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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. Prospective comparison of retinal fluid grades from human retinal specialists and the Notal OCT Analyzer (NOA) on SD-OCT scans from 2 common devices. 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). 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. Accuracy (primary), sensitivity, specificity, precision, and F1-score. 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. 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. [ABSTRACT FROM AUTHOR]

Purpose: The Age-Related Eye Disease Study (AREDS) demonstrated beneficial effects of oral supplementation with antioxidant vitamins and minerals on the development of advanced age-related macular degeneration (AMD) in persons with at least intermediate AMD (bilateral large drusen with or without pigment changes). Observational data suggest that other oral nutrient supplements might further reduce the risk of progression to advanced AMD. The primary purpose of the Age-Related Eye Disease Study 2 (AREDS2) is to evaluate the efficacy and safety of lutein plus zeaxanthin (L+Z) and/or ω-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation in reducing the risk of developing advanced AMD. The study also assesses the reduction in zinc and the omission of β-carotene from original AREDS formulation. Design: Multicenter, phase III, randomized, controlled clinical trial. Participants: Persons aged 50 to 85 with bilateral intermediate AMD or advanced AMD in 1 eye. Methods: All participants were randomly assigned to placebo (n = 1012), L+Z (10 mg/2 mg; n = 1044), ω-3 LCPUFAs (eicosapentaenoic acid + docosahexaenoic acid [650 mg/350 mg]; n = 1069), or the combination of L+Z and ω-3 LCPUFAs (n = 1078). All participants were offered a secondary randomization to 1 of 4 variations of the original AREDS formulation keeping vitamins C (500 mg) and E (400 IU) and copper (2 mg) unchanged while varying zinc and β-carotene as follows: Zinc remains at the original level (80 mg), lower only zinc to 25 mg, omit β-carotene only, or lower zinc to 25 mg and omit β-carotene. Main Outcome Measures: Progression to advanced AMD determined by centralized grading of annual fundus photographs. Results: We enrolled 4203 participants at 82 clinical centers located in the United States. Population characteristics at baseline were as follows: Mean age, 74 years; 57% female; 97% white; 7% current smokers; 19% with prior cardiovascular disease; and 44% and 50% taking statin-class cholesterol-lowering drugs and aspirin, respectively. Ocular characteristics include 59% with bilateral large drusen, 32% with advanced AMD in 1 eye and mean visual acuity of 20/32 in eyes without advanced AMD. Conclusions: This report presents the AREDS2 study design and the participants'' baseline demographic and ocular characteristics. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Objective To develop a simplified clinical scale defining risk categories for development of advanced age-related macular degeneration (AMD). Methods Following development of a detailed scale for individual eyes based on gradings of fundus photographs in the Age-Related Eye Disease Study, rates of progression to advanced AMD were assessed in cross-tabulations of presence or absence in each eye of 2 easily identified retinal abnormalities, drusen and pigment abnormalities. Large drusen and any pigment changes were particularly predictive of developing advanced AMD. Results The scoring system developed for patients assigns to each eye 1 risk factor for the presence of 1 or more large (≥125 μm, width of a large vein at disc margin) drusen and 1 risk factor for the presence of any pigment abnormality. Risk factors are summed across both eyes, yielding a 5-step scale (0-4) on which the approximate 5-year risk of developing advanced AMD in at least one eye increases in this easily remembered sequence: 0 factors, 0.5%; 1 factor, 3%; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50%. For persons with no large drusen, presence of intermediate drusen in both eyes is counted as 1 risk factor. Conclusion This simplified scale provides convenient risk categories for development of advanced AMD that can be determined by clinical examination or by less demanding photographic procedures than used in the Age-Related Eye Disease Study. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to determine the usefulness of indocyanine green angiography (ICGA) in establishing the diagnosis of macular telangiectasia (MacTel). It cites that the study performed ICGA on the first 276 patients with MacTel type 2 enrolled in the study. It states that the study found that ICGA did not exhibit unique findings specific to MacTel type 2 which suggests that ICGA might not be useful for identifying the disease.

