Comparison of Early Treatment Diabetic Retinopathy Study Standard 7-Field Imaging With Ultrawide-Field Imaging for Determining Severity of Diabetic Retinopathy

Key Points

Question  Is ultrawide-field imaging comparable with Early Treatment Diabetic Retinopathy Study (ETDRS) imaging when assessing the severity of diabetic retinopathy within the 7 standard fields?

Findings  In this cross-sectional study, there were 737 gradable eyes on both ETDRS 7-field images and ultrawide-field images masked to contain the same 7 fields after adjudication; 435 eyes (59.0%) had exact agreement, and 714 eyes (96.9%) were within 1 step of agreement.

Meaning  These findings could justify ultrawide-field imaging for assessing the severity of diabetic retinopathy end points in future studies.

Importance  Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials.

Objective  To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging.

Design, Setting, and Participants  This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017.

Main Outcomes and Measures  Agreement between UWF images, UWF images masked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics.

Results  A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%).

Conclusions and Relevance  Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.

For 2 decades, the standard for determining severity of diabetic retinopathy (DR) has been the extended modified Airlie House classification used in the Early Treatment Diabetic Retinopathy Study (ETDRS).¹ In this defined classification system, the location and extent of specific retinal lesions are evaluated in the posterior pole, using 7 stereoscopic pairs of photographs per eye (ETDRS 7 standard fields). The DR severity determined in this manner is highly correlated with the risk of DR progression.² Current DR therapeutic and management guidelines are based on clinical trials using the ETDRS classification system. A condensed version of this classification has been proposed internationally for general clinical DR assessment.³

Substantial diabetic retinal pathology can exist in the retinal periphery located outside the ETDRS 7 standard fields, which in total compose about 34% of the retinal surface.^4-6 Advances in retinal imaging technology now allow ultrawide-field (UWF) cameras to evaluate up to 82% of the retinal surface in a single image.⁷ Several single-center studies have suggested moderate to substantial agreement between UWF and ETDRS imaging.^8-10 Furthermore, UWF studies have shown that DR occurs in areas peripheral to the ETDRS fields in up to 40% of eyes and is extensive enough to imply a more severe level of DR in 9% to 15% of eyes.^5,11-13

This study is a preplanned cross-sectional analysis of baseline data from an ongoing 4-year evaluation of 764 eyes of 385 participants to assess how the retinal far periphery observed using mydriatic UWF images (with a 200° view) affects the ability to assess DR severity and is associated with rates of DR worsening over time compared with ETDRS 7-field imaging. Severity grading between the ETDRS 7-field and UWF images within the ETDRS 7-field area was compared to assess whether UWF images can be used reliably in place of ETDRS imaging in future clinical trials. We also evaluated the peripheral area in the UWF images to determine presence, type, severity, and location of DR lesions outside the ETDRS 7-field area and how these peripheral lesions might change grading of DR severity compared with ETDRS images.

This study is a prospective observational study conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) at 38 clinical sites in the United States and Canada. (The protocol, labeled AA, can be found at http://drcrnet.jaeb.org.) The study adhered to the tenets of the Declaration of Helsinki and was approved by multiple institutional review boards. Study participants provided written informed consent.

Enrolled participants were adults (≥18 years) with type 1 or type 2 diabetes. Study eyes had nonproliferative DR (NPDR; defined as ETDRS retinopathy severity at levels 35 through 53), no history of panretinal photocoagulation, and no central-involved diabetic macular edema on optical coherence tomography, based on DRCR.net sex-based and machine-based thresholds or clinical examination.¹⁴ This article includes data from the eyes included in the study (n = 579) and additional nonstudy eyes (n = 185) that had available ETDRS and UWF images at baseline.

At baseline, after pupil dilation, ETDRS 7-field stereoscopic images, UWF images, and a fundus examination were performed on both eyes of each participant. Fundus photographs were obtained based on the DRCR.net image acquisition procedure. The UWF images were obtained using the Optos 200Tx (Optos, PLC). The UWF imaging procedure included two 200° central images and four 200° steered images. In the present report, only the central images were evaluated. The professionals capturing ETDRS 7-field images were certified by the Fundus Photograph Reading Center at the University of Wisconsin, and those capturing UWF images were certified by Optos, PLC.

