Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Macular Atrophy Affecting Visual Outcomes in Patients Undergoing Anti-VEGF Treatment in Routine Clinical Practice

Nathaniel B. Rieveschl, MD; Weilin Song, BS; Ang Li, MD; Thais F. Conti, MD; Grant L. Hom, BA; Grace J. Tsai, BA; Felipe F. Conti, MD; Amy S. Babiuch, MD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVE:

To explore how baseline macular atrophy (MA) affects visual acuity (VA) in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) injections for neovascular age-related macular degeneration (nAMD).

PATIENTS AND METHODS:

A retrospective, case control series. Patients were grouped into three cohorts based on baseline spectral-domain optical coherence tomography image findings: foveal MA, nonfoveal MA, and no MA. Outcomes were assessed at 1, 2, and 3 years following anti-VEGF therapy.

RESULTS:

No differences existed in MA growth between eyes with foveal and nonfoveal MA (0.89 mm2 [95% confidence interval (CI), 0.64–1.14] vs. 0.88 mm2 [95% CI, 0.72–1.05]) after adjusting for baseline lesion sizes at 3 years. Foveal MA patients lost an average of 19.4 ETDRS letters (95% CI, −30.8 to −8.0) after 3 years. Nonfoveal MA patients gained an average of 1.1 ETDRS letters (95% CI, −6.8 to 9.0), and patients without MA averaged a gain of 9.7 ETDRS letters (95% CI, 5.5–14.0).

CONCLUSION:

In patients with nAMD receiving anti-VEGF in routine clinical practice, presence of baseline foveal MA was associated with significant vision loss.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:68–75.]

Abstract

BACKGROUND AND OBJECTIVE:

To explore how baseline macular atrophy (MA) affects visual acuity (VA) in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) injections for neovascular age-related macular degeneration (nAMD).

PATIENTS AND METHODS:

A retrospective, case control series. Patients were grouped into three cohorts based on baseline spectral-domain optical coherence tomography image findings: foveal MA, nonfoveal MA, and no MA. Outcomes were assessed at 1, 2, and 3 years following anti-VEGF therapy.

RESULTS:

No differences existed in MA growth between eyes with foveal and nonfoveal MA (0.89 mm2 [95% confidence interval (CI), 0.64–1.14] vs. 0.88 mm2 [95% CI, 0.72–1.05]) after adjusting for baseline lesion sizes at 3 years. Foveal MA patients lost an average of 19.4 ETDRS letters (95% CI, −30.8 to −8.0) after 3 years. Nonfoveal MA patients gained an average of 1.1 ETDRS letters (95% CI, −6.8 to 9.0), and patients without MA averaged a gain of 9.7 ETDRS letters (95% CI, 5.5–14.0).

CONCLUSION:

In patients with nAMD receiving anti-VEGF in routine clinical practice, presence of baseline foveal MA was associated with significant vision loss.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:68–75.]

Introduction

Age-related macular degeneration (AMD) is a leading cause of blindness among individuals older than 50 years of age, with an estimated prevalence of approximately 8.7% of the world's population.1,2 As of this year, 196 million people worldwide were projected to have AMD.2 Late-stage AMD is characterized as either exudative or nonexudative. In exudative AMD, choroidal neovascularization (CNV) develops and causes accelerated vision loss. Intravitreal anti-vascular endothelial growth factor (VEGF) injection is now the gold standard treatment for neovascular AMD (nAMD).3–8 Atrophy of retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris may occur in both the dry and wet forms of late AMD with severe visual consequence. Geographic atrophy (GA) is a term used to describe this phenomenon in nonexudative AMD when no CNV exists. Macular atrophy (MA) describes incident atrophy in eyes with nAMD and distinguishes this type of atrophy from GA in nonexudative AMD, since the pathogenesis may involve separate mechanisms.9,10 No approved treatment has been shown to delay or stop the progression of atrophy from either cause.