To analyze associations between the dietary intake of multiple nutrients and risk of progression to late age-related macular degeneration (AMD), its subtypes, and large drusen. Post hoc analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. Eyes with no late AMD at baseline among AREDS participants (n = 4504) and AREDS2 participants (n = 3738) totaled 14 135 eyes. Mean age was 71.0 years (standard deviation, 6.7 years), and 56.5% of patients were women. Fundus photographs were collected at annual study visits and graded centrally for late AMD. Dietary intake of multiple nutrients was calculated from food frequency questionnaires. Progression to late AMD, geographic atrophy (GA), neovascular AMD, and (separate analyses) large drusen. Over median follow-up of 10.2 years, of the 14 135 eyes, 32.7% progressed to late AMD. For 9 nutrients, intake quintiles 4 or 5 (vs. 1) were associated significantly (P ≤ 0.0005) with decreased risk of late AMD: vitamin A, vitamin B6, vitamin C, folate, β-carotene, lutein and zeaxanthin, magnesium, copper, and alcohol. For 3 nutrients, quintiles 4 or 5 were associated significantly with increased risk: saturated fatty acid, monounsaturated fatty acid, and oleic acid. Similar results were observed for GA. Regarding neovascular AMD, 9 nutrients were associated nominally with decreased risk—vitamin A, vitamin B6, β-carotene, lutein and zeaxanthin, magnesium, copper, docosahexaenoic acid, omega-3 fatty acid, and alcohol—and 3 nutrients were associated with increased risk—saturated fatty acid, monounsaturated fatty acid, and oleic acid. In separate analyses (n = 5399 eyes of 3164 AREDS participants), 12 nutrients were associated nominally with decreased risk of large drusen. Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD. These associations are stronger for GA than for neovascular AMD. The same nutrients also tend to show protective associations against large drusen development. Strong genetic interactions exist for some nutrient–genotype combinations, particularly omega-3 fatty acids and CFH. These data may justify further research into underlying mechanisms and randomized trials of supplementation. [ABSTRACT FROM AUTHOR]

Comments on the vitamin E and the age-related eye disease study (AREDS) for age-related macular degeneration (AMD). Use of meta-analysis to determine the risk of death; Views of the authors on the increased risk of mortality associated with the AREDS supplements; benefits of the AREDS supplementation for those at risk for advanced AMD.

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. [ABSTRACT FROM AUTHOR]

Objective: To describe the long-term effects (10 years) of the Age-Related Eye Disease Study (AREDS) formulation of high-dose antioxidants and zinc supplement on progression of age-related macular degeneration (AMD). Design: Multicenter, randomized, controlled, clinical trial followed by an epidemiologic follow-up study. Participants: We enrolled 4757 participants with varying severity of AMD in the clinical trial; 3549 surviving participants consented to the follow-up study. Methods: Participants were randomly assigned to antioxidants C, E, and β-carotene and/or zinc versus placebo during the clinical trial. For participants with intermediate or advanced AMD in 1 eye, the AREDS formulation delayed the progression to advanced AMD. Participants were then enrolled in a follow-up study. Eye examinations were conducted with annual fundus photographs and best-corrected visual acuity assessments. Medical histories and mortality were obtained for safety monitoring. Repeated measures logistic regression was used in the primary analyses. Main Outcome Measures: Photographic assessment of progression to, or history of treatment for, advanced AMD (neovascular [NV] or central geographic atrophy [CGA]), and moderate visual acuity loss from baseline (≥15 letters). Results: Comparison of the participants originally assigned to placebo in AREDS categories 3 and 4 at baseline with those originally assigned to AREDS formulation at 10 years demonstrated a significant (P<0.001) odds reduction in the risk of developing advanced AMD or the development of NV AMD (odds ratio [OR], 0.66, 95% confidence interval [CI], 0.53–0.83 and OR, 0.60; 95% CI, 0.47–0. 78, respectively). No significant reduction (P = 0.93) was seen for the CGA (OR, 1.02; 95% CI, 0.71–1.45). A significant reduction (P = 0.002) for the development of moderate vision loss was seen (OR 0.71; 95% CI, 0.57–0.88). No adverse effects were associated with the AREDS formulation. Mortality was reduced in participants assigned to zinc, especially death from circulatory diseases. Conclusions: Five years after the clinical trial ended, the beneficial effects of the AREDS formulation persisted for development of NV AMD but not for CGA. These results are consistent with the original recommendations that persons with intermediate or advanced AMD in 1 eye should consider taking the AREDS formulation. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. [Copyright &y& Elsevier]