Ultrawide-field and ETDRS 7-field images were transferred digitally to the Joslin Diabetes Reading Center (Boston, Massachusetts) for standardized grading by 3 senior readers masked to all clinical characteristics and the grading of the other imaging modality. All readers had extensive experience grading retinopathy images (range, 14-37 years). To ensure reproducibility, all grading was performed using high-resolution displays that are color calibrated and gamma corrected biannually. More than 43 000 UWF images have been evaluated by the reading center. Grader agreement for DR severity (weighted κ) was 0.88 to 0.93 for UWF images and 0.83 to 0.84 for ETDRS 7 standard field images.¹⁵ Using images that were not part of this study, agreement between the 2 primary readers for UWF vs ETDRS images was substantial (κ, 0.80 ± 0.13).⁸

An individual reader graded either UWF or ETDRS images but never both modalities for the same eye. When grading the UWF images, images were initially presented with a template mask, which had been digitally overlaid automatically to obscure the retinal periphery such that only the ETDRS 7-field area was visible (UWF masked; Figure 1A). After complete grading of the UWF-masked image, the mask was removed, and the full image including the UWF periphery was evaluated (UWF unmasked; Figure 1B).

The UWF images stereographically projected by Optos software were used to determine DR severity. For all 3 image approaches, the presence and severity of the following lesions were assessed in temporal, superior temporal, inferior temporal, superior nasal, and inferior nasal fields (fields 3-7): hemorrhages and/or microaneurysms, intraretinal microvascular abnormalities, venous beading, new vessels on the disc, new vessels elsewhere, hard exudates, retinal thickening, preretinal hemorrhage, vitreous hemorrhage, traction retinal detachment, and central fields.

For the unmasked UWF images, each lesion type was characterized as (1) not observed, (2) predominantly observed within the ETDRS fields, (3) predominantly observed outside the ETDRS fields, or (4) observed uniformly distributed within and outside the ETDRS fields, or (5) ETDRS field obscured, (6) periphery obscured, or (7) ungradable. For each field, a lesion was considered predominantly peripheral if more than 50% of the lesion was observed in the retinal periphery compared with the area within the modified ETDRS fields. A lesion was considered uniformly distributed if it was equivalently located both within and outside the ETDRS field. A lesion was considered predominantly posterior if 50% of the lesion was within the modified ETDRS fields.

Based on the extent and severity of the lesions, a composite ETDRS DR grade was derived: no DR (level 10-12), minimal NPDR (level 14-20), mild NPDR (level 35), moderate NPDR (level 43), severe NPDR (level 47-53), very severe NPDR (level 53E), inactive proliferative DR (PDR) (level 60), non–high-risk PDR (level 61-65), and high-risk PDR (level 71-75). Proliferative DR was defined as new vessels in at least 1 field. In the absence of new vessels, if the eye had NPDR characteristics in at least 1 field, then the eye was considered to have NPDR regardless of any areas obscured. An eye was classified as having no DR if all fields were gradable and did not have DR characteristics. Sensitivity analyses using other approaches for missing fields (eg, assessing only eyes with data available for at least 3 fields) did not appreciably change the results.

The ETDRS 7-field and UWF masked images do not necessarily visualize the exact same retinal area because of asynchronous image capture and the unique imaging methodology of each instrument. Thus, preplanned side-by-side adjudication of all eyes with DR severity differing by 2 or more steps between the ETDRS and UWF masked imaging was performed by a senior grader (L.P.A.), who was not involved in prior grading, to assess the reasons underlying the discrepancy, including grader error, suboptimal image quality, or differences in visualized areas. The senior grader also determined from all available image information which modality provided the overall more accurate DR severity grade (recorded as “ETDRS more accurate,” “UWF more accurate,” or “modalities similar”).

