Critical Dependence on Area in Relationship between ARMS2/HTRA1 Genotype and Faster Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report Number 33.

PURPOSE: To analyze ARMS2/HTRA1 as a risk factor for faster geographic atrophy (GA) enlargement according to (1) GA area and (2) contiguous enlargement versus progression to multifocality. DESIGN: Age-Related Eye Disease Study 2 (AREDS2) cohort analysis. PARTICIPANTS: Eyes with GA: 546 eyes of 406 participants. METHODS: Geographic atrophy area was measured from color fundus photographs at annual visits. Mixed-model regression of square root of GA area and proportional hazards regression of progression to multifocality were analyzed by ARMS2 genotype. MAIN OUTCOME MEASURES: Change in square root GA area and progression to multifocality. RESULTS: Geographic atrophy enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.224 mm/year (95% CI, 0.195-0.252 mm/year), 0.298 mm/year (95% CI, 0.271-0.324 mm/year), and 0.317 mm/year (95% CI, 0.279-0.355 mm/year), for 0 to 2 risk alleles, respectively. However, a significant interaction (P = 0.011) was observed between genotype and baseline area. In eyes with very small area (< 1.9 mm2), enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.193 mm/year (95% CI, 0.162-0.225 mm/year) versus 0.304 mm/year (95% CI, 0.280-0.329 mm/year) for 0 versus 1 to 2 risk alleles, respectively. With moderately small (1.9-3.8 mm2) or medium to large (≥ 3.8 mm2) area, enlargement was not significantly faster with ARMS2 risk alleles (P = 0.66 and P = 0.70, respectively). In nonmultifocal GA, enlargement was significantly faster with ARMS2 risk alleles (P = 0.001) at 0.175 mm/year (95% CI, 0.142-0.209 mm/year), 0.226 mm/year (95% CI, 0.193-0.259 mm/year), and 0.287 mm/year (95% CI, 0.237-0.337 mm/year) with 0 to 2 risk alleles, respectively. ARMS2 genotype was not associated significantly with progression to multifocal GA. CONCLUSIONS: The relationship between ARMS2/HTRA1 genotype and faster GA enlargement depends critically on GA area: risk alleles represent a strong risk factor for faster enlargement only in eyes with very small area. They increase the growth rate more through contiguous enlargement than progression to multifocality. ARMS2/HTRA1 genotype is more important in increasing risk of progression to GA and initial GA enlargement (contiguously) than in subsequent enlargement or progression to multifocality. These findings may explain some discrepancies between previous studies and have implications for both research and clinical practice. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Neuroprotection for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.

Supplemental nutrition for retinal health: Evidence based analysis of commercial preparations in India.

Purpose: Antioxidants have been lately postulated as supportive and prophylactic supplements for various retinal disorders, especially age-related macular degeneration (AMD). Forty-eight brands of such supplements containing lutein and zeaxanthin are available in India. The aim of the study was to assess the market leaders in supplements for ophthalmology in view of AREDS recommendations. Methods: Descriptive review of top-selling supplements for eye health were compared to the contents of the AREDS-recommended levels. Results: None of the top 10 selling brands had exact or near similar composition as recommended in the AREDS-2 study, which is the most widely accepted level-1 evidence in AMD prevention. Conclusion: Physicians prescribing these antioxidants, especially for the prevention of advanced AMD, should be vigilant and aware of the contents of the prescribed brands.

Adherence to a Mediterranean Diet and Geographic Atrophy Enlargement Rate: Age-Related Eye Disease Study 2 Report 29.