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. Post hoc analysis of an Age-Related Eye Disease Study 2 cohort. Eyes with GA: n = 771 from 563 participants. 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. Change in square root of GA area. 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. 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. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Purpose To investigate whether the 2-year change in lens opacity severity on the Age-Related Eye Disease Study (AREDS) lens grading scale predicts progression to cataract surgery or loss of visual acuity by 5 years. Design Prospective cohort study within a randomized clinical trial of oral supplements. Participants The AREDS participants whose eyes were phakic at baseline and free of late age-related macular degeneration throughout the study. Methods Baseline and annual lens photographs of AREDS participants (n = 3466/4757; 73%) were graded for severity of cataracts using the AREDS system for classifying cataracts from photographs. Clinical examinations conducted semiannually collected data on cataract surgery and visual acuity. Association of the change in lens opacities at 2 years with these outcomes at 5 years was analyzed with adjusted Cox proportional hazard models. Main Outcome Measurements Progression of lens opacities on stereoscopic lens photographs at 2 years, cataract surgery, and visual acuity loss of 2 lines or more at 5 years. Results The adjusted hazard ratios (HRs) for association of progression to cataract surgery at 5 years were: nuclear cataract increase of 1.0 unit or more compared with less than 1.0-unit change at 2 years, 2.77 (95% confidence interval [CI], 2.07–3.70; P < 0.001); cortical cataract increase of 5% or more in lens opacity in the central 5 mm of the lens compared with less than 5% increase at 2 years, 1.91 (95% CI, 1.27–2.87; P = 0.002); and posterior subcapsular cataract increase of 5% or more versus less than 5% in the central 5 mm of the lens, 8.25 (95% CI, 5.55–12.29; P < 0.001). Similarly, HRs of vision loss of 2 lines or more at 5 years for this degree of lens changes at 2 years were the following: nuclear, 1.83 (95% CI, 1.49–2.25; P < 0.001); cortical, 1.13 (95% CI, 0.78–1.65; P = 0.519); and posterior subcapsular cataract, 3.05 (95% CI, 1.79–5.19; P < 0.001). Conclusions Two-year changes in severity of lens opacities on the AREDS lens grading scale are predictive of long-term clinically relevant outcomes, making them potential surrogate end points in follow-up studies. [ABSTRACT FROM AUTHOR]

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. Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants). 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. Progression to late AMD, geographic atrophy (GA), and neovascular AMD. 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. 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. [ABSTRACT FROM AUTHOR]

To evaluate the risk of developing late age-related macular degeneration (AMD) after incident cataract surgery. A prospective cohort study within a randomized controlled clinical trial of oral supplementation for the treatment of AMD, the Age-Related Eye Disease Study 2 (AREDS2). AREDS2 participants aged 50 to 85 years with bilateral large drusen or unilateral late AMD. In eyes free of cataract surgery and late AMD at baseline, 2 groups were compared for incident late AMD: (1) eyes that received cataract surgery after the baseline visit and before any evidence of late AMD and (2) eyes that remained phakic until study completion. Eyes with at least 2 years of follow-up after cataract surgery were included in the analysis. We used Cox regression models, matched-pairs analysis, and logistic regression models that were adjusted for age, sex, smoking, education, study treatment group, and AMD severity. Late AMD was defined as the presence of geographic atrophy or neovascular AMD detected on annual stereoscopic fundus photographs or as documented by medical records, including intravitreous injections of anti-vascular endothelial growth factor medication. A total of 1767 eligible eyes (1195 participants) received cataract surgery; 1981 eyes (1524 participants) developed late AMD during a mean (range) follow-up of 9 (1–12) years. The Cox regression model showed no increased risk of developing late AMD after cataract surgery: hazard ratio, 0.96; 95% confidence interval (CI), 0.81–1.13 (P = 0.60) for right eyes and hazard ratio, 1.05; 95% CI, 0.89–1.25 (P = 0.56) for left eyes. Of the matched pairs, late AMD was identified in 408 eyes that received cataract surgery and in 429 phakic controls: odds ratio (OR) 0.92 (95% CI, 0.77–1.10; P = 0.34). The risk of late AMD after cataract surgery from the logistic regression model was not statistically significant (risk ratio, 0.92; 95% CI, 0.56–1.49; P = 0.73). Cataract surgery did not increase the risk of developing late AMD among AREDS2 participants with up to 10 years of follow-up. This study provides data for counseling AMD patients who might benefit from cataract surgery. [ABSTRACT FROM AUTHOR]