Percentages and 95% CIs were calculated using generalized estimating equations to account for the correlation between eyes of the same participant. Levels of agreement were calculated using κ statistics. For multilevel outcomes, quadratic weights were used to estimate κ statistics and 95% CIs. Strength of agreement beyond chance alone was determined using the Landis and Koch interpretation of κ statistics (0.20 indicates slight agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, substantial agreement; and 0.81-1.00, almost perfect agreement). A sensitivity analysis was conducted to adjust for the correlation between eyes of the same participant, but the results did not change appreciably.¹⁶ All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc).

Baseline characteristics are shown in eTable 1 in the Supplement. Among the 385 participants, the median (IQR) age was 62 (53-69) years; 194 (50.4%) were women, 256 (66.5%) were white, and 51 (13.2%) had type 1 diabetes. A total of 764 eyes were included, with a median (IQR) visual acuity letter score of 85 (80-89) letters (Snellen equivalent, 20/20). The distribution of DR severity graded for each image type is shown in eTable 2 in the Supplement. Based on ETDRS imaging, NPDR was present in 695 of 752 eyes (92.4%), with 559 eyes (74.3%) having minimal or moderate NPDR.

A total of 19 images were ungradable on either the ETDRS 7-field system (n=9) or UWF masked images (n=10), while 3 images were ungradable on both modalities, leaving 742 eyes for analyses. Severity of DR classified into 8 categories (with severe and very severe NPDR combined into 1 category) matched exactly between ETDRS 7-field images and UWF masked images in 359 eyes (48.4% [95% CI, 44.4%-52.4%]) and was within 1 severity level in 653 eyes (88.0% [95% CI, 85.2%-90.3%]), with moderate agreement (weighted κ, 0.51 [95% CI, 0.44-0.58]; Table 1, Figure 2A). Discrepancies of 2 or more steps were equally distributed between ETDRS and UWF masked images.

There were 130 eyes (17.0% [95% CI, 14.3%-20.1%]) that were 2 or more steps discrepant. Images could not be compared in 14 eyes because the ETDRS or UWF masked image was ungradable, leaving 116 eyes for adjudication.

After adjudication of these 116 eyes, DR severity between ETDRS and UWF masked images (n = 737) matched exactly in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and within 1 severity grade in 714 eyes (96.9% [95% CI, 95.1%-98.0%]). There was substantial agreement between the 2 imaging modalities (weighted κ,0.77 [95% CI, 0.73-0.82]; Table 2, Figure 2B).

Among adjudicated images, the ability of ETDRS and UWF masked images to accurately detect retinopathy was considered equivalent in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), ETDRS 7-field images were considered more accurate in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and UWF masked images were considered more accurate in 31 eyes (26.7% [95% CI, 18.8%-36.5%]). For the 59 eyes with similarly accurate images, grading error was the major reason for the difference, which was equivalently distributed between ETDRS images (n = 25) or UWF masked images (n = 29). When either ETDRS images (n = 22) or UWF masked images (n = 31) were identified as the more accurate modality, the major reason for the difference was suboptimal image quality of the other modality (UWF, n = 17; ETDRS, n = 27). The distribution of the lesions underlying these differences is in eTable 3 in the Supplement.

There were 751 gradable eyes on both UWF masked and UWF unmasked images. The severity of DR between UWF masked images and UWF unmasked images (both 200°) matched exactly in 648 eyes (86.3% [95% CI, 83.4%-88.7%]), was more severe in the masked grade in 9 eyes (1.2% [95% CI, 0.6%-2.3%]), more severe by 1 step in the unmasked grade in 59 eyes (7.9% [95% CI, 6.0%-10.2%]), and more severe by 2 or more steps in the unmasked grade in 35 eyes (4.7% [95% CI, 3.3%-6.6%]) (eTable 4 and eFigure 1 in the Supplement). Comparing ETDRS images with the unmasked UWF images (n = 743), DR severity was more severe by 2 or more steps in the unmasked grade in 76 eyes (10.2% [95% CI, 8.1%-12.9%]) (eFigure 2 in the Supplement).

Predominantly peripheral DR lesions were present in 1 or more fields for 308 of 751 eyes (41.0%). In 222 of these eyes (72.1% [95% CI, 66.5%-77.1%]), masked and unmasked UWF DR grades matched exactly. In 83 eyes (26.9% [95% CI, 22.0%-32.5%]), greater DR severity was observed on the UWF unmasked image (eTable 5 in the Supplement), and 34 eyes (11.0%) had greater DR severity by 2 steps or more.