PURPOSE: To determine whether closer adherence to a Mediterranean diet was associated with altered speed of geographic atrophy (GA) enlargement. DESIGN: Post hoc analysis of a cohort within the Age-Related Eye Disease Study 2. PARTICIPANTS: The study included 1155 eyes (850 participants; mean age, 74.9 years) with GA at 2 or more visits. METHODS: Geographic atrophy area was measured from color fundus photographs at annual visits. An alternative Mediterranean Diet index (aMedi) was calculated for each participant by food frequency questionnaire. Mixed-model regression of square root GA area was performed by aMedi. MAIN OUTCOME MEASURES: Change in square root of GA area over time. RESULTS: Over a mean follow-up of 3.1 years, the mean GA enlargement rate was 0.282 mm/year (95% confidence interval, 0.270-0.293). Enlargement was significantly slower in those with higher aMedi at 0.256 mm/year (0.236-0.276), 0.290 (0.268-0.311), and 0.298 (0.280-0.317; P = 0.008) for aMedi tertiles 3, 2, and 1, respectively. Of the 9 aMedi components considered separately, significant differences in enlargement rate were observed for 4 (whole fruit [P = 0.0004], red meat [P = 0.0002], alcohol [P = 0.006], and monounsaturated fatty acid to saturated fatty acid ratio ([MUFA:SFA] [P = 0.040]) but not for fish (P = 0.14). Enlargement was slower in those with higher whole fruit, lower red meat, moderate alcohol, and higher MUFA:SFA intake. In the 768 eyes with noncentral GA, aMedi was not associated with slower progression to central involvement: hazard ratios were 1.11 (0.83-1.48) and 0.95 (0.71-1.26) for tertiles 2 and 3, respectively. CONCLUSIONS: A Mediterranean-type diet was associated with slower GA enlargement. Diet patterns like this may therefore lead to clinically meaningful delays in vision loss. Several components seemed to contribute most to this association in a pattern that differed from those most associated with decreased progression to GA. Hence, the Mediterranean diet is associated with protection against both faster progression to GA and faster enlargement of GA but for partially distinct reasons. These findings may help inform evidence-based dietary recommendations. Understanding the mechanisms responsible may provide insights into the underlying biology and lead to the development of nutritional supplements.

Landmark trials in ophthalmology: The age-related eye diseases studies.

BACKGROUND: There are many landmark clinical trials in ophthalmology, the context of which provide a more relevant understanding of their results. The Age-related Eye Diseases (AREDS) studies were conducted in a large population to understand the effect of nutritional supplements on the progress of age-related macular degeneration. PURPOSE: This instructional video is being presented to familiarize the postgraduate residents as well as interested researchers of the details of the landmark AREDS studies. SYNOPSIS: The video describes the enrollment of participants, their demographics, the protocols of the studies, and the key results. HIGHLIGHTS: The AREDS formulations, the specific effects of key components of the formulations, and results of the trials that guide present day treatment guidelines are discussed. VIDEO LINK: https://youtu.be/SPsikgx8SCI.

Real-World Performance of a Self-Operated Home Monitoring System for Early Detection of Neovascular Age-Related Macular Degeneration.

The real-world performance of a home telemonitoring strategy (ForeseeHome AMD Monitoring System®, Notal Vision, Inc.,Manassas VA, USA) was evaluated and compared to the device arm of the AREDS2-HOME study among patients with intermediate AMD (iAMD) who converted to neovascular AMD (nAMD). All patients with confirmed conversion to nAMD who used the home monitoring system from 10/2009 through 9/2018 were identified by Notal Vision Diagnostic Clinic's medical records. Selected outcome variables were evaluated, including visual acuity (VA) at baseline and at conversion, and change in visual acuity (VA) from baseline to time of conversion. In total, 8991 patients performed 3,200,999 tests at a frequency of 5.6 ± 3.2 times/week. The 306 eyes that converted from iAMD to nAMD over the study period (a 2.7% annual rate) were included in the analyses. There was a median (interquartile range) change of -3.0 (0.0-(-10.0)) letters among converted eyes, 81% [95% confidence interval (72-88%)] maintained a VA ≥ 20/40 at the time of conversion, while 69% of the conversion detections were triggered by system alerts. The real-world performance of an at-home testing strategy was similar to that reported for the device arm of the AREDS2-HOME study. The home telemonitoring system can markedly increase early detection of conversion to nAMD.

Outcome of Off-Label AREDS 2 Supplementation for the Treatment of Macular Degeneration in Non-Proliferative Idiopathic Type 2 Macular Telangiectasia.