To determine whether closer adherence to a Mediterranean diet (and its individual components) was associated with altered risk of progression to late age-related macular degeneration (AMD) and large drusen. Additional objectives were to assess interactions with AMD genotype. Retrospective analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. Eyes with no late AMD at baseline in AREDS participants (n = 4255) and AREDS2 participants (n = 3611): total of 13 204 eyes (7756 participants). Mean age was 71 years (standard deviation, 6.6); 56.5% were female. Color fundus photographs were collected at annual study visits and graded centrally for late AMD. The modified Alternative Mediterranean Diet Index (aMedi) score was calculated for each participant from food frequency questionnaires. Progression to late AMD, geographic atrophy (GA), and neovascular AMD; progression to large drusen. Over a median follow-up of 10.2 years, of the 13 204 eyes, 34.0% progressed to late AMD. Hazard ratios (HRs) for progression in aMedi tertile 3 versus 1 were 0.78 (95% confidence interval [CI], 0.71–0.85, P < 0.0001) for late AMD, 0.71 (0.63–0.80, P < 0.0001) for GA, and 0.84 (0.75–0.95, P = 0.005) for neovascular AMD. For fish consumption, HRs for late AMD in quartile 4 versus 1 were 0.69 (0.58–0.82, P < 0.0001; AREDS) and 0.92 (0.78–1.07, P = 0.28; AREDS2). In AREDS, both aMedi and its fish component interacted with CFH rs10922109 for late AMD (P = 0.01 and P = 0.0005, respectively); higher aMedi and fish intake were each associated with decreased risk only in participants with protective alleles. In separate analyses (n = 5029 eyes of 3026 AREDS participants), the HR for progression to large drusen in aMedi tertile 3 versus 1 was 0.79 (0.68–0.93, P = 0.004). Closer adherence to a Mediterranean-type diet was associated with lower risk of progression to late AMD and to large drusen. The signal was greater for GA than neovascular AMD. Fish intake contributed to this protective association. CFH genotype strongly influenced these relationships. These findings may help inform evidence-based dietary recommendations. [ABSTRACT FROM AUTHOR]