Lesions were observed in 4504 fields: 2312 (51.3%) were predominantly within the ETDRS fields, 660 (14.7%) were predominantly peripheral to the ETDRS fields, and 1532 (34.0%) were uniformly distributed. Of these fields, 3056 had hemorrhages and/or microaneurysms, with 458 fields (15.0%) predominantly peripheral; 1299 intraretinal microvascular abnormalities, with 168 fields (12.9%) predominantly peripheral; 110 venous beading, with 13 fields (11.8%) predominantly peripheral; and 39 new vessels elsewhere, with 21 fields (53.8%) predominantly peripheral (Figure 3). Of the 660 predominantly peripheral fields, 458 (69.4%) had hemorrhages and/or microaneurysms, 168 (25.5%) had intraretinal microvascular abnormalities, 21 (3.2%) had new vessels elsewhere, and 13 (2.0%) had venous beading. The distribution of specific predominantly peripheral DR lesions within individual eyes is shown in eFigure 3 in the Supplement.

Nearly all modern formal imaging assessments of DR severity have been based on grading the location and extent of key DR lesions within the ETDRS 7-standard field area.¹ However, given the technological advances now enabling UWF imaging and the potential benefits of this approach,¹⁷ there may be substantial impetus for moving to UWF imaging if it is comparable in determining DR severity and if pathology in the retinal periphery provides additional clinically useful information on prospective worsening of retinopathy.^8,11,12

In this study, we found that ETDRS images had moderate agreement with UWF images that were masked to reveal only the ETDRS 7-field area, and substantial agreement after open adjudication of known discrepancies by 2 masked graders. Unpublished data from a Wisconsin reading center report exact agreement and agreement within 1 step between 2 graders evaluating the exact same ETDRS image to be 78% and 99%, respectively (Barbara Blodi, MD, written communication, December 26, 2017). Predominantly peripheral lesions were common on UWF imaging, and results from this study showed that the UWF peripheral area may suggest increased DR severity by 2 or more steps in approximately 11.0% of eyes.

Although these data suggest that ETDRS and UWF imaging can both be used in clinical studies for assessing DR severity, it is important that the 2 imaging approaches do not visualize the exact same retinal area because of asynchronous image capture, manual positioning of each of the 7 ETDRS fields, and idealized ETDRS masking area used on the UWF masked images. Side-by-side comparison of the images derived from the 2 approaches was a crucial, preplanned component of this study to determine whether discrepancies were owing to inherent image quality, grading differences, or areas of retina visualized in 1 modality but not the other. Adjudication assessed whether each modality was more likely to accurately demonstrate presence of disease in an individual eye, or if the 2 imaging modalities were similar.

Both approaches to imaging were judged to similarly demonstrate retinopathy findings in more than half of the discrepant eyes. The major reason for the difference in eyes with 2 or more step discrepancy was grading errors. These cases were equivalently distributed between ETDRS and UWF masked images. Correcting these grading errors resulted in a 2 or more step difference in DR severity in 3.1% of eyes. When either modality was identified as the more accurate images, the major reason for the difference was suboptimal image quality of the other modality. The suboptimal image quality was equally distributed between modalities. These findings further suggest that (1) the 2 imaging modalities are comparable for determining DR severity when following the protocol used in this study and (2) maximizing image quality is of paramount importance. Differences in field definition accounted for only a small percentage of discrepant cases.

As reported previously, unmasked UWF images frequently identified additional DR lesions in the retinal periphery.^12,15,18 Given that imaging of the ETDRS fields identifies a more severe DR level based on grading variability in approximately 1.0% of cases, UWF unmasked images likely suggest a net increase of DR severity in 10.0% of eyes. This is similar to prior reports of 9.0% to 15.0% of eyes.^5,11-13

A potentially important and yet unresolved issue regarding comparisons of 7-field and UWF imaging in management of DR concerns how an ophthalmologist might evaluate DR severity in the clinic without an expert grader or adjudication and how such evaluation may change over time. However, important for clinical trials, the data from this analysis suggest that, following the protocol for this study, moderate to substantial agreement of DR severity is possible when comparing 7-field and UWF modalities across a diversity of DR stages.