PURPOSE: To evaluate if off-label Age-Related Eye Disease Study 2 (AREDS2) supplementation prevents visual and anatomical deterioration in non-proliferative Idiopathic Macular Telangiectasia Type 2 (IMT2). PATIENTS AND METHODS: This is a single-center retrospective, comparative study of 82 IMT2 eyes treated with AREDS2 from January 1st, 2013 to January 1st, 2018. The study analysis consisted of a non-comparative arm, which included all AREDS2 eyes, and a comparative arm (27 AREDS2 and 42 untreated eyes) that only included eyes with complete follow-up data. Eyes were evaluated at baseline, 12 and 24 months. Better/worse eye sub-analysis was performed in the comparative study arm. Primary outcomes were best corrected visual acuity (BCVA) and optical coherence tomography (OCT) anatomical characteristics including largest cavitation diameter, central macular thickness (CMT), and length of ellipsoid zone (EZ) loss at 24 months. RESULTS: In the non-comparative arm, AREDS2 eyes showed stable BCVA (0.28 ± 0.18 logMAR at baseline vs 0.26 ± 0.19 logMAR at 24 months; p = 0.35) and OCT anatomical features after 24 months of supplementation. In the comparative arm, BCVA mean difference was greater for untreated eyes at 24 months (-0.09 ± 0.15 vs 0.03 ± 0.11 logMAR; p = <0.001). AREDS2 eyes had decreased cavitary diameter and EZ loss compared to untreated eyes at the study endpoint (p = 0.01 and p = 0.02, respectively). CMT remained stable for both cohorts throughout the study. For better/worse eye analysis, untreated eyes had worse BCVA at 24 months in both better and worse eyes (both p = 0.01). For anatomical outcomes, increases in both EZ loss (p = 0.04) and cavitary diameter (p = 0.001) among untreated eyes were only significant for eyes with worse baseline BCVA. CONCLUSION: Our results suggest that off-label AREDS2 supplementation in non-proliferative IMT2 may prevent anatomical and visual deterioration in a subset of eyes.

Patient Use of Dietary Supplements, Home Monitoring, or Genetic Testing for Nonneovascular Age-Related Macular Degeneration.

Purpose: This work evaluated the use and type of dietary supplements and home monitoring for nonneovascular age-related macular degeneration (AMD), as well as the prevalence of genetic testing among patients with AMD. Methods: A cross-sectional study was conducted of 129 participants older than 50 years who completed self-administered questionnaires regarding usage and type of dietary supplements and home monitoring, as well as the participants' use of genetic testing for AMD. Results: Of 91 participants with AMD, 83 (91.2%) took vitamins, including 55 (60.4%) who used an Age-Related Eye Disease Study (AREDS) or AREDS2 formulation. Of 38 without AMD, 31 (81.6%) took vitamins (difference from participants with AMD = 9.6% [95% CI, 0%-23.2%]), including 2 on an AREDS formulation. Among 82 participants with AMD who were AREDS candidates (intermediate or advanced AMD in 1 or both eyes), 51 (62.2%; 95% CI, 51.7%-72.7%) took an AREDS or AREDS2 formulation, and 31 (37.8%) did not (5 were unsure). Additionally, 50 (61.0%; 95% CI, 50.4%-71.6%) AREDS candidates did some type of home monitoring. Only 1 (1.2%; 95% CI, 0%-3.6%) underwent genetic testing for AMD. Among 9 with AMD who were not AREDS candidates, 4 (44.4%) used an AREDS formulation, 4 (44.4%) did not, and 1 (11.1%) was unsure; only 1 (11.1%) of these 9 performed home monitoring. Conclusions: Despite similar results from past surveys and AREDS2 data supporting supplement use in 2013 and home monitoring in 2014, these findings suggest about one-third of AREDS candidates do not do so, providing further support for improving education regarding appropriate supplement and home monitoring usage. Genetic testing for AMD also appears infrequent.

Improving Interpretability in Machine Diagnosis: Detection of Geographic Atrophy in OCT Scans.