To report the natural history of untreated neovascular age-related macular degeneration (nAMD) regarding subsequent macular atrophy. Prospective cohort within a randomized, controlled trial of oral micronutrient supplements. Age-Related Eye Disease Study (AREDS) participants (55–80 years) who demonstrated nAMD during follow-up (1992–2005), prior to anti–vascular endothelial growth factor (VEGF) therapy. Color fundus photographs were collected at annual study visits and graded centrally for late age-related macular degeneration (AMD). Incident macular atrophy after nAMD was examined by Kaplan-Meier analysis and proportional hazards regression. Incident macular atrophy after nAMD. Of the 4757 AREDS participants, 708 eyes (627 participants) demonstrated nAMD during follow-up and were eligible. The cumulative risks of incident macular atrophy after untreated nAMD were 9.6% (standard error, 1.2%), 31.4% (standard error, 2.2%), 43.1% (standard error, 2.6%), and 61.5% (standard error, 4.3%) at 2, 5, 7, and 10 years, respectively. This corresponded to a linear risk of 6.5% per year. The cumulative risk of central involvement was 30.4% (standard error, 3.2%), 43.4% (standard error, 3.8%), and 57.0% (standard error, 4.8%) at first appearance of atrophy, 2 years, and 5 years, respectively. Geographic atrophy (GA) in the fellow eye was associated with increased risk of macular atrophy (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.17–2.49; P = 0.006). However, higher 52-single nucleotide polymorphism AMD genetic risk score was not associated with increased risk of macular atrophy (HR, 1.03; 95% CI, 0.90–1.17; P = 0.67). Similarly, no significant differences were observed according to SNPs at CFH , ARMS2 , or C3. The rate of incident macular atrophy after untreated nAMD is relatively high, increasing linearly over time and affecting half of eyes by 8 years. Hence, factors other than anti-VEGF therapy are involved in atrophy development, including natural progression to GA. Comparison with studies of treated nAMD suggests it may not be necessary to invoke a large effect of anti-VEGF therapy on inciting macular atrophy, although a contribution remains possible. Central involvement is present in one third of eyes at the outset (similar to pure GA) and increases linearly to half at 3 years. [ABSTRACT FROM AUTHOR]

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. Prospective cohort study. 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. 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. Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD. 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). 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. [ABSTRACT FROM AUTHOR]

To analyze the potential association between aspirin use and progression of age-related macular degeneration (AMD). Two prospective cohort studies within 2 controlled clinical trials of oral supplementation for age-related eye disease. Age-Related Eye Disease Study (AREDS) participants 55 to 80 years of age and AREDS2 participants 50 to 85 years of age. Propensity scores for aspirin use were calculated for AREDS and AREDS2 participants separately by logistic regression. Of the participants without late AMD (geographic atrophy [GA] or neovascular AMD) in either eye at study baseline, aspirin users were matched 1:1 with nonusers by propensity score (separately for AREDS and AREDS2). Proportional hazards regression was performed, adjusting for age, on the matched participants to evaluate associations between aspirin propensity score and progression to late AMD (and its subtypes). Progression to late AMD on color fundus photographs, graded centrally. Of the 3734 eligible AREDS participants, 1049 (28.1%) were taking aspirin, and of the 2403 eligible AREDS2 participants, 1198 (49.9%) were taking aspirin. After matching by propensity score, the characteristics of the users and nonusers were similar in both studies. Of the 1950 matched AREDS participants and 1694 matched AREDS2 participants, over a median follow-up of 10.1 years and 5.0 years, respectively, the numbers who progressed to late AMD, GA, or neovascular AMD were 454 (23.3%), 345 (17.7%), and 278 (14.3%), respectively, in AREDS and 643 (38.0%), 402 (24.6%), and 341 (20.1%) in AREDS2. The hazard ratios of progression in quintile 5 (highest propensity for aspirin use) versus 1 (reference) were 1.17 (P = 0.35), 1.24 (0.25), and 0.95 (0.81), respectively, in AREDS and 1.26 (0.09), 1.46 (0.03), and 1.12 (0.58) in AREDS2. No significant association with progression to late AMD was observed for quintiles 2 through 5 for any of the 3 outcomes in either study. Aspirin use was not associated significantly with progression to late AMD or its subtypes in either the AREDS or AREDS2. Patients with AMD need not avoid aspirin for this reason when its use is medically indicated. [ABSTRACT FROM AUTHOR]

Purpose Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. Design Cohort study. Participants AREDS and AREDS2 participants. Methods AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. Main Outcome Measures Genotype–phenotype associations. Results A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub–retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31–1.84], P = 2.67 × 10 −7 ). This novel association remained significant after conditioning on participants with neovascular AMD ( P = 2.42 × 10 −4 ). Carriers of rs3750846 had poorer visual acuity during follow-up ( P = 6.82 × 10 −7 ) and were more likely to have a first-degree relative with AMD ( P = 5.38 × 10 −6 ). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid ( P = 2.29 × 10 −11 and P = 3.20 × 10 −9 , respectively) and the center subfield ( P = 1.24 × 10 −9 and P = 6.68 × 10 −8 , respectively). SNP rs570618 was additionally associated with the presence of calcified drusen ( P = 5.38 × 10 −6 ). Except for positive family history of AMD with rs3750846, all genotype–phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. Conclusions The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD. [ABSTRACT FROM AUTHOR]