Another unresolved issue is the extent to which DR findings peripheral to the area of retina visualized with ETDRS 7-field imaging can affect the risk of DR progression. Future findings from the longitudinal data in this study might provide a definitive answer as to whether UWF images can improve methods to assess and triage eyes at risk for DR worsening.

The identification of a subset of patients at greatly increased risk of experiencing DR progression and onset of proliferative DR that cannot be assessed by ETDRS 7-field imaging would have important implications for the evaluation and care of diabetic eye disease. Not only would UWF devices be the preferred imaging modality, but their use would be important in clinical trial settings requiring precise assessment of prospective DR progression rates, in clinical care for accurate patient counseling, and in teleophthalmology programs to improve risk assessment and triage in eyes that otherwise would not have the peripheral retina evaluated. The current study suggests that enough patients have predominantly peripheral DR lesions at baseline to answer this question at the conclusion of this trial.

These baseline data show that ETDRS 7-field and UWF imaging can have moderate to substantial agreement when determining DR severity within the ETDRS area. These findings could justify UWF imaging for assessing DR severity end points in future studies. The use of UWF imaging in clinical settings not only increases the frequency of DR identification nearly 2-fold, but also reduces acquisition time by more than half, ungradable image rate by 71% (to <3%), and image evaluation time by 28% compared with nonmydriatic fundus photography.¹¹ However, this study was performed with the assistance of a dedicated image grading center. Additional investigations may determine if these data hold true within the clinical setting or how UWF images perform in the development of artificial intelligence approaches. Furthermore, UWF imaging identifies peripheral lesions not captured by ETDRS imaging in a large percentage of eyes. Whether identification of these peripheral lesions will substantially affect the ability to assess the risk of future DR progression awaits final data from this ongoing study.

Corresponding Author: Isoken Odia, OD, Jaeb Center for Health Research, 1530 Amberly Dr, Ste 350, Tampa, FL 33647 (drcrstat9@jaeb.org).

Accepted for Publication: August 29, 2018.

Correction: This article was corrected on November 15, 2018, to change “imagesmasked” to “images masked” in the Abstract.

Published Online: October 18, 2018. doi:10.1001/jamaophthalmol.2018.4982

Author Contributions: Dr Odia 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: Aiello, Glassman, Jampol, Bressler, Kiss, Silva, Sun.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Aiello, Odia, Glassman, Jampol, Kiss.

Critical revision of the manuscript for important intellectual content: Aiello, Odia, Melia, Jampol, Bressler, Kiss, Silva, Wykoff, Sun.

Statistical analysis: Odia, Glassman, Melia.

Obtained funding: Glassman, Jampol.

Administrative, technical, or material support: Aiello, Odia, Glassman, Jampol, Bressler, Silva, Wykoff.

Supervision: Glassman, Melia, Sun.

Conflict of Interest Disclosures: Dr Glassman reports receiving grants from National Institutes of Health, Allergan, and Genentech. Dr Jampol reports a grant from the National Eye Institute. Dr Kiss reports grants and personal fees from Optos and personal fees from Alimera, Alcon, Adverum, Regeneron, Novartis, Genentech, Spark, RegenXBio, and Fortress Bio. Ms Melia reports grants from the National Eye Institute and the Juvenile Diabetes Research Foundation during the conduct of the study and personal fees from National Eye Institute and other support from Vindico outside the submitted work. Dr Sun reports nonfinancial support from Optovue, Boston Micromachines, Novartis, Novo Nordisk, Adaptive Sensory Technologies, and Genentech; grants from Genentech, Juvenile Diabetes Research Foundation, and Kalvista; and personal fees from Eleven Biotherapeutics, Vindico Medical Education, Current Diabetes Reports, Merck, Allergan, Kowa, Novartis, Regeneron, and Bayer. Additionally, a complete list of all DRCR.net investigator financial disclosures is at http://drcrnet.jaeb.org.

Funding/Support: This study was supported through a cooperative agreement from the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the US Department of Health and Human Services (grants EY14231 and EY23207), and a grant from the Juvenile Diabetes Research Foundation.