Purpose: Manually identifying geographic atrophy (GA) presence and location on OCT volume scans can be challenging and time consuming. This study developed a deep learning model simultaneously (1) to perform automated detection of GA presence or absence from OCT volume scans and (2) to provide interpretability by demonstrating which regions of which B-scans show GA. Design: Med-XAI-Net, an interpretable deep learning model was developed to detect GA presence or absence from OCT volume scans using only volume scan labels, as well as to interpret the most relevant B-scans and B-scan regions. Participants: One thousand two hundred eighty-four OCT volume scans (each containing 100 B-scans) from 311 participants, including 321 volumes with GA and 963 volumes without GA. Methods: Med-XAI-Net simulates the human diagnostic process by using a region-attention module to locate the most relevant region in each B-scan, followed by an image-attention module to select the most relevant B-scans for classifying GA presence or absence in each OCT volume scan. Med-XAI-Net was trained and tested (80% and 20% participants, respectively) using gold standard volume scan labels from human expert graders. Main Outcome Measures: Accuracy, area under the receiver operating characteristic (ROC) curve, F1 score, sensitivity, and specificity. Results: In the detection of GA presence or absence, Med-XAI-Net obtained superior performance (91.5%, 93.5%, 82.3%, 82.8%, and 94.6% on accuracy, area under the ROC curve, F1 score, sensitivity, and specificity, respectively) to that of 2 other state-of-the-art deep learning methods. The performance of ophthalmologists grading only the 5 B-scans selected by Med-XAI-Net as most relevant (95.7%, 95.4%, 91.2%, and 100%, respectively) was almost identical to that of ophthalmologists grading all volume scans (96.0%, 95.7%, 91.8%, and 100%, respectively). Even grading only 1 region in 1 B-scan, the ophthalmologists demonstrated moderately high performance (89.0%, 87.4%, 77.6%, and 100%, respectively). Conclusions: Despite using ground truth labels during training at the volume scan level only, Med-XAI-Net was effective in locating GA in B-scans and selecting relevant B-scans within each volume scan for GA diagnosis. These results illustrate the strengths of Med-XAI-Net in interpreting which regions and B-scans contribute to GA detection in the volume scan.

Visual Function and Macular Carotenoid Changes in Eyes with Retinal Drusen-An Open Label Randomized Controlled Trial to Compare a Micronized Lipid-Based Carotenoid Liquid Supplementation and AREDS-2 Formula.

PURPOSE: To compare the changes in visual and ocular parameters in individuals with retinal drusen who were treated with two commercially available nutritional supplements. METHODS: An open-label, single-center, randomized, parallel-treatment with an observational control group design was utilized. The treatment groups included individuals with fine retinal drusen sub-clinical age-related macular degeneration (AMD), while the control group consisted of ocular normal individuals. The treatment groups were randomly assigned to the micronized lipid-based carotenoid supplement, Lumega-Z (LM), or the PreserVision Age-Related Eye Disease Study 2 (AREDS-2) soft gel (PV). Visual performance was evaluated using the techniques of visual acuity, dark adaptation recovery and contrast sensitivity, at baseline, three months, and six months. Additionally, the macular pigment optical density (MPOD) was measured. The control group was not assigned any carotenoid supplement. The right eye and left eye results were analyzed separately. RESULTS: Seventy-nine participants were recruited for this study, of which 68 qualified and 56 participants had useable reliable data. Of the individuals who completed this study, 25 participants belonged to the LM group, 16 belonged to the PV group, and 15 to the control group. The LM group demonstrated statistically significant improvements in contrast sensitivity function (CSF) in both eyes at six months (p < 0.001). The LM group displayed a positive linear trend with treatment time in CSF (p < 0.001), with benefits visible after just three months of supplementation. Although there was a trend showing improvement in CSF in the PV group, the change was not significant after a Bonferroni-corrected p-value of p < 0.00625. Visual acuity, dark adaptation recovery and MPOD did not significantly improve in either treatment groups. CONCLUSION: The LM group demonstrated greater and faster benefits in visual performance as measured by CSF when compared to the PV group. This trial has been registered at clinicaltrials.gov (NCT03946085).