Although the general effectiveness of anti-VEGF for treating nAMD is clear, there is significant variability in individual responses to the therapy.3,8 MARINA was a 2-year, multicenter, double-blind, sham-controlled study that assigned 716 patients with nAMD to monthly ranibizumab (Lucentis; Genentech, South San Francisco, CA) injections or sham injections and was designed to measure the efficacy and safety of repeated anti-VEGF injections. The MARINA study showed a mean increase of 7 ETDRS letters after 2 years of anti-VEGF therapy, but around 10% of patients lost three or more lines of vision despite adequate treatment.8 Recent studies suggest that variance in final visual outcomes may be associated with baseline factors including age, visual acuity (VA), and CNV lesion size.11–14 HARBOR was a phase 3, prospective, randomized, controlled clinical trial that assessed the efficacy of two doses and two regimens of ranibizumab in patients with nAMD. A post hoc analysis of the HARBOR study evaluated the effect of MA on best-corrected VA (BCVA) outcomes in 1,095 patients treated with ranibizumab for nAMD.15 At 24 months, eyes with and without MA both experienced BCVA improvement from baseline, but those with MA recovered fewer letters.

Although fundus autofluorescence (FAF) has been the current standard for MA assessment, spectral-domain optical coherence tomography (SD-OCT) also allows for MA measurement.16 SD-OCT is a noninvasive and time-efficient modality that enables evaluation of individual retinal layers and quantification of MA lesion progression. Lesions due to MA characteristically present on SD-OCT as distinct areas of RPE and photoreceptor degradation with increased reflectivity at the level of the choroid.16 Automated software that identifies subillumination is increasingly utilized for MA quantification due to its efficiency and good level of agreement with manually defined MA on both SD-OCT and FAF.17

The significance of baseline fovea-involving MA and fovea-sparing MA on visual outcomes for eyes receiving anti-VEGF therapy has not been established. The main purpose of this study is to explore how baseline MA affects VA outcomes in patients receiving anti-VEGF injections for nAMD and to characterize the degree of MA progression over at least 2 years.

Patients and Methods

Study Design

This retrospective cohort study was conducted at Cole Eye Institute, Cleveland, Ohio, and received approval from the Cleveland Clinic Investigational Review Board. A comprehensive chart review was performed to identify qualified patients and assess ophthalmic data. Written informed consent was not required because of the retrospective nature of this study. All study-related procedures were performed in accordance with the Health Insurance Portability and Accountability Act.

Study Population

Data from patients with nAMD who received intravitreal anti-VEGF injections with ranibizumab, bevacizumab (Avastin; Genentech, South San Francisco, CA), or aflibercept (Eylea; Regeneron, Tarrytown, NY) at the Cleveland Clinic Cole Eye Institute from January 2012 to January 2016 were collected. Patients with nAMD in at least one eye who were naïve to anti-VEGF therapy at the first documented injection (baseline visit) were included in this study. Additional eligibility criteria included having at least 2 years of documented annual follow-up visits and SD-OCT images at baseline and yearly follow-up intervals. Eyes with prior photodynamic therapy, laser photocoagulation, retinal detachment, disciform scar, RPE tear, or other causes of CNV were excluded. The patients were measured with Snellen charts either with or without pinhole correction. They were not refracted at each visit. The best vision was recorded by any method for each vision and converted to approximate ETDRS.18 The number of anti-VEGF injections received was noted for each study eye. Demographic data, such as age, gender, smoking status, and presence of systemic disease, were collected for each patient. The anti-VEGF drug, treatment regimen, and dose were determined by the treating physician's preference.

Eligible eyes were grouped into three cohorts based on SD-OCT findings. Eyes were included in the “no MA” control cohort if MA was absent at baseline and did not develop within 2 years. Eyes were included in the “foveal MA” cohort if they exhibited MA involving the foveal center on OCT at baseline. The “nonfoveal MA” cohort included eyes if there was MA that spared the fovea at baseline, or if they had no atrophy at baseline but developed nonfoveal MA within 1 year of the baseline visit.

Macular Atrophy Measurement

Identification of atrophy was automated with RPE subillumination analysis on SD-OCT (Cirrus Software Version 7.0; Carl Zeiss Meditec, Jena, Germany) by segmenting areas of increased reflectivity at the level of the choroid on B-scans and quantifying atrophy dimensions on the sub-RPE slabs (Figure 1). Additionally, trained graders reviewed the SD-OCT images to confirm measurements using specific atrophy criteria including increased signal transmission into the choroidal layer, RPE band thinning, and ellipsoid zone loss. Based on these criteria, the graders manually corrected the segmented borders on the en face images and atrophy area was recalculated. Additional values, such as central subfield thickness (CST), macular volume (MV), and cube average thickness (CAT), were obtained via automated analyses by Cirrus Review software.