Role of the Sponsor: The funders participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, nor in the collection, management, analysis, or interpretation of the data, or in the preparation of the manuscript.

Group Information: DRCR.net Coordinating Center: Jaeb Center for Health Research, Tampa, FL (staff as of 12/20/2017): Adam R. Glassman (Director and Principal Investigator), Roy W. Beck (Executive Director), Daphne Auza, Alyssa Baptista, Wesley T. Beaulieu, Sharon R. Constantine, Brian B. Dale, Simone S. Dupre, Julie Davis, Meagan L. Huggins, Paula A. Johnson, Brittany Kelly, Danni Liu, Brenda L. Loggins, Maureen Maguire, Michele Melia, Ilona Nemeth, Isoken Odia, Carrie Preston, Cynthia R. Stockdale, Katie Stutz. Beetham Eye Institute Ophthalmic Reading Center, Joslin Diabetes Center, Boston, Massachusetts: Lloyd Paul Aiello, MD, PhD (Principal Investigator); Jerry D. Cavallerano, OD, PhD; Paolo S. Silva, MD; Dorothy Tolls, OD. DRCR.net Network Chair: Jennifer K. Sun, Daniel F. Martin, Lee M. Jampol, and Neil M. Bressler. DRCR.net Vice Chairs: Carl W. Baker, Chirag Jhaveri, Mathew MacCumber, Andrew Antoszyk, Susan B. Bressler, Scott Friedman, Judy Kim, Ingrid U. Scott, Jennifer K. Sun, John A. Wells, III. National Eye Institute: Sangeeta Bhargava, Eleanor Schron, Donald F. Everett, Päivi H. Miskala. DRCR.net Executive Committee: Lloyd Paul Aiello, Andrew N. Antoszyk, Carl W. Baker, Roy W. Beck, Sangeeta Bhargava, Barbra Blodi, Neil M. Bressler, Susan B. Bressler, Matthew D. Davis, Michael J. Elman, Frederick L. Ferris III, Adam R. Glassman, Glenn J. Jaffe, Lee M. Jampol, Chirag D. Jhaveri, Brandon Lujan, Mathew MacCumber, Dennis M. Marcus, Daniel F. Martin, Raj K. Maturi, Jennifer K. Sun; Prior Members: Abdhish Bhavsar, Alexander J. Brucker, Kakarla V. Chalam, Ronald P. Danis, Donald F. Everett, Joan Fish, Scott Friedman, Joseph Googe, Jr., Jeffrey G. Gross, Diana M. Holcomb, Judy E. Kim, Andreas Lauer, Ashley McClain, Brandi J. Perez, Eleanor Schron, Ingrid U. Scott, JoAnn Starr, John A. Wells, III. Florida Retina Consultants, Lakeland: Scott M. Friedman, Nader Moinfar, Damanda F. Fagan, Kimberly A. Williamson, Paige N. Walters, Tiara L. Reed, Allen McKinney, Brenda J. Bobbitt, Krystal Nikki Holmes, Steve Carlton. Elman Retina Group, P.A., Baltimore, Maryland: Michael J. Elman, Henry A. Leder, JoAnn Starr, Jennifer L. Belz, Pamela V. Singletary, Peggy R Orr, Jennifer L. Simmons, Dallas R. Sandler, Amy Thompson, Teresa Coffey, Peter Sotirakos, Ashley M. Metzger. Retina Consultants of Houston, Houston, Texas: Charles C. Wykoff, Matthew S. Benz, Amy C. Schefler, David M. Brown, Eric Chen, James C. Major, Tien P. Wong, Richard H. Fish, Amy Hutson, Meredith Berry, Stacy M. Supapo, Nubia Landaverde, Diana Rodriguez, Veronica A. Sneed, Elizabeth Quellar, Belinda A. Almanza, Brenda Dives, Tamara L Dodel, Eric N. Kegley, Beau A Richter, Cary A. Stoever. Charlotte Eye, Ear, Nose and Throat Associates, Charlotte, North Carolina: David Browning, Omar S. Punjabi, Andrew N. Antoszyk, Angela K. Price, Jenna T. Herby, Sherry L. Fredenberg, Courtney Mahr, Angella