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.

An Updated Simplified Severity Scale for Age-Related Macular Degeneration Incorporating Reticular Pseudodrusen: Age-Related Eye Disease Study Report Number 42.

PURPOSE: To update the Age-Related Eye Disease Study (AREDS) simplified severity scale for risk of late age-related macular degeneration (AMD), including incorporation of reticular pseudodrusen (RPD), and to perform external validation on the Age-Related Eye Disease Study 2 (AREDS2). DESIGN: Post hoc analysis of 2 clinical trial cohorts: AREDS and AREDS2. PARTICIPANTS: Participants with no late AMD in either eye at baseline in AREDS (n = 2719) and AREDS2 (n = 1472). METHODS: Five-year rates of progression to late AMD were calculated according to levels 0 to 4 on the simplified severity scale after 2 updates: (1) noncentral geographic atrophy (GA) considered part of the outcome, rather than a risk feature, and (2) scale separation according to RPD status (determined by validated deep learning grading of color fundus photographs). MAIN OUTCOME MEASURES: Five-year rate of progression to late AMD (defined as neovascular AMD or any GA). RESULTS: In the AREDS, after the first scale update, the 5-year rates of progression to late AMD for levels 0 to 4 were 0.3%, 4.5%, 12.9%, 32.2%, and 55.6%, respectively. As the final simplified severity scale, the 5-year progression rates for levels 0 to 4 were 0.3%, 4.3%, 11.6%, 26.7%, and 50.0%, respectively, for participants without RPD at baseline and 2.8%, 8.0%, 29.0%, 58.7%, and 72.2%, respectively, for participants with RPD at baseline. In external validation on the AREDS2, for levels 2 to 4, the progression rates were similar: 15.0%, 27.7%, and 45.7% (RPD absent) and 26.2%, 46.0%, and 73.0% (RPD present), respectively. CONCLUSIONS: The AREDS AMD simplified severity scale has been modernized with 2 important updates. The new scale for individuals without RPD has 5-year progression rates of approximately 0.5%, 4%, 12%, 25%, and 50%, such that the rates on the original scale remain accurate. The new scale for individuals with RPD has 5-year progression rates of approximately 3%, 8%, 30%, 60%, and 70%, that is, approximately double for most levels. This scale fits updated definitions of late AMD, has increased prognostic accuracy, seems generalizable to similar populations, but remains simple for broad risk categorization. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Reticular Pseudodrusen Status, ARMS2/HTRA1 Genotype, and Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report 32.

PURPOSE: To determine whether reticular pseudodrusen (RPD) status, ARMS2/HTRA1 genotype, or both are associated with altered geographic atrophy (GA) enlargement rate and to analyze potential mediation of genetic effects by RPD status. DESIGN: Post hoc analysis of an Age-Related Eye Disease Study 2 cohort. PARTICIPANTS: Eyes with GA: n = 771 from 563 participants. METHODS: Geographic atrophy area was measured from fundus photographs at annual visits. Reticular pseudodrusen presence was graded from fundus autofluorescence images. Mixed-model regression of square root of GA area was performed by RPD status, ARMS2 genotype, or both. MAIN OUTCOME MEASURES: Change in square root of GA area. RESULTS: Geographic atrophy enlargement was significantly faster in eyes with RPD (P < 0.0001): 0.379 mm/year (95% confidence interval [CI], 0.329-0.430 mm/year) versus 0.273 mm/year (95% CI, 0.256-0.289 mm/year). Enlargement was also significantly faster in individuals carrying ARMS2 risk alleles (P < 0.0001): 0.224 mm/year (95% CI, 0.198-0.250 mm/year), 0.287 mm/year (95% CI, 0.263-0.310 mm/year), and 0.307 mm/year (95% CI, 0.273-0.341 mm/year) for 0, 1, and 2, respectively. In mediation analysis, the direct effect of ARMS2 genotype was 0.074 mm/year (95% CI, 0.009-0.139 mm/year), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI, -0.006 to 0.009 mm/year). In eyes with incident GA, RPD presence was not associated with an altered likelihood of central involvement (P = 0.29) or multifocality (P = 0.16) at incidence. In eyes with incident noncentral GA, RPD presence was associated with faster GA progression to the central macula (P = 0.009): 157 µm/year (95% CI, 126-188 µm/year) versus 111 µm/year (95% CI, 97-125 µm/year). Similar findings were observed in the Age-Related Eye Disease Study. CONCLUSIONS: Geographic atrophy enlargement is faster in eyes with RPD and in individuals carrying ARMS2/HTRA1 risk alleles. However, RPD status does not mediate the association between ARMS2/HTRA1 genotype and faster enlargement. Reticular pseudodrusen presence and ARMS2/HTRA1 genotype are relatively independent risk factors, operating by distinct mechanisms. Reticular pseudodrusen presence does not predict central involvement or multifocality at GA incidence but is associated with faster progression toward the central macula. Reticular pseudodrusen status should be considered for improved predictions of enlargement rate. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30.