Representative optical coherence tomography images. (A) Nonfoveal macular atrophy (MA) at baseline (above) and 36 months (below). (B) Foveal MA at baseline (above) and 36 months (below).

Figure 1.

Representative optical coherence tomography images. (A) Nonfoveal macular atrophy (MA) at baseline (above) and 36 months (below). (B) Foveal MA at baseline (above) and 36 months (below).

Statistical Analyses

Continuous measures were evaluated for normality using graphs and the Shapiro-Wilk test. To compare trends in responses over time on BCVA, MA, and CST, linear mixed-effect models were fit. In each model, patient group, time, and an interaction between time and group were included as predictors. An autoregressive correlation structure was assumed to account for correlated responses within the eye over time. A random intercept was included to account for correlation between eyes from the same patient. The models were fit using changes at each follow-up time point as the outcome and group as the primary predictor, unadjusted and then adjusting for baseline measure, number of injections, and age, to account for differences between groups on these measures. If patients were missing data beyond 24 months, the linear mixed-effect models were used to extrapolate measures out to 36 months using maximum likelihood estimation.19

Fit of the model was evaluated based on graphical evaluation of residuals and investigation of influential points. Overall comparisons of trends and mean changes were performed at the 0.05 level, and then post-hoc pairwise comparisons of groups were performed at the Bonferroni corrected significance level of 0.0167. Tests of whether the mean changes at each time point were significant for each group were performed at the 0.05 level. Data management and model fitting was performed using SAS software (version 9.4; Cary, NC).

Results

A total of 270 patients with nAMD treated for at least 2 years with anti-VEGF therapy at the Cole Eye Institute between 2012 and 2016 were reviewed. Among these, 19 eyes from 15 patients were eligible for the foveal MA group, 26 eyes from 26 patients were eligible for the nonfoveal MA group, and 29 eyes from 24 patients were included in the control group. Annual measures of BCVA, MA, CST, CAT, and MV were available for three consecutive years of follow-up in 58 eyes. The most common reasons for exclusion were prior anti-VEGF therapy, lack of baseline SD-OCT, and, for the nonfoveal MA group specifically, no detectable atrophy by the 1-year encounter.

A summary of patient demographics and baseline characteristics can be found in Table 1. The mean (± standard deviation [SD]) age was 78.5 (±8.6 SD) for the control group, 86.2 (±6.2 SD) for the foveal MA group, and 83.4 (±4.5 SD) for the nonfoveal MA group. The percentage of eyes from patients with diabetes was significantly higher in the foveal group (55%) compared to the nonfoveal (15%) and control groups (17%). In terms of initial anti-VEGF agent used, 74% of the Foveal group received bevacizumab versus 65% of the nonfoveal group, and 5% of the foveal group received ranibizumab versus 15% of the nonfoveal group.

Baseline Characteristics by Group

Table 1:

Baseline Characteristics by Group

Effect of Baseline Macular Atrophy on Visual Acuity After Anti-VEGF Treatment

There were significant differences in mean BCVA between the foveal MA (ETDRS letters, 50.4 ± 16.2) and control (ETDRS letters, 65.2 ± 13.1) groups at baseline (P < .017, Table 1) and each follow-up visit (P < .001; Figure 2). At 12, 24, and 36 months, there were significant differences in mean BCVA between the foveal MA and nonfoveal MA groups (P < .001, P = .001, and P = .001, respectively; Figure 2).;

Best-corrected visual acuity (BCVA) progression in foveal macular atrophy (MA), nonfoveal MA, and non-MA patients undergoing anti-vascular endothelial growth factor injections. CI = confidence interval; f/u = follow-up

Figure 2.