S. Karow, Sarah A. Ennis, Gina M. Lester, Autumn K. Finch, Beverly O. Rowland, Donna McClain, Lynn Watson, Teneisha A. Ragin, Swann J. Bojaj, Uma M. Balasubramaniam, Lisa A. Jackson, Michael D. McOwen, Loraine M. Clark. Joslin Diabetes Center, Boston, Massachusetts: Paolo S. Silva, Sabera T. Shah, Jennifer K. Sun, Lloyd Paul Aiello, Deborah K. Schlossman, George S. Sharuk, Timothy J. Murtha, Hanna Kwak, Margaret E. Stockman, Jerry D. Cavallerano, William Carli, Rita K. Kirby, Michael N. Krigman, Elizabeth S. Weimann, Leila Bestourous, Robert W. Cavicchi. Southeast Retina Center, P.C., Augusta, Georgia: Dennis M. Marcus, Harinderjit Singh, Siobhan O. Ortiz, Amina Farooq, Lindsay Allison Foster, Brook Parsons, Michele Woodward, Ken Ivey. Southeastern Retina Associates, P.C., Knoxville, Tennessee: Joseph M. Googe, R. Keith Shuler, Nicholas G. Anderson, Oliver, Lisa Lovelady, Patricia Coppola, Justin Walsh, Raul E. Lince, Sarah M. Oelrich, Steve Morris. Retina Research Center, Austin, Texas: Chirag D. Jhaveri, Saradha Chexal, Ivana Gunderson, Kimberly Hosein, Tina A Seidu, Tori Moore, Ryan M. Reid, Angela N. Palacios, Boris Corak, Yong Ren. Dean A. McGee Eye Institute, Oklahoma City, Oklahoma: Ronald M. Kingsley, Vinay A. Shah, Vanessa A. Bergman, Sonny Icks, Shannon R. Almeida, Lauren D. Ukleya, Russ Burris, Keven Lunsford, Alisha Brewer. Raj K. Maturi, M.D., P.C., Indianapolis, Indiana: Raj K. Maturi, Ashley M. Harless, Charlotte Harris. Wolfe Eye Clinic, West Des Moines, Iowa: Jared S. Nielsen, Kyle J. Alliman, Tami Jo Woehl, Marianne Parker, Jamie Spillman, Marilyn A. Johnson, Lisa M. Boender, Jay Rostvold, Spencer D Ridgway. National Ophthalmic Research Institute, Fort Myers, Florida: A. Thomas Ghuman, Ashish G. Sharma, Paul A. Raskauskas, Glenn Wing, Joseph P. Walker, Eileen Knips, Anita H. Leslie, Danielle Dyshanowitz, Raymond K. Kiesel. Rush University Medical Center, Chicago, Illinois: Mathew W. MacCumber, Eileen E. Tonner, Kisung Woo, Len Richine. Austin Retina Associates, Austin, Texas: Robert W. Wong, Phillip V. Le, Chris A. Montesclaros, Cory Mangham. Kittner Eye Center, Chapel Hill, North Carolina: Seema Garg, Jan Niklas Ulrich, Elizabeth L. DuBose, Debra Cantrell, Rona Lyn Esquejo. Department of Ophthalmology, Jacksonville Health Science Center, University of Florida College of Medicine, Jacksonville: Sandeep Grover, Kakarla V. Chalam, Ghulam Shabbir Hamdani, Kumar Sambhav. Medical College of Wisconsin, Milwaukee: Judy E. Kim, William J. Wirostko, Dennis P. Han, Thomas B. Connor, Eleanor Dorsey, Krissa L. Packard, Vesper V. Williams, Pat A. Winter, Joseph R. Beringer, Stephanie J. Moebius, Kristy L. Keller, Hannah Sheppard, Marriner Altmann, Brittany Rego. Paducah Retinal Center, Paducah, Kentucky: Carl W. Baker, Tracey M. Caldwell, Jill D. Baker, Lynnette F. Lambert, Margaret J. Orr, Samantha Kettler, Alecia B. Camp. Retina-Vitreous Surgeons of Central New York, P.C., Syracuse: G. Robert Hampton, Jamin S. Brown, Laurie J. Sienkiewycz, Michelle L. Manley, Lynn M. Kwasniewski, Stefanie R. DeSantis, Nicole E. Robarge. Wilmer Eye Institute