PURPOSE: To analyze reticular pseudodrusen (RPD) as an independent risk factor for progression to late age-related macular degeneration (AMD), alongside traditional macular risk factors (soft drusen and pigmentary abnormalities) considered simultaneously. DESIGN: Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants). METHODS: Color fundus photographs (CFPs) from annual visits were graded for soft drusen, pigmentary abnormalities, and late AMD. Presence of RPD was from grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFPs (AREDS). Proportional hazards regression analyses were performed, considering AREDS AMD severity scales (modified simplified severity scale [person] and 9-step scale [eye]) and RPD presence simultaneously. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), and neovascular AMD. RESULTS: In AREDS, for late AMD analyses by person, in a model considering the simplified severity scale simultaneously, RPD presence was associated with a higher risk of progression: hazard ratio (HR), 2.15 (95% confidence interval [CI], 1.75-2.64). However, the risk associated with RPD presence differed at different severity scale levels: HR, 3.23 (95% CI, 1.60-6.51), HR, 3.81 (95% CI, 2.38-6.10), HR, 2.28 (95% CI, 1.59-3.27), and HR, 1.64 (95% CI, 1.20-2.24), at levels 0-1, 2, 3, and 4, respectively. Considering the 9-step scale (by eye), RPD presence was associated with higher risk: HR, 2.54 (95% CI, 2.07-3.13). The HRs were 5.11 (95% CI, 3.93-6.66) at levels 1-6 and 1.78 (95% CI, 1.43-2.22) at levels 7 and 8. In AREDS2, by person, RPD presence was not associated with higher risk: HR, 1.18 (95% CI, 0.90-1.56); by eye, it was HR, 1.57 (95% CI, 1.31-1.89). In both cohorts, RPD presence carried a higher risk for GA than neovascular AMD. CONCLUSIONS: Reticular pseudodrusen represent an important risk factor for progression to late AMD, particularly GA. However, the added risk varies markedly by severity level, with highly increased risk at lower/moderate levels and less increased risk at higher levels. Reticular pseudodrusen status should be included in updated AMD classification systems, risk calculators, and clinical trials.

Artificial Intelligence Algorithms in Diabetic Retinopathy Screening.

PURPOSE OF REVIEW: In this review, we focus on artificial intelligence (AI) algorithms for diabetic retinopathy (DR) screening and risk stratification and factors to consider when implementing AI algorithms in the clinic. RECENT FINDINGS: AI algorithms have been adopted, and have received regulatory approval, for automated detection of referable DR with clinically acceptable diagnostic performance. While these metrics are an important first step, performance metrics that go beyond measures of technical accuracy are needed to fully evaluate the impact of AI algorithm on patient outcomes. Recent advances in AI present an exciting opportunity to improve patient care. Using DR as an example, we have reviewed factors to consider in the implementation of AI algorithms in real-world clinical practice. These include real-world evaluation of safety, efficacy, and equity (bias); impact on patient outcomes; ethical, logistical, and regulatory factors.

