Macular Telangiectasia Type 2: A Classification System Using MultiModal Imaging MacTel Project Report Number 10.

Purpose: To develop a severity classification for macular telangiectasia type 2 (MacTel) disease using multimodal imaging. Design: An algorithm was used on data from a prospective natural history study of MacTel for classification development. Subjects: A total of 1733 participants enrolled in an international natural history study of MacTel. Methods: The Classification and Regression Trees (CART), a predictive nonparametric algorithm used in machine learning, analyzed the features of the multimodal imaging important for the development of a classification, including reading center gradings of the following digital images: stereoscopic color and red-free fundus photographs, fluorescein angiographic images, fundus autofluorescence images, and spectral-domain (SD)-OCT images. Regression models that used least square method created a decision tree using features of the ocular images into different categories of disease severity. Main Outcome Measures: The primary target of interest for the algorithm development by CART was the change in best-corrected visual acuity (BCVA) at baseline for the right and left eyes. These analyses using the algorithm were repeated for the BCVA obtained at the last study visit of the natural history study for the right and left eyes. Results: The CART analyses demonstrated 3 important features from the multimodal imaging for the classification: OCT hyper-reflectivity, pigment, and ellipsoid zone loss. By combining these 3 features (as absent, present, noncentral involvement, and central involvement of the macula), a 7-step scale was created, ranging from excellent to poor visual acuity. At grade 0, 3 features are not present. At the most severe grade, pigment and exudative neovascularization are present. To further validate the classification, using the Generalized Estimating Equation regression models, analyses for the annual relative risk of progression over a period of 5 years for vision loss and for progression along the scale were performed. Conclusions: This analysis using the data from current imaging modalities in participants followed in the MacTel natural history study informed a classification for MacTel disease severity featuring variables from SD-OCT. This classification is designed to provide better communications to other clinicians, researchers, and patients. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

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.

Extramacular Drusen and Progression of Age-Related Macular Degeneration: Age Related Eye Disease Study 2 Report 30.

PURPOSE: To identify the prevalence of extramacular drusen and their role in the progression of age-related macular degeneration (AMD). DESIGN: Retrospective analysis of a prospective cohort study. PARTICIPANTS: The study was conducted in 4168 eyes (2998 participants) with intermediate AMD in one or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplements. METHODS: Baseline 3-field 30-degree color photographs were evaluated for drusen characteristics outside the macular grid, including size, area, and location. The characteristics of extramacular drusen were compared with those of drusen within the macula. MAIN OUTCOME MEASURES: Progression rates to late AMD. RESULTS: Although extramacular drusen were observed in 3624 (86.9%) eyes, they represented a small area (< 0.5 mm2) in 50.3% of eyes, with only 17.5% exhibiting an area of > 1 disc area. Eyes with extramacular drusen exhibited larger macular drusen size and area than eyes without extramacular drusen (P < 0.001). Extramacular drusen were not associated with progression to late AMD. The hazard ratio adjusted for baseline age, sex, smoking, AMD severity level, and reticular pseudodrusen for 4043 eyes at risk of developing late AMD over 5 years was 1.17 (95% confidence interval [CI], 0.88-1.54; P = 0.27) for geographic atrophy and 0.96 (95% CI, 0.76-1.2; P = 0.7) for neovascