by 1.56 points per year. The sensitivity of the points of 12 dB or greater at baseline (12-20 dB) changed by a mean (SD) of −3.01 (9.84) dB (95% CI, −4.03 to −1.99 dB; P < .001) (Table 1).
In the univariate analysis of rates of changes of MS, relatively normal points, and deep scotoma points with different variables, we found that nonwhite race was associated with a positive change in MS (ie, there was improvement in nonwhite patients; 95% CI, 0.19-1.71 dB; P = .01). Case-by-case analysis of all 18 eyes of all nonwhite patients with functional improvement did not reveal any technical errors except for 1 case with improper grid placement. The analysis did not reveal single cases of extreme improvement that would have driven this result. Patient age of at least 50 years was associated with a yearly increase of deep scotoma point count of 2.30 (95% CI, 0.29-4.32; P = .02) higher compared with younger age and 2.56 (95% CI, 0.63-4.48; P = .009) higher in the multivariate analysis. The Bland-Altman analysis in eFigure 1 in the Supplement shows that the yearly change did not depend on the magnitude of MS.
For the longitudinal analysis of subfield sensitivity variables, we required use of the follow-up function and good or fair pattern placement on both study visits. Therefore, the count of eyes for this analysis decreased to 106. Mean sensitivity values decreased by a similar amount. Although the increase in deep scotoma points was similar in the inner and outer ring of the test grid, the decrease in normal test locations was highest in the outer ring. When looking at changes in count of test locations, it must be considered that the different regions comprise a different number of test locations (Table 2).
We investigated whether the change of MS was associated with the initial baseline MS. We divided the entire cohort into 5 quintiles according to their baseline MS. The yearly changes in mean sensitivity were −0.70 (95% CI, −8.7 to 2.8; P = .01) in the third, −0.95 (95% CI, −6.5 to 3.4; P < .001) in the fourth, and −1.26 (95% CI, −10.0 to 4.3; P < .001) in the fifth quintile. The individual mean changes for each quintile are presented in eTable 2 and eFigure 2 in the Supplement.
The ProgStar studies have examined structural abnormalities over time in STGD1 using fundus autofluorescence (FAF)7,11-13 and spectral-domain optical coherence tomography.14 Ideally, structural changes would be associated with functional loss. Microperimetry allows the measurement of functional deficits before they become apparent on FAF imaging,15,16 thereby potentially allowing interventions in early stages.
Microperimetry has previously been studied longitudinally in STGD1.17 A threshold change is necessary to ascertain that a measured change is not secondary to test-retest variability. The retest variability may worsen in regions with a steep slope in the hill of vision because a slight adjustment in stimulus position may cause a point undetected in a deep scotoma to move to an area of the retina where the point would be detected. In the case of fundus-controlled (micro)perimetry, however, there is evidence for the particular case of STGD1 that variability is not associated with the extent of the scotoma, mean sensitivity, or the local slope of sensitivity,6 which is why MP-1 has been suggested for progression in transition zones. For a clinical trial, a standardized grid likely allows best comparison between visits and between patients. A previous functional report10 found that the cases in ProgStar were relatively advanced, and MP-1 testing had a mean (SD) MS of 11.0 (5.0) dB and a mean number of 41.3 of 68 normal points. This finding may be associated with a minimum FAF lesion size as an inclusion criterion for a natural history study in which the primary end point was the rate of anatomical change in atrophy,7 resulting in a floor effect.
Our main end point was overall mean sensitivity irrespective of the quality of pattern placement or use of the follow-up function but stratified by use of the follow-up function because the stratified analysis by both variables showed a stronger association of the follow-up function with the estimates of change over time. We prefer the overall MS change because displacement of the grid had a larger association with location-specific changes. We did not require good or fair quality of pattern placement on the foveal center or the use of the follow-up function, which together would reduce the number of eyes to an unrepresentative 106 (eTable 3 in the Supplement). The overall yearly change in MS was slightly less than the −1.19 dB per year change reported by others.17 An initial practice session avoided learning effects. The relatively similar changes in MS from baseline to month 6 and from month 6 to 12 suggest that a learning effect was not present. Furthermore, the stability of fixation remained unchanged.18 Previous research in age-related macular degeneration found that retinal sensitivity decreases faster in intermediate stages than in early ones (11 dB vs 4 dB every 6 years).19
To our knowledge, there are no data on STGD1 about what change in microperimetric MS is clinically significant. Two examples from the glaucoma literature are that surgical reduction of intraocular pressure for glaucoma was associated with a reduction in mean (SD) visual field progression rate from −1.0 (0.9) dB per year before surgery to −0.2 (0.38) dB per year postoperatively.20 De Moraes et al21 described the progression of visual field change in eyes with and without documented optic disc progression (−0.66 [0.7] vs −0.36 [0.7] dB per year; P < .01). The studies20,21 considered these differences clinically significant. We therefore believe that −0.68 dB per year in STGD1, as reported here, can be considered as a clinically significant change.
Another previously reported10,22 way to measure progression involves counting the number of deep scotoma points. An advantage is that the deep scotoma count can be translated into an area. Assuming that the tested 20° field is 6000 μm in diameter and 28.3 mm2 in area, the approximate area covered by each point is 28.3/68.0 = 0.42 mm2, and the annual growth rate of the deep scotoma is 0.66 mm2. This finding is comparable to the rate of 0.51 mm2 per year, which is the yearly progression of definitely decreased autofluorescence signal in STGD1,13 but closer structure-function analysis will be necessary to substantiate this association.
A software update resulted in 1 part of the cohort being assessed using the follow-up function, whereas others were not. When we performed stratified analysis by the quality of pattern placement and the follow-up function, the follow-up function had a stronger association with the estimates of change over time than the quality of pattern placement.
There is evidence of different progression rates in patients with STGD1. Earlier disease onset (ie, age at diagnosis of STGD1), longer disease duration, and older patient age are associated with more eccentric and more unstable fixation,18,23 lower mean sensitivity, but higher deep scotoma count.10 An older age at onset is associated with slower yearly change of BCVA2 but overall better BCVA.3,12 However, the rate of BCVA change is not associated with patient age.24 Estimated growth rates of decreased autofluorescence signals are higher in patients older than 30 years.13 Our current analysis, however, showed that there was no association between many demographics and the change in MS or the normal point count in univariate analysis. Only the change in the number of deep scotoma points demonstrated associations in both univariate and multivariate analyses (eTable 4 in the Supplement). Our case-by-case analysis of nonwhite patients with functional improvement over time suggests that the slower progression rate among nonwhite participants may be coincidental.
Macular sensitivity was lowest in the center, but this type of analysis requires accurate placement of the test grid (on the fovea at baseline and on follow-up) because small misplacements of the grid may result in completely different subregions tested. One option is to include only examination results with good or fair pattern placement at both visits and with the follow-up function. This approach substantially reduced the number of eyes for the analysis. The sample of 106 of 359 eyes was not meant to represent the ProgStar cohort but to demonstrate the feasibility of reporting location-specific changes under ideal conditions. A very advanced stage, especially in the 4 foveal points, limits the analysis.10 Despite this floor effect, the eyes in this cohort exhibited a measurable yearly change in MS and a yearly increase in deep scotoma points. Nevertheless, the measured mean changes in MS in the foveal center, the inner ring, and the outer ring were similar. The mean decrease in points with light sensitivity in a normal range was higher with increasing distance from the fovea; however, one has to take into account the increasing number of test locations for the 3 regions. Both MS and the counts of normal or deeply scotomatous points yielded measurable change. Following MS over time may be useful especially for foveal-sparing cases of STGD1 and early cases without deep scotomata.
Previous ProgStar reports2,3,13,25 have found that the progression rate of both visual acuity and atrophic lesion size depends on baseline vision or lesion size. A similar association with microperimetric MS appeared intuitive. We would have assumed that eyes with near-normal MS do not exhibit measurable change because the functional loss would not progress fast enough and that eyes with very poor sensitivity would not show change because of a consequent floor effect (ie, test locations that already show zero function cannot get any worse). We divided the cohort into 5 quintiles and investigated whether a statistically significant change occurred in all 5 quintiles. Of interest, the quintile with the lowest and the 2 quintiles with the best and second-best baseline MS were the ones to show statistically significant change. This finding suggests that different rules apply to the change of MS based on baseline visual function.
Limitations of this study include the exclusion of a relatively large number of eyes from the analysis (Figure 1). The method is inherently limited by a floor effect: because a mean of 16 points indicated deep scotomas at baseline,10 the value of many test points could not further decrease in these test locations. The selective analysis of the scotoma edge will be useful to measure progression around the dense scotoma.26 In addition, our results demonstrate that individual eyes can show an improvement of MS over time. There may be several reasons for this observation. A learning effect appears unlikely because all patients underwent a practice session before their first visit. Functional variability may be affected by factors that we did not record, such as time of day, season, or the patient’s individual activity and light exposure before testing. The exclusion of a large number of eyes is another important aspect. However, we compared the distribution of MS at month 12 in eyes not included because of missing baseline values with the MS in included eyes and did not find a difference. We may therefore conclude that no obvious exclusion bias influenced the results.
The findings suggest that simple microperimetric measures, such as overall MS or the count of normal, relative, or deep scotomatous points, may detect functional changes during a study period of 12 months. More sophisticated analyses may specifically investigate the scotoma edge.27 Potentially, microperimetry may detect changes in early stages of STGD1 before structural changes can be detected. Results from the prospective Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study28 will compare scotopic microperimetric changes with mesopic microperimetry data. In this study, microperimetry was a sensitive test for detecting progression within a relatively short study period; this may be useful for future clinical trials of emerging therapies for STGD1.29,30
Accepted for Publication: March 30, 2020.
Corresponding Author: Hendrik P. N. Scholl, MD, Institute of Molecular and Clinical Ophthalmology Basel, Mittlere Strasse 91, CH-4031 Basel, Switzerland (email@example.com).
Published Online: May 28, 2020. doi:10.1001/jamaophthalmol.2020.1735
Author Contributions: Dr Scholl had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Schönbach, Strauss, Zrenner, Sunness, Ip, West, Scholl.
Acquisition, analysis, or interpretation of data: Schönbach, Strauss, Muñoz, Wolfson, Ibrahim, Birch, Zrenner, Sunness, Ip, Sadda, Scholl.
Drafting of the manuscript: Schönbach, Ip, Scholl.
Critical revision of the manuscript for important intellectual content: Schönbach, Strauss, Muñoz, Wolfson, Ibrahim, Birch, Zrenner, Sunness, Sadda, West, Scholl.
Statistical analysis: Schönbach, Muñoz, Ip, West.
Obtained funding: Schönbach, Scholl.
Administrative, technical, or material support: Schönbach, Strauss, Ibrahim, Birch, Zrenner, Scholl.
Supervision: Strauss, Ip, Scholl.
Conflict of Interest Disclosures: Dr Schönbach reported receiving grants from the Leopoldina German Academy of Sciences and the Foundation Fighting Blindness during the conduct of the study. Dr Wolfson reported receiving grants from the Foundation Fighting Blindness Clinical Research Institute, the US Department of Defense, and the US Army Medical Research and Development Command Telemedicine and Advanced Technology Research Center during the conduct of the study. Dr Birch reported receiving personal fees from Applied Technologies Genetics Corporation, Nacuity Pharmaceuticals, the Foundation Fighting Blindness, and ProQR outside the submitted work. Dr Ip reported receiving personal fees from Boehringer Ingelheim, Thrombogenics, Quark, Omeros, Allergan, Amgen, Astellas, Alimera, Novartis, Genentech, Clearside, and Biogen outside the submitted work. Dr Sadda reported receiving personal fees and/or nonfinancial support from Heidelberg, Optos, Centervue, Roche/Genentech, Regeneron, Amgen, Novartis, 4DMT, Merck, Topcon, Nidek, and Carl Zeiss Meditec outside the submitted work. Dr West reported receiving grants from the Foundation Fighting Blindness during the conduct of the study. Dr Scholl reported receiving grants from the Swiss National Science Foundation, Wellcome Trust, the Foundation Fighting Blindness Clinical Research Institute, Novartis Pharma AG, and Pharma Research & Early Development of F. Hoffmann-La Roche Ltd and receiving personal fees from ReNeuron Group Plc/Ora Inc, Novo Nordisk, Boehringer Ingelheim Pharma GmbH & Co, Gerson Lehrman Group, and Guidepoint outside the submitted work. No other disclosures were reported.
Funding/Support: The Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies are supported by the Foundation Fighting Blindness Clinical Research Institute and grants W81-XWH-07-1-0720 and W81-XWH-09-2-0189 from the US Department of Defense, US Army Medical Research and Development Command Telemedicine and Advanced Technology Research Center. Dr Strauss is supported by project J 3383-B23 from the Austrian Science Fund and the Foundation Fighting Blindness Clinical Research Institute. Dr Schönbach is supported by grant LPDS 2015-14 from the Leopoldina German National Academy of Sciences and the Foundation Fighting Blindness Clinical Research Institute.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: Chair’s office: Hendrik P. N. Scholl, MD; Rupert W. Strauss, MD; Yulia Wolfson, MD; Millena Bittencourt, MD; Syed Mahmood Shah, MD; Mohamed Ahmed, MD; Etienne Schönbach, MD; Kaoru Fujinami, MD, PhD. Cole Eye Institute, Cleveland, Ohio: Elias Traboulsi, MD; Justis Ehlers, MD; Meghan Marino, MS; Susan Crowe, BS; Rachael Briggs, COA; Angela Borer, BS; Anne Pinter, CRA; Tami Fecko; Nikki Burgnoni, MS. Greater Baltimore Medical Center, Towson, Maryland: Janet S. Sunness, MD; Carol Applegate, MLA, COT; Leslie Russell, MAc. Moorfields Eye Hospital, London, England: Michel Michaelides, MD; Simona Degli Esposti, MD; Anthony Moore, MD; Andrew Webster, MD; Sophie Connor, BSc; Jade Barnfield, BA; Zaid Salchi, MD; Clara Alfageme, MD; Victoria McCudden; Maria Pefkianaki, MD; Jonathan Aboshiha, MA, MB; Gerald Liew; Graham Holder, PhD; Anthony Robson, PhD; Alexa King, BA; Daniela Ivanova Cajas Narvaez, MSc; Katy Barnard, BS; Catherine Grigg, BSc; Hannah Dunbar, PhD; Yetunde Obadeyi; Karine Girard-Claudon, MST; Hilary Swann, BSc; Avani Rughani, BSc; Charles Amoah, NVQ; Dominic Carrington; Kanom Bibi, BSc; Emerson Ting Co, DMD; Mohamed Nafaz Illiyas; Hamida Begum, BSc; Andrew Carter, BSc; Anne Georgiou, PhD; Selma Lewism BSc; Saddaf Shaheen, PGDip, BSc; Harpreet Shinmar, MSc; Linda Burton, BS. Moran Eye Center, Salt Lake City, Utah: Paul Bernstein, MD, PhD; Kimberley Wegner, BS; Briana Lauren Sawyer, MS; Bonnie Carlstrom, COA; Kellian Farnsworth, COA; Cyrie Fry, AS, CRA, OCT-C; Melissa Chandler, BS, CRC, OCT-a; Glen Jenkins, BS, COA, CRC, OCT-a; Donnel Creel, PhD. Retina Foundation of the Southwest, Dallas, Texas: David Birch, PhD; Yi-Zhong Wang, PhD; Luis Rodriguez, BS; Kirsten Locke, BS; Martin Klein, MS; Paulina Mejia, BS. Scheie Eye Institute, Philadelphia, Pennsylvania: Artur V. Cideciyan, PhD; Samuel G. Jacobson, MD, PhD; Sharon B. Schwartz, MS, CGC; Rodrigo Matsui, MD; Michaela Gruzensky, MD; Jason Charng, OD, PhD; Alejandro J. Roman, MS. University of Tübingen, Tübingen, Germany: Eberhart Zrenner, PhD; Fadi Nasser, MD; Gesa Astrid Hahn, MD; Barbara Wilhelm, MD; Tobias Peters, MD; Benjamin Beier, BSc; Tilman Koenig; Susanne Kramer, Dipl Biol. The Vision Institute, Paris, France: José-Alain Sahel, MD; Saddek Mohand-Said, MD, PhD; Isabelle Audo, MD, PhD; Caroline Laurent-Coriat, MD; Ieva Sliesoraityte, MD, PhD; Christina Zeitz, PhD; Fiona Boyard, BS; Minh Ha Tran, BS; Mathias Chapon, COT; Céline Chaumette, COT; Juliette Amaudruz, COT; Victoria Ganem, COT; Serge Sancho, COT; Aurore Girmens, COT. The Wilmer Eye Institute, Baltimore, Maryland: Hendrik P. N. Scholl, MD; Rupert W. Strauss, MD; Yulia Wolfson, MD; Syed Mahmood Shah, MD; Mohamed Ahmed, MD; Etienne Schönbach, MD; Robert Wojciechowski, PhD; Shazia Khan, MD; David G. Emmert, BA; Dennis Cain, CRA; Mark Herring, CRA; Jennifer Bassinger, COA; Lisa Liberto, COA. Dana Center Data Coordinating Center: Sheila West, PhD; Ann-Margret Ervin, PhD; Beatriz Munoz, MS; Xiangrong Kong, PhD; Kurt Dreger, BS; Jennifer Jones, BA. Doheny Image Reading Center: SriniVas Sadda, MD; Michael S. Ip, MD; Anamika Jha, MBS; Alex Ho, BS; Brendan Kramer, BA; Ngoc Lam, BA; Rita Tawdros, BS; Yong Dong Zhou, MD, PhD; Johana Carmona, HS; Akihito Uji, MD, PhD; Amirhossein Hariri, MD; Amy Lock, BS; Anthony Elshafei, BS; Anushika Ganegoda, BS; Christine Petrossian, BS; Dennis Jenkins, MPH; Edward Strnad, BS; Elmira Baghdasaryan, MD; Eric Ito, OD; Feliz Samson, BS; Gloria Blanquel, BS; Handan Akil, MD, FEBOpht; Jhanisus Melendez, MS; Jianqin Lei, MD; Jianyan Huang, MD, PhD; Jonathan Chau, BS; Khalil G. Falavarjani, MD; Kristina Espino, BS; Manfred Li, BS; Maria Mendoza, BS; Muneeswar Gupta Nittala, MPhil Opt; Netali Roded, BS; Nizar Saleh, MD; Ping Huang, MD, PhD; Sean Pitetta, BS; Siva Balasubramanian, MD, PhD; Sophie Leahy, BA; Sowmya J. Srinivas, MBBS; Swetha B. Velaga, B Opt; Teresa Margaryan, BA; Tudor Tepelus, PhD; Tyler Brown, BS; Wenying Fan, MD; Yamileth Murillo, BA; Yue Shi, MD, PhD; Katherine Aguilar, BS; Cynthia Chan, BS; Lisa Santos, HS; Brian Seo, BA; Christopher Sison, BS; Silvia Perez, BS; Stephanie Chao, HS; Kelly Miyasato, MPH; Julia Higgins, MS; Zoila Luna, MHA; Anita Menchaca, BS; Norma Gonzalez, MA; Vicky Robledo, BS; Karen Carig, BS; Kirstie Baker, HS; David Ellenbogen, BS; Daniel Bluemel, AA; Theo Sanford, BS; Daisy Linares, HS; Mei Tran, BA; Lorane Nava, HS; Michelle Oberoi, BS; Mark Romero, HS; Vivian Chiguil, HS; Grantley Bynum-Bain, BA; Monica Kim, BS; Carolina Mendiguren, MEM; Xiwen Huang, MPH; Monika Smith, HS; Teresa Margaryan, BS; Natalie Sarreal, BS.
Additional Contributions: Marco Cattaneo, PhD, Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland, provided additional statistical support and was compensated as part of his work for the Institute of Molecular and Clinical Ophthalmology Basel.
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