Disease-modifying effects of ranibizumab for central retinal vein occlusion.

PURPOSE: To identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes. METHODS: A post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy. RESULTS: At 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: - 1.17 [sham], - 2.37 [ranibizumab 0.3 mg], - 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups. CONCLUSIONS: Ranibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO.

Retinal Specialist versus Artificial Intelligence Detection of Retinal Fluid from OCT: Age-Related Eye Disease Study 2: 10-Year Follow-On Study.

PURPOSE: To evaluate the performance of retinal specialists in detecting retinal fluid presence in spectral domain OCT (SD-OCT) scans from eyes with age-related macular degeneration (AMD) and compare performance with an artificial intelligence algorithm. DESIGN: Prospective comparison of retinal fluid grades from human retinal specialists and the Notal OCT Analyzer (NOA) on SD-OCT scans from 2 common devices. PARTICIPANTS: A total of 1127 eyes of 651 Age-Related Eye Disease Study 2 10-year Follow-On Study (AREDS2-10Y) participants with SD-OCT scans graded by reading center graders (as the ground truth). METHODS: The AREDS2-10Y investigators graded each SD-OCT scan for the presence/absence of intraretinal and subretinal fluid. Separately, the same scans were graded by the NOA. MAIN OUTCOME MEASURES: Accuracy (primary), sensitivity, specificity, precision, and F1-score. RESULTS: Of the 1127 eyes, retinal fluid was present in 32.8%. For detecting retinal fluid, the investigators had an accuracy of 0.805 (95% confidence interval [CI], 0.780-0.828), a sensitivity of 0.468 (95% CI, 0.416-0.520), a specificity of 0.970 (95% CI, 0.955-0.981). The NOA metrics were 0.851 (95% CI, 0.829-0.871), 0.822 (95% CI, 0.779-0.859), 0.865 (95% CI, 0.839-0.889), respectively. For detecting intraretinal fluid, the investigator metrics were 0.815 (95% CI, 0.792-0.837), 0.403 (95% CI, 0.349-0.459), and 0.978 (95% CI, 0.966-0.987); the NOA metrics were 0.877 (95% CI, 0.857-0.896), 0.763 (95% CI, 0.713-0.808), and 0.922 (95% CI, 0.902-0.940), respectively. For detecting subretinal fluid, the investigator metrics were 0.946 (95% CI, 0.931-0.958), 0.583 (95% CI, 0.471-0.690), and 0.973 (95% CI, 0.962-0.982); the NOA metrics were 0.863 (95% CI, 0.842-0.882), 0.940 (95% CI, 0.867-0.980), and 0.857 (95% CI, 0.835-0.877), respectively. CONCLUSIONS: In this large and challenging sample of SD-OCT scans obtained with 2 common devices, retinal specialists had imperfect accuracy and low sensitivity in detecting retinal fluid. This was particularly true for intraretinal fluid and difficult cases (with lower fluid volumes appearing on fewer B-scans). Artificial intelligence-based detection achieved a higher level of accuracy. This software tool could assist physicians in detecting retinal fluid, which is important for diagnostic, re-treatment, and prognostic tasks.

Deep Learning Automated Detection of Reticular Pseudodrusen from Fundus Autofluorescence Images or Color Fundus Photographs in AREDS2.