[Practical application of ophthalmic nutraceuticals in patients with dry form of age-related macular degeneration]. / Primenenie oftal'monutritsevtika pri «sukhoi¼ forme vozrastnoi makulyarnoi degeneratsii.

Development and progression of age-related macular degeneration (AMD) is associated with insufficiency of protective antioxidant systems of the body. Nutraceutical medications can positively affect the course of the disease and the visual functions of patients with AMD. PURPOSE: To conduct a placebo-controlled clinical monitoring of visual functions in patients with dry AMD while taking a drug Complex that corresponds to the AREDS 2 formula. MATERIAL AND METHODS: The study included 90 people in 3 equivalent parallel groups, two of which were represented by patients with AMD who took the Complex for 3-6 months or Placebo for 3 months. The third group included healthy subjects of the same age. In addition to standard eye examination, participants underwent evaluation of the macular pigment optical density (MPOD), spatial-frequency contrast sensitivity (CS), photostress test, and reading parameters on the Salzburg Reading Desk device. The changes of blood plasma antioxidant activity (AOA) were also evaluated in the main group. RESULTS: By day 90 of the study, patients of the main group showed statistically significant (p<0.001) growth of MPOD from 0.24±0.13 to 0.32±0.1, reduction of photostress recovery time from 68.2±17.8 to 57.3±17.5 seconds, improvement of high-spatial-frequency CS - from 25.0±8.2 to 30.6±6.8 dB, increase of near visual acuity logMAR from 0.22±0.04 to 0.19±0.03 and reading speed, and decrease of reading mistakes. Statistically significant (p<0.05) reduction of in AOA was seen during the observation period from 1.52±0.16 to 1.68±0.16. Patients of the main group who received the Complex for 180 days demonstrated additional improvements of visual functions. CONCLUSION: The drug Complex corresponding to the AREDS 2 formula contributes to a significant increase in MPOD, improvements of visual functions and overall antioxidant status of patients, which confirms the feasibility of its use in patients with dry AMD.

Long-term Results of Taking Anti-oxidant Nutritional Supplement in Intermediate Age-related Macular Degeneration

PURPOSE: We prospectively investigated clinical changes and long-term outcomes after administration of the drugs recommended by the Age-Related Eye Disease Study-2 to patients with intermediate age-related macular degeneration (AMD). METHODS: This prospective multicenter study enrolled 79 eyes of 55 patients taking lutein and zeaxanthin. The primary endpoint was contrast sensitivity; this was checked every 12 months for a total of 36 months after treatment commenced. The secondary endpoints were visual acuity, central macular thickness, and drusen volume; the latter two parameters were assessed using spectral domain optical coherence tomography. RESULTS: The mean patient age was 72.46 ± 7.16 years. Contrast sensitivity gradually improved at both three and six cycles per degree. The corrected visual acuity was 0.13 ± 0.14 logMAR and did not change significantly over the 36 months. Neither the central macular thickness nor drusen volume changed significantly. CONCLUSIONS: Contrast sensitivity markedly improved after treatment, improving vision and patient satisfaction. Visual acuity, central retinal thickness, and drusen volume did not deteriorate. Therefore, progression of AMD and visual function deterioration were halted.

The Age-Related Eye Disease 2 Study: Micronutrients in the Treatment of Macular Degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly. With an increasingly aged population worldwide, the need for the prevention of AMD is rising. Multiple studies investigating AMD with the use of animal models and cell culture have identified oxidative stress-related retinal damage as an important contributing factor. In general, diet is an excellent source of the antioxidants, vitamins, and minerals necessary for healthy living; moreover, the general public is often receptive to recommendations made by physicians and health care workers regarding diet and supplements as a means of empowering themselves to avoid common and worrisome ailments such as AMD, which has made epidemiologists and clinicians enthusiastic about dietary intervention studies. A wide variety of nutrients, such as minerals, vitamins, ω-3 (n-3) fatty acids, and various carotenoids, have been associated with reducing the risk of AMD. Initial results from the Age-Related Eye Disease Study (AREDS) indicated that supplementation with antioxidants (ß-carotene and vitamins C and E) and zinc was associated with a reduced risk of AMD progression. The AREDS2 follow-up study, designed to improve upon the earlier formulation, tested the addition of lutein, zeaxanthin, and ω-3 fatty acids. In this review, we examine the science behind the nutritional factors included in these interventional studies and the reasons for considering their inclusion to lower the rate of AMD progression.