Best-corrected visual acuity (BCVA) progression in foveal macular atrophy (MA), nonfoveal MA, and non-MA patients undergoing anti-vascular endothelial growth factor injections. CI = confidence interval; f/u = follow-up

At 12, 24, and 36 months, the foveal MA group showed significant mean BCVA loss from baseline (ETDRS letters: −14.2 [95% CI, −24.1 to −4.3], −14.6 [95% CI, −24.7 to −4.5], and −19.4 [95% CI, −30.8 to −8.0]; P < .001, respectively). At 36 months, the control group had significant mean BCVA gains from baseline (ETDRS letters, +9.7 [95% CI, 5.5, 14.0],P < .001) (Table 2). Although the nonfoveal MA group had an initial BCVA gain of 7.1 (95% CI, −0.6 to 14.7) ETDRS letters at 12 months, this was gradually lost so that by 36 months, the mean BCVA gain from baseline was 1.1 (95% CI, −6.8 to 9.0) ETDRS letters (Table 2). After adjusting for baseline BCVA, these visual outcome differences were statistically significant between the foveal MA and control groups (P < .001) and between the foveal MA and nonfoveal MA groups (P = .004) (Table 2).

Comparisons of Mean Changes Across Groups by Time — Adjusted

Table 2:

Comparisons of Mean Changes Across Groups by Time — Adjusted

Retinal Measurements With SD-OCT

Table 3:

Retinal Measurements With SD-OCT

Macular Atrophy Progression

There were significant differences in MA lesion sizes between the three groups at baseline (foveal, 2.8 ± 1.5 mm2 vs. nonfoveal, 1.0 ± 1.3 mm2 vs. control, 0.0 mm2; P < .001) (Table 1). Square root transformation of MA area measurements was performed to reduce the dependency of MA growth on baseline MA lesion size. After adjusting for baseline MA lesion size, number of injections, and age, the MA mean changes in the foveal group at 12, 24, and 36 months were 0.72 mm2 [95% CI, 0.47–0.97], 0.75 mm2 [95% CI, 0.50–1.00], and 0.89 mm2 [95% CI, 0.64–1.14], respectively. The MA mean changes in the nonfoveal group at 12, 24, 36 months were 0.57 mm2 [95% CI, 0.40–0.73], 0.73 mm2 [95% CI, 0.57–0.89], and 0.88 mm2 [95% CI, 0.72–1.05], respectively. There were no statistically significant differences in atrophy progression between the foveal and nonfoveal MA groups at 12, 24, or 36 months. At the 36-month visit, the control group (0.26 mm2 [95% CI, 0.08–0.43]) had significantly slower atrophy growth than the foveal group (0.89 mm2 [95% CI, 0.64–1.14]; P = .001) and nonfoveal group (0.88 mm2 [95% CI, 0.72–1.05]; P < .001) (Table 2). Of the eyes in the nonfoveal MA group, 42% (11 of 26) developed atrophy involving the fovea by 24 months. To assess the measurement of atrophy in treatment-naïve eyes, baseline MA measurements were compared to 3-month MA measurements once the fluid resolved. The mean foveal MA was 2.82 mm2 [95% CI, 2.12–3.52] at baseline and 3.07 [95% CI, 2.29–3.85] at 3 months. The mean nonfoveal MA was 0.99 mm2 [95% CI, 0.49–1.49] at baseline and 1.05 [95% CI, 0.53–1.57] at 3 months.

Retinal Thickness Following Anti-VEGF Treatment

At baseline, CST for the nonfoveal group was greater than that for the foveal group (349.2 ± 73.9 vs. 281.2 ± 66.3; P = .008) (Table 1). However, there was no significant difference in CST mean change between the three groups at 12, 24, and 36 months (Table 2).

Discussion

The study demonstrated that eyes with foveal MA experienced significant vision loss following anti-VEGF therapy, indicating that foveal MA at baseline negatively impacts vision outcomes. In eyes with no MA and nonfoveal MA, not only prevention of vision loss but also a mean improvement in vision was maintained through 36 months. There was no statistically significant difference in BCVA outcomes between eyes without MA and eyes with nonfoveal MA, indicating that nonfoveal MA does not substantially impact VA outcomes. Study eyes with nAMD in the MARINA sham arm experienced a mean loss of −14.9 letters from baseline at 2 years.8 Thus, the rate of vision loss associated with anti-VEGF treatment in the setting of foveal MA may be comparable to that of untreated nAMD, raising the question of whether the benefits of anti-VEGF therapy outweigh the potential risks such as endophthalmitis and retinal detachment in eyes with foveal MA.

In the current study, eyes with nonfoveal MA and eyes without MA experienced mean gains of +3.8 and +10.3 ETDRS letters, respectively, at 2 years. The 2-year HARBOR trial found that eyes with and without MA experienced mean BCVA gains from baseline (+6.7 and +9.1 ETDRS letters, respectively).15 The HARBOR study did not differentiate between foveal versus nonfoveal MA, which may explain the tendency for BCVA improvement among eyes with MA in the trial.