PURPOSE: To develop deep learning models for detecting reticular pseudodrusen (RPD) using fundus autofluorescence (FAF) images or, alternatively, color fundus photographs (CFP) in the context of age-related macular degeneration (AMD). DESIGN: Application of deep learning models to the Age-Related Eye Disease Study 2 (AREDS2) dataset. PARTICIPANTS: FAF and CFP images (n = 11 535) from 2450 AREDS2 participants. Gold standard labels from reading center grading of the FAF images were transferred to the corresponding CFP images. METHODS: A deep learning model was trained to detect RPD in eyes with intermediate to late AMD using FAF images (FAF model). Using label transfer from FAF to CFP images, a deep learning model was trained to detect RPD from CFP (CFP model). Performance was compared with 4 ophthalmologists using a random subset from the full test set. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC), κ value, accuracy, and F1 score. RESULTS: The FAF model had an AUC of 0.939 (95% confidence interval [CI], 0.927-0.950), a κ value of 0.718 (95% CI, 0.685-0.751), and accuracy of 0.899 (95% CI, 0.887-0.911). The CFP model showed equivalent values of 0.832 (95% CI, 0.812-0.851), 0.470 (95% CI, 0.426-0.511), and 0.809 (95% CI, 0.793-0.825), respectively. The FAF model demonstrated superior performance to 4 ophthalmologists, showing a higher κ value of 0.789 (95% CI, 0.675-0.875) versus a range of 0.367 to 0.756 and higher accuracy of 0.937 (95% CI, 0.907-0.963) versus a range of 0.696 to 0.933. The CFP model demonstrated substantially superior performance to 4 ophthalmologists, showing a higher κ value of 0.471 (95% CI, 0.330-0.606) versus a range of 0.105 to 0.180 and higher accuracy of 0.844 (95% CI, 0.798-0.886) versus a range of 0.717 to 0.814. CONCLUSIONS: Deep learning-enabled automated detection of RPD presence from FAF images achieved a high level of accuracy, equal or superior to that of ophthalmologists. Automated RPD detection using CFP achieved a lower accuracy that still surpassed that of ophthalmologists. Deep learning models can assist, and even augment, the detection of this clinically important AMD-associated lesion.

Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 Report 21.

PURPOSE: To determine the prevalence of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD), assess the role of RPD as an independent risk factor for late AMD development, and evaluate genetic association with RPD. DESIGN: Prospective cohort study. PARTICIPANTS: Participants with intermediate AMD in 1 or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplement. METHODS: Fundus autofluorescence (FAF) images from a subset of AREDS2 participants were evaluated at annual visits for presence of RPD. Six single nucleotide polymorphisms-rs10490924 (ARMS2), rs1061170 (CFH), rs2230199 (C3), rs116503776 and rs114254831 (C2/CFB), and rs943080 (VEGF-A)-and the genetic risk score (GRS) were assessed for association with RPD. Development of late AMD, defined as geographic atrophy (GA) or neovascular AMD (NVAMD), was identified. MAIN OUTCOME MEASURES: Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD. RESULTS: The FAF images were evaluated for 5021 eyes (2516 participants). Reticular pseudodrusen were seen in 1186 eyes (24% of eyes, 29% of participants). Prevalence of RPD varied with baseline AREDS AMD severity level: 6% in early AMD (n = 458), 26% in intermediate AMD (n = 2606), 36% in GA (n = 682), and 19% in NVAMD (n = 1246). Mean age of participants with RPD was 79 years (standard deviation [SD], 7) and 75 years (SD, 8) in those without RPD (P < 0.0001). Reticular pseudodrusen were more frequent in female participants (65% RPD vs. 53% no RPD). Odds ratio adjusted for baseline age, gender, race, educational status, smoking, and AMD severity level for 1710 eyes at risk of developing late AMD at the next annual visit was 2.42 (95% confidence interval [CI], 1.80-3.24; P < 0.001) for GA and 1.21 (95% CI, 0.87-1.7; P = 0.26) for NVAMD. Presence of RPD was significantly associated with higher GRS (P < 0.0001) and ARMS2 risk alleles (P < 0.0001) and, at a nominal level, with C3 risk alleles (P = 0.04) and CFH risk alleles (P = 0.048 for homozygotes). CONCLUSIONS: Participants with RPD have an increased risk of progression to GA but not NVAMD. ARMS2 risk alleles and higher GRS were associated with the presence of RPD. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis.