Objective: To develop a parameter that can assess the relative rate of progression of geographic atrophy (GA) based on the hypothesis that noncircular configuration of the atrophic lesion may be a risk factor for enlargement. Design: Cohort study. Participants: Digitized color photographs of 593 eyes with GA from the Age-Related Eye Disease Study (AREDS). Methods: A novel parameter called the “Geographic Atrophy Circularity Index” (GACI) was developed on the basis of area and perimeter measurements to categorize the irregularity of the shape of GA. The GACI ranges from 0.0 to 1.0 and is categorized into 3 groups: 0.25 (very irregular), 0.25 to <0.75 (partly irregular), and ≥0.75 (circular). Main Outcome Measures: Growth rate of GA. Results: The mean growth rate in the 3 categories was 0.40 (±0.18), 0.36 (±0.30), and 0.21 (±0.22) mm/year, respectively (P < 0.001). By adjusting for known confounders, baseline area, duration of GA, and configuration, GACI categories were significantly associated with increased growth rate of GA (P < 0.001). Conclusions: The GACI was associated with the progression rate of GA and may be a useful measure for clinical trial eligibility. The association also suggests that enlargement of GA may be related to the extent of the junctional zone of damaged retinal pigment epithelium, which increases with noncircularity for a given GA area. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Objective: To investigate potential risk factors associated with incident nuclear, cortical, and posterior subcapsular (PSC) cataracts and cataract surgery in participants in the Age-Related Eye Disease Study (AREDS). Design: Clinic-based prospective cohort study. Participants: Persons (n = 4425) 55 to 80 years of age enrolled in a controlled clinical trial of antioxidant vitamins and minerals, AREDS, for age-related macular degeneration and cataract. Methods: Lens photographs were graded centrally for nuclear, cortical, and PSC opacities using the AREDS system for classifying cataracts. Type-specific incident cataracts were defined as an increase in cataract grade from none or mild at baseline to a grade of moderate at follow-up, also with a grade of at least moderate at the final visit, or cataract surgery. Cox regression analyses were used to assess baseline risk factors associated with type-specific opacities and cataract surgery. Main Outcome Measures: Moderate cataract was defined as a grade of 4.0 or more for nuclear opacity, 10% or more involvement within the full visible lens for cortical opacity, and 5% or more involvement of the central 5-mm circle of the lens for PSC opacity. These were graded on baseline and annual lens photographs. Results: A clinic-based cohort of 4425 persons 55 to 80 years of age at baseline was followed up for an average of 9.8±2.4 years. The following associations were found: increasing age with increased risk of all types of cataract and cataract surgery; males with increased risk of PSC and decreased risk of cortical cataracts; nonwhite persons with increased risk of cortical cataract; hyperopia with decreased risk of PSC, nuclear cataract, and cataract surgery; Centrum (Wyeth Consumer Healthcare, Madison, NJ) use with decreased risk of nuclear cataract; diabetes with increased risk of cortical, PSC cataract, and cataract surgery; higher educational level with decreased risk of cortical cataract; and smoking with increased risk of cortical cataract and cataract surgery. Estrogen replacement therapy in female participants increased the risk of cataract surgery. Conclusions: These findings largely are consistent with the results of previous studies, providing further evidence for possible modifiable risk factors for age-related cataract. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Purpose: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. Design: Cohort study. Participants: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). Methods: Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. Main Outcome Measures: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). Results: The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82–1.75) for NV AMD, 0.80 (95% CI, 0.61–1.06) for GA, and 0.87 (95% CI, 0.64–1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72–1.58) for NV AMD, 0.94 (95% CI, 0.71–1.25) for GA, and 0.86 (95% CI, 0.63–1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65–1.72) for NV AMD and 0.98 (95% CI, 0.64–1.49) for CGA. Conclusions: The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]