Because the cohort in this study was limited and further dividing the groups by anti-VEGF agent would further lessen the number of patients in each group, investigation into the growth rate of atrophy between ranibizumab and bevacizumab was not pursued. The study was not powered to perform this analysis.

Over 3 years, there was no significant difference in MA progression between foveal and nonfoveal MA groups after correction with square root transformation of the MA area to account for baseline lesions.20 Several studies have shown that extrafoveal MA lesions tend to progress faster than foveal lesions.21,22 One reason why the results of the current study do not reflect the same growth pattern may be because the nonfoveal group criteria included several eyes without baseline MA that developed MA by 12 months. Meanwhile, all foveal group eyes had MA at baseline. This baseline MA status distinction would tend toward reducing the mean MA change from baseline in the nonfoveal group and may explain the similar atrophy progression rates in the Non-foveal and foveal groups in this study.

One strength of this study was that only treatment-naïve patients were included to account for total treatment course. This cohort's treatment was in a large, multidisciplinary ophthalmological practice and was determined based on the individual practitioner's preference, which resembles real-life experience of chronic anti-VEGF therapy. One limitation of the study was the challenge of evaluating atrophy on SD-OCT, whereas exudative disease was simultaneously active because intraretinal and subretinal fluid obstructs the discernment of new MA margins. Another drawback was the presence of differences between groups in baseline characteristics and number of injections although they were adjusted for. The extrapolation of 36-month measures in a number of patients was based on the idea that the pattern of missing data was not systematic, which may not be an accurate assumption. Since this study was limited to 3 years, the analysis did not speak to the long-term effect of baseline atrophy on vision in patients with nAMD. Loss of vision may ultimately be anticipated in patients with nonfoveal MA if the atrophy progresses with time.

In conclusion, this study showed baseline foveal MA was associated with vision loss in previously treatment-naïve patients with nAMD. On the basis of manual correction of SD-OCT auto-segmentation data, MA progression was not significantly different between eyes with foveal and nonfoveal MA. Being able to predict a patient's response to anti-VEGF therapy may allow ophthalmologists and patients to adjust their expectations for visual outcomes. Further research is needed to understand how baseline foveal MA affects long-term vision outcomes. This will have important implications on the future of nAMD treatment because it may direct changes to the therapeutic approach for patients with baseline foveal MA while also guiding prognosis.

References

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Baseline Characteristics by Group

No MA Foveal MA Nonfoveal MA P Value

N 29 19 26

Age (mean ± SD) 78.5 ± 8.61,2 86.2 ± 6.23 83.4 ± 4.53 < .001 a

Male, n (%) 11 (38%) 9 (45%) 8 (31%) NSb

Smoking, n (%)
  Never 15 (52%) 10 (50%) 9 (35%) NSb
  Past 14 (48%) 10 (50%) 16 (61%) NSb
  Current 0 (0%) 0 (0%) 1 (4%) NSb

Diabetes Mellitus, n (%) 5 (17%)1 11 (55%)2,3 4 (15%)1 .004 b

Hypertension, n (%) 20 (69%) 17 (85%) 20 (77%) NSb

Coronary ArteryDisease, n (%) 7 (24%) 10 (50%) 11 (42%) NSb

BCVA (Mean ± SD) 65.2 ± 13.11 50.4 ± 16.23 59.0 ± 22.2 .018 a

MA (mm2, Mean ± SD) 0.0 ± 0.01,2 2.8 ± 1.52,3 1.0 ± 1.31,3 < .001 a

CST (μm, Mean ± SD) 319.2 ± 72.2 281.2 ± 66.32 349.2 ± 73.91 .008 a

No. of Injections (Mean ± SD)
  1st year 6 ± 2.4 6 ± 2.7 7 ± 3.0 NSb
  2nd year 5 ± 2.5 2 ± 2.3 4 ± 2.9 NSb
  3rd year 4 ± 2.41 2 ± 2.13 3 ± 2.3 .024 b