Natural History of Drusenoid Pigment Epithelial Detachment Associated with Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report No. 17.

PURPOSE: To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). DESIGN: Retrospective analysis of a prospective cohort study. PARTICIPANTS: Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. METHODS: Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 µm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan-Meier analyses and multivariable proportional hazard regressions were performed. MAIN OUTCOME MEASURES: Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. RESULTS: Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98-2.82; P < 0.001); 67% of eyes progressed to late AMD 5 years after DPED detection. Drusenoid pigment epithelial detachment was associated with increased risk of ≥3 lines of VA loss (HR, 3.08; CI, 2.41-3.93; P < 0.001) with 46% of eyes experiencing vision loss at 5 years (with or without progression to late AMD). ARMS2 risk alleles (1 vs. 0: HR, 2.72, CI, 1.58-4.70; 2 vs. 0: HR, 3.16, CI, 1.60-6.21, P < 0.001) and increasing GRS group (4 vs. 1) (HR, 12.17, CI, 3.66-40.45, P < 0.001) were significantly associated with DPED development in AREDS. There were no significant genetic results in AREDS2. CONCLUSIONS: This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16.

PURPOSE: To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. DESIGN: Prospective cohort study within a controlled clinical trial. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. METHODS: Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. MAIN OUTCOME MEASURES: (1) Presence or development of GA; (2) change in the square root of GA area over time. RESULTS: At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes. CONCLUSIONS: Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group.

PURPOSE: To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen). DESIGN: Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study. PARTICIPANTS: Participants from prospective studies. METHODS: The 200° pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions. MAIN OUTCOME MEASURES: Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities. RESULTS: A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls. CONCLUSIONS: Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas pigment changes and features of advanced AMD are less frequent. Age-related macular degeneration may be more than a "macular" condition but one that involves the entire retina. Future longitudinal studies of peripheral changes in AMD and their impact on visual function may contribute to understanding AMD pathogenesis.

Evaluation of Geographic Atrophy from Color Photographs and Fundus Autofluorescence Images: Age-Related Eye Disease Study 2 Report Number 11.

PURPOSE: To compare measurements of area of geographic atrophy (GA) and change in GA area from color photographs and fundus autofluorescence (FAF) images. DESIGN: The Age-Related Eye Disease Study 2 (AREDS2) was a prospective multicenter randomized clinical trial evaluating progression of dry age-related macular degeneration (AMD) using color photographs at annual visits over a 5-year study period. The FAF images were acquired in a subset of participants who joined the FAF ancillary study at any of the annual visits over the study period. PARTICIPANTS: The AREDS2 FAF ancillary study included 8070 corresponding color and FAF visits of 2202 participants with variable follow-up. METHODS: Corresponding color and FAF images were independently evaluated at a central reading center for GA area measurement, lesion growth, and involvement of the macula center. MAIN OUTCOME MEASURES: Presence, area, growth rate of GA, and involvement of center of macula from color and FAF images. RESULTS: Hypoautofluorescence was visible in 2048 visits (25.4%). Agreement for the presence of GA between the 2 modalities had a kappa of 0.79, with 23% of visits with hypoautofluorescence not presenting with GA on color photographs. Percentage agreement for GA presence ranged from 43% at baseline to 81% at year 5 with improving agreement over time. The mean difference in GA area between the 2 modalities was 0.5 mm2, with larger areas on FAF. Growth rate of GA was 1.45 mm2 from color photographs and 1.43 mm2 from FAF images. The center of the macula was involved in 51% of color photographs and 56% with FAF images. CONCLUSIONS: Geographic atrophy may be detected earlier by the use of FAF images, but over the course of the study, the 2 modalities become comparable. Progression of GA area is comparable between color photographs and FAF images, but evaluating involvement of the center of the macula may differ, probably because of macular pigmentation blocking autofluorescence.