at Johns Hopkins University, Baltimore, Maryland: Sharon D. Solomon, Susan Bressler, Lisa K. Levin, Deborah Donohue, David Emmert, Dennis Cain. Ross Eye Institute, State University of New York, Buffalo: Gareth M.C. Lema, Pradeepa Yoganathan, Christopher M. Brown, Luann Wiechelt, Sandra L. Boglione. Retinal Consultants of San Antonio, San Antonio, Texas: Calvin E. Mein, Lita Kirschbaum, Jaynee Baker, Tori R. Moore, Elaine Castillo, Christopher Sean Wienecke, Brenda Nakoski. Department of Ophthalmology and Eye Care Services, Henry Ford Health System, Detroit, Michigan: Paul Andrew Edwards, Katie M. Ventimiglia, Nicole M. Massu, Bradley A. Stern. Halifax, Nova Scotia District Health Authority, Halifax, Nova Scotia, Canada: Alan F. Cruess, Ann Hoskin-Mott, Andrea Dean, Christine Morrison, Trina MacDonnell. Retina Northwest, P.C., Portland, Oregon: Mark A. Peters, Paul S. Tlucek, Colin Ma, Stephanie L. Ho, Stephen Hobbs, Christine Hoerner. University of British Columbia/VCHA Eye Care Centre, Vancouver, British Columbia, Canada: David A.L. Maberley, Eduardo Vitor Navajas, Farzin Forooghian, Andrew William Kirker, Theresa Wiens, Mira Jovanovic, Aleksandra Kuzmanovic, Angela Chang, Garnet Louise Elvena, Laura J. Hall, Anne-Marie Godfrey, Bryan Harrison. Retinal Consultants of Southern California Medical Group, Inc., West Lake Village: Kenneth R. Diddie, Deborah M. Cadwell, Taryn F. Boisvert, Adrienne C Swann. Ophthalmic Consultants of Boston, Boston, Massachusetts: Chirag P. Shah, Jennifer L. Stone, Margie Graham. Retina and Vitreous Associates of Kentucky, Lexington: Thomas W. Stone, Diana M. Holcomb, Jeanne Van Arsdall, Edward A Slade. Palmetto Retina Center, West Columbia, South Carolina: John A. Wells, John F. Payne, Tiffany R. Swinford, Tiffany N. Ogbuewu, Ashley Studebaker, Robbin Spivey. University of Illinois at Chicago Medical Center, Chicago: Jennifer I. Lim, Felix Y. Chau, Tametha Johnson, Yesenia Ovando, Catherine Carroll, Mark Janowicz, Lauren Talasnik, Marcia Niec. University of Pennsylvania Scheie Eye Institute, Philadelphia: Alexander J. Brucker, Benjamin J. Kim, Sheri Drossner, Sara Morales, Jim M. Berger. California Retina Consultants, Santa Barbara: Dante J. Pieramici, Alessandro A. Castellarin, Gina Hong, Kelly Avery, Aimee Walker, Matthew Giust. Retina Associates, P.A., Shawnee Mission, Kansas: Gregory M. Fox, Ravi S. J. Singh, Lexie R. Ainley, Kiersten Bruce, Frank T. Yeager, Katherine Pippin. University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada: Michael Henry Brent, Bilgin Turhal, Ian Brown. Sabates Eye Centers Research Division, Kansas City, Missouri: Felix N. Sabates, Yin C. Chen, Gary S. Gallimore. Weill Cornell Medical College, New York, New York: Szilard Kiss, Anton Orlin, Susan P. Herder, Courtney Nichole Lenane, Tom Reeves, Andrzej Kozbial.

Disclaimer: Dr Bressler is the Editor and Dr Sun is the CME Editor of JAMA Ophthalmology, but they were not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: We thank Optos, PLC, which provided some equipment for the study. They were not compensated for this contribution.