Comparisons of Mean Changes Across Groups by Time — Adjusted

Factor Time (Months) Foveal Mean (95% CI) Nonfoveal Mean (95% CI) Control Mean (95% CI) Overall Foveal vs. Control Nonfoveal vs. Control Nonfoveal vs. Foveal
BCVA 12 −14.20 (−24.13 to −4.26) 7.09 (−0.55−14.73) 6.54 (2.26–10.82) < .001 < .001 .90 < .001
BCVA 24 −14.61 (−24.70 to −4.51) 3.79 (−3.65−11.23) 10.29 (6.16–14.41) < .001 < .001 .13 .004
BCVA 36 −19.39 (−30.77 to −8.00) 1.08 (−6.80–8.95) 9.74 (5.45–14.03) < .001 < .001 .058 .003
MA 12 0.72 (0.47–0.97) 0.57 (0.40–0.73) −0.11 (−0.28–0.06) < .001 < .001 < .001 .27
MA 24 0.75 (0.50–1.00) 0.73 (0.57–0.89) 0.03 (−0.14–0.20) < .001 < .001 < .001 .89
MA 36 0.89 (0.64–1.14) 0.88 (0.72–1.05) 0.26 (0.08–0.43) < .001 .001 < .001 .95
CST 12 −74.4 (−100.9 to −47.9) −73.8 (−96.6 to −51.1) −50.0 (−69.0 to −31.0) .17 .14 .11 .97
CST 24 −63.1 (−90.1 to −36.1) −64.4 (−86.5 to −42.3) −64.3 (−83.0 to −45.7) .99 .94 .99 .94
CST 36 −62.7 (−93.8 to −31.6) −49.1 (−73.0 to −25.2) −80.9 (−99.8 to −61.9) .12 .33 .043 .48

Retinal Measurements With SD-OCT

No MAa Foveal MAb P Valuesa,b Nonfoveal MAc P Values a,c P Values b,c

Baseline
  CST 314 (275, 341) 263 (235, 304) .0361 332 (310, 409) .0985 .0015
  MV 10.5 (9.8, 11.2) 9.65 (9.3, 10.35) .0071 10.05 (9.4, 10.8) .0722 .3127
  CAT 293 (272.5, 310) 269 (257, 288) .0062 278 (260, 301) .0546 .3239

1-Year Follow-Up
  CST 285 (232, 316.5) 245 (198, 278) .0246 254 (225, 299) .3281 .2026
  MV 10 (9.5, 10.45) 9.15 (8.8, 9.8) .0011 9.4 (8.9, 9.95) .0154 .5055
  CAT 280 (265.5, 290) 253 (247, 271) .0011 260 (245, 277) .0312 .313

2-Year Follow-Up
  CST 265 (223.5, 289.5) 247 (212, 292) .4516 261 (232, 298) .8661 .3635
  MV 9.7 (9.3, 10.2) 9.45 (8.9, 9.8) .1053 9.5 (8.98, 9.9) .1635 .7814
  CAT 271 (256.5, 283) 263 (248, 273) .1058 263 (249, 275) .1856 .7312

3-Year Follow-Up
  CST 225 (214, 269) 233 (158, 294) .7297 263 (223, 310) .0722 .1117
  MV 9.6 (9.1, 10.2) 9.25 (8.8, 9.5) .0254 9.4 (8.9, 10.3) .4468 .251
  CAT 265 (251.5, 284) 257 (246, 264) .0785 262 (247, 286) .6686 .2856
Authors

From Case Western Reserve University School of Medicine, Cleveland (NBR, RPS); Cleveland Clinic Lerner College of Medicine at Case Western Reserve University School of Medicine, Cleveland (WS); Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (WS, AL, TFC, GLH, GJT, FFC, ASB, RPS); Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (TFC, GLH, FFC, ASB, RPS); and School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland (GJT).

Dr. Babiuch has received personal fees from Vindico and MCME Global, as well as grants from Regeneron Pharmaceuticals, outside the submitted work. Dr. Singh has received grants and personal fees from Regeneron Pharmaceuticals and Genentech/Roche; personal fees from Optos, Zeiss, and Biogen; and grants from Apellis and Alcon/Novartis outside the submitted work. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

Address correspondence to Rishi P. Singh, MD, Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Mail Code i-32, Cleveland, OH 44195; email: singhr@ccf.org.

Received: February 08, 2019
Accepted: August 27, 2019

10.3928/23258160-20200129-01

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