Effects of intravitreal ranibizumab on retinal hard exudate in diabetic macular edema: findings from the RIDE and RISE phase III clinical trials.

PURPOSE: To evaluate the effect of monthly intravitreal ranibizumab on hard exudate (HE) area and the impact of HE on visual acuity (VA) outcomes in diabetic macular edema (DME) patients using data from 2 phase III clinical trials. DESIGN: Exploratory analyses of phase III, randomized, double-masked, sham-controlled, multicenter clinical trials. PARTICIPANTS: Adults with DME, baseline best-corrected VA 20/40 to 20/320 Snellen equivalent, and central foveal thickness of ≥275 µm. METHODS: Between the 2 studies, 759 patients with DME were randomized to receive monthly 0.3 or 0.5 mg intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or sham injections. MAIN OUTCOME MEASURES: Hard exudate area was assessed from color fundus stereophotographs both on an ordinal scale and using continuous estimates of areas within the Early Treatment Diabetic Retinopathy Study grid. RESULTS: Data from 739 eyes were available for analysis. Mean baseline HE area was similar across treatment groups, ranging from 0.65 to 0.82 mm(2). Through month 24, the percentage of eyes without HE increased from 20.9% to 36.3% in the sham group and from 22.1% to 61.3% and 23.6% to 62.0% in the ranibizumab 0.3-mg and 0.5-mg groups, respectively. Resolution of HE became apparent sometime after month 6 in ranibizumab-treated eyes. At baseline, there was no meaningful correlation between VA and presence or absence of HE. After baseline, there also was no consistent correlation between presence or absence of HE and change in VA over time. CONCLUSIONS: In this exploratory analysis, monthly intravitreal ranibizumab resulted in significantly greater reduction of HE area compared with sham (P < 0.0001). In contrast to the rapid effects of ranibizumab on macular edema, changes in HE area were more gradual. Contrary to prior expectations, the presence and area of HE did not increase as DME resolved (either in the ranibizumab or sham groups). Importantly, baseline VA was not correlated with presence of HE, nor was the therapeutic benefit of ranibizumab on VA affected negatively by the presence of HE. These data suggest that in the context of intravitreal anti-vascular endothelial growth factor therapy, the presence of HE is not a prognostic indicator of poor visual outcomes.

Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy.

PURPOSE: To assess the effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity when administered for up to 3 years, evaluate the effect of delayed initiation of ranibizumab therapy on DR severity, and identify baseline patient characteristics associated with the development of proliferative DR (PDR). DESIGN: Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials. PARTICIPANTS: Adults with diabetic macular edema (DME) (N = 759), baseline best-corrected visual acuity 20/40 to 20/320 Snellen equivalent, and central foveal thickness ≥275 µm. METHODS: Patients were randomized to monthly 0.3 or 0.5 mg ranibizumab or sham injections. Sham participants could switch to 0.5 mg ranibizumab during the third year (sham/0.5 mg crossover). Baseline risk factors were evaluated to explore potential associations with development of PDR. Time to first development of PDR was analyzed by Kaplan-Meier methods to calculate cumulative probabilities by group. MAIN OUTCOME MEASURES: Study eye change on the Early Treatment Diabetic Retinopathy Study severity scale and a composite clinical outcome evaluating progression to PDR based on photographic changes plus clinically important events defining PDR. RESULTS: At month 36, a greater proportion of ranibizumab-treated eyes had ≥2- or ≥3-step DR improvement compared with sham/0.5 mg crossover. A ≥3-step improvement was achieved at 36 months by 3.3%, 15.0%, and 13.2% of sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab-treated eyes, respectively (P < 0.0001). Through 36 months, 39.1% of eyes in the sham/0.5 mg group developed PDR, as measured by composite outcome, compared with 18.3% and 17.1% of eyes treated with 0.3 or 0.5 mg ranibizumab, respectively. The presence of macular capillary nonperfusion at baseline seems to be associated with progression to PDR in ranibizumab-treated eyes but did not meaningfully influence visual acuity improvement in eyes with DME after ranibizumab therapy. CONCLUSIONS: Ranibizumab, as administered to patients with DME for 12 to 36 months in these studies, can both improve DR severity and prevent worsening. Prolonged delays in initiation of ranibizumab therapy may limit this therapeutic effect. Although uncommon, the development of PDR still occurs in a small percentage of eyes undergoing anti-vascular endothelial growth factor therapy and may be related to the presence of macular nonperfusion.

