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.

Oral Antioxidant and Lutein/Zeaxanthin Supplements Slow Geographic Atrophy Progression to the Fovea in Age-Related Macular Degeneration.

PURPOSE: To determine whether oral micronutrient supplementation slows geographic atrophy (GA) progression in age-related macular degeneration (AMD). DESIGN: Post hoc analysis of Age-Related Eye Disease Study (AREDS) and AREDS2, multicenter randomized placebo-controlled trials of oral micronutrient supplementation, each with 2 × 2 factorial design. PARTICIPANTS: A total of 392 eyes (318 participants) with GA in AREDS and 1210 eyes (891 participants) with GA in AREDS2. METHODS: The AREDS participants were randomly assigned to oral antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg ß-carotene), 80 mg zinc, combination, or placebo. The AREDS2 participants were randomly assigned to 10 mg lutein/2 mg zeaxanthin, 350 mg docosahexaenoic acid/650 mg eicosapentaenoic acid, combination, or placebo. Consenting AREDS2 participants were also randomly assigned to alternative AREDS formulations: original; no beta-carotene; 25 mg zinc instead of 80 mg; both. MAIN OUTCOME MEASURES: (1) Change in GA proximity to central macula over time and (2) change in square root GA area over time, each measured from color fundus photographs at annual visits and analyzed by mixed-model regression according to randomized assignments. RESULTS: In AREDS eyes with noncentral GA (n = 208), proximity-based progression toward the central macula was significantly slower with randomization to antioxidants versus none, at 50.7 µm/year (95% confidence interval [CI], 38.0-63.4 µm/year) versus 72.9 µm/year (95% CI, 61.3-84.5 µm/year; P = 0.012), respectively. In AREDS2 eyes with noncentral GA, in participants assigned to AREDS antioxidants without ß-carotene (n = 325 eyes), proximity-based progression was significantly slower with randomization to lutein/zeaxanthin versus none, at 80.1 µm/year (95% CI, 60.9-99.3 µm/year) versus 114.4 µm/year (95% CI, 96.2-132.7 µm/year; P = 0.011), respectively. In AREDS eyes with any GA (n = 392), area-based progression was not significantly different with randomization to antioxidants versus none (P = 0.63). In AREDS2 eyes with any GA, in participants assigned to AREDS antioxidants without ß-carotene (n = 505 eyes), area-based progression was not significantly different with randomization to lutein/zeaxanthin versus none (P = 0.64). CONCLUSIONS: Oral micronutrient supplementation slowed GA progression toward the central macula, likely by augmenting the natural phenomenon of foveal sparing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

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.