Prevention and treatment of age-related macular degeneration: an update for pharmacists.

OBJECTIVE: Review the current recommendations for the prevention and treatment of age-related macular degeneration (AMD). DATA SOURCES: Articles indexed in PubMed (National Library of Medicine), the Cochrane Reviews and Trials, Dynamed, and Iowa Drug Information Service (IDIS) in the last 10 years using the key words macular degeneration, agerelated macular degeneration (AMD), AMD and treatment, AMD and prevention. STUDY SELECTION AND DATA EXTRACTION: Sixty-nine published papers were reviewed, and criteria supporting the primary objective were used to identify useful resources. DATA SYNTHESIS: The literature included practice guidelines, original research articles, review articles, product prescribing information, and supplement product information for the prevention and treatment of AMD. CONCLUSION: AMD is a leading cause of visual impairment in older adults. At present there is no cure for advanced AMD, but intravitreal vascular endothelial growth factor inhibitors minimize and even reverse vision loss in patients with AMD of the neovascular type. In the Age-Related Eye Disease Study (AREDS), participants with intermediate AMD who received a supplement combination of vitamins C and E, beta-carotene, and zinc had a greater delay in progression to advanced AMD than those participants who received a portion of these supplements. In the second AREDS, AREDS2, the addition of lutein + zeaxanthin, docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA), or lutein + zeaxanthin and DHA + EPA to the complete AREDS formulation did not further reduce the risk of progression to advanced AMD. Subgroup analyses indicated that additional research with lutein + zeaxanthin supplementation is warranted as it was beneficial in participants with low dietary intake of lutein + zeaxanthin. A formulation without beta-carotene may be best for most patients, especially smokers or former smokers. Health care professionals will want to consider patient-specific information before recommending ocular health supplements.

Evaluation of optimized digital fundus reflex photographs for lens opacities in the age-related eye disease study 2: AREDS2 report 7.

PURPOSE: We described the system for grading lens opacities using stereoscopic digital fundus reflex photographs in the Age-Related Eye Disease Study 2 (AREDS2) and compared reproducibility with the AREDS lens grading system, which used retroillumination film images. METHODS: Stereoscopic fundus reflex photographs were acquired in a standardized fashion at baseline and annually. Images were enhanced and evaluated in the red channel at a central reading center. Percentage involvement of cortical and posterior subcapsular (PSC) lens opacities within the central 5 mm diameter zone of a modified AREDS lens grid was estimated. Reproducibility was assessed for contemporaneous variability (ongoing, monthly regrade on 5% of submissions, n = 777 eyes) and temporal drift (regrading a subset of baseline photographs annually, n = 88). RESULTS: In the contemporaneous exercise, the agreement for presence of cortical opacities was 93% (κ = 0.86) and for PSC opacities it was 97% (κ = 0.83). Intraclass correlation (ICC) for area of central zone involvement was 0.95 for cortical and 0.99 for PSC opacities. Historic data for contemporaneous regrading of film-based images in AREDS showed an ICC of 0.94 for cortical and 0.82 for PSC. The final annual temporal drift exercise had a reproducibility of 95% for cortical and PSC opacities. CONCLUSIONS: Digital grading using fundus reflex images with image enhancing tools has reproducibility comparable to film-based retroillumination images, and may be useful for centralized objective lens opacity assessment in clinical trials using widely available fundus cameras. Red reflex images limit evaluation to cortical and PSC opacities, and do not permit assessment of nuclear opacities. (ClinicalTrials.gov number, NCT00345176.).