Randomized trial of a home monitoring system for early detection of choroidal neovascularization home monitoring of the Eye (HOME) study.

OBJECTIVE: To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular degeneration-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. The main predictor of treatment outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment. DESIGN: Unmasked, controlled, randomized clinical trial. PARTICIPANTS: One thousand nine hundred and seventy participants 53 to 90 years of age at high risk of CNV developing were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 clinical centers. INTERVENTIONS: In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. In the device arm, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination. MAIN OUTCOME MEASURES: The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols. RESULTS: Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy. CONCLUSIONS: Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development, which increases the likelihood of better visual acuity results after intravitreal anti-VEGF therapy.

Comparison of Standard 7-Field, Clarus, and Optos Ultrawidefield Imaging Systems for Diabetic Retinopathy (COCO Study).

Purpose: The purpose of this study was to compare diabetic retinopathy (DR) severity levels assessed from 7 standard-field stereoscopic color photographs on a 35° fundus camera to both Clarus and Optos ultrawidefield color images. Design: Cross-sectional, comparative imaging study. Participants: Participants with DR imaged at a single-center retina practice. Methods: Participants were imaged on 3 cameras at a single visit with the Topcon 35° fundus camera, Clarus, and Optos. The DR Severity Scale (DRSS) level was determined within the 7-field (7F) area of each image set using the ETDRS scale. An additional global DRSS was assigned for both Clarus and Optos images using the entire visible retina. Weighted kappa (wκ) measured the agreement between cameras. Main Outcome Measures: The primary outcome was a 3-way comparison of DRSS level within the 7F area imaged on the 3 cameras. Secondary outcomes included a comparison of the DRSS obtained with standard 7F imaging to the global DRSS of Clarus and Optos and a comparison of the global DRSS between Clarus and Optos only. Results: Ninety-seven eyes (50 participants) were evaluated. Agreement within 1-step of ETDRS levels between standard 7F imaging and Clarus 7F was 90.1% (wκ = 0.65), and with Optos 7F in 85.9%, (wκ = 0.58). Agreement within 1-step between standard 7F imaging and Clarus global was 88.9% of eyes (wκ = 0.63), and Optos global was 85.7%, (wκ = 0.54). Agreement between Clarus and Optos global DR level within 1-step was 89.1% (wκ = 0.68). Intergrader agreement for the 7F ETDRS level was 96% for standard 7F imaging, 98% for Clarus, and 95.5% for Optos. Conclusions: These findings suggest that when evaluating the 7F area on Clarus and Optos, DR severity grades are comparable to standard 7F imaging. However, it is important to understand the unique attributes and differences of each fundus camera when changing the type of system used in a clinical setting due to upgrading equipment. Additionally, if the facility has access to > 1 device, there should not be an exchange between cameras for the same patient. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Local and Global Associations of Reticular Pseudodrusen in Age-Related Macular Degeneration.

PURPOSE: To investigate the spatial distribution of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD) and their correlation with functional measures, retinal thickness, and changes over time. DESIGN: Longitudinal, cohort study. PARTICIPANTS: Thirty-five participants with RPD and spectrum of AMD severity (including no AMD). METHODS: Multimodal imaging was graded by a reading center, including evaluation of color fundus imaging to assess AMD severity scores. Reticular pseudodrusen presence on OCT volumes was confirmed on en face imaging and the RPD extent was contoured on infrared images. One study eye per participant underwent rod-mediated dark adaptation, measuring rod intercept time (RIT) at 5° and, if needed, 12° superior to the fovea. MAIN OUTCOME MEASURES: The primary outcome was RIT and OCT thickness measures which were correlated with RPD area. RESULTS: A total of 51 eyes had ≥ 1 visit with RPD detected (mean follow-up, 2.19 ± 2.04 years; range, 0-5 years), totaling 169 eye-based visits with RPD. Of the 51 eyes with RPD, 5 (9.8%) developed geographic atrophy and 17 (33.3%) progressed to neovascular AMD. Larger RPD areas were detected more frequently in AMD severity scores 6-7. Reticular pseudodrusen area within an eye generally increased over time. The lesion distribution showed a predilection for the superior retina, especially the outer superior subfield of the ETDRS grid, with the central subfield having least involvement. Reticular pseudodrusen area was inversely correlated with central subfield thickness and positively correlated with RIT at 5° (P = 0.001; r2 = 0.01) and 12° (P = 0.004; r2 = 0.01). Rod-mediated dark adaptation at 5° reached the test ceiling in > 85% of visits, irrespective of RPD lesion presence/absence at the test location. Retinal thickness decreased monotonically, with the central subfield demonstrating the greatest percentage change over 5 years (Δ = -5.47%). CONCLUSIONS: In AMD, RPD involve predominantly the superior retina but can involve all ETDRS subfields and evolve over time. Eyes with RPD exhibit structural and functional impairments that can be measured beyond the boundaries of the RPD lesions, suggesting changes associated with RPD are associated with both local changes and a more widespread process. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Strong versus Weak Data Labeling for Artificial Intelligence Algorithms in the Measurement of Geographic Atrophy.

Purpose: To gain an understanding of data labeling requirements to train deep learning models for measurement of geographic atrophy (GA) with fundus autofluorescence (FAF) images. Design: Evaluation of artificial intelligence (AI) algorithms. Subjects: The Age-Related Eye Disease Study 2 (AREDS2) images were used for training and cross-validation, and GA clinical trial images were used for testing. Methods: Training data consisted of 2 sets of FAF images; 1 with area measurements only and no indication of GA location (Weakly labeled) and the second with GA segmentation masks (Strongly labeled). Main Outcome Measures: Bland-Altman plots and scatter plots were used to compare GA area measurement between ground truth and AI measurements. The Dice coefficient was used to compare accuracy of segmentation of the Strong model. Results: In the cross-validation AREDS2 data set (n = 601), the mean (standard deviation [SD]) area of GA measured by human grader, Weakly labeled AI model, and Strongly labeled AI model was 6.65 (6.3) mm2, 6.83 (6.29) mm2, and 6.58 (6.24) mm2, respectively. The mean difference between ground truth and AI was 0.18 mm2 (95% confidence interval, [CI], -7.57 to 7.92) for the Weakly labeled model and -0.07 mm2 (95% CI, -1.61 to 1.47) for the Strongly labeled model. With GlaxoSmithKline testing data (n = 156), the mean (SD) GA area was 9.79 (5.6) mm2, 8.82 (4.61) mm2, and 9.55 (5.66) mm2 for human grader, Strongly labeled AI model, and Weakly labeled AI model, respectively. The mean difference between ground truth and AI for the 2 models was -0.97 mm2 (95% CI, -4.36 to 2.41) and -0.24 mm2 (95% CI, -4.98 to 4.49), respectively. The Dice coefficient was 0.99 for intergrader agreement, 0.89 for the cross-validation data, and 0.92 for the testing data. Conclusions: Deep learning models can achieve reasonable accuracy even with Weakly labeled data. Training methods that integrate large volumes of Weakly labeled images with small number of Strongly labeled images offer a promising solution to overcome the burden of cost and time for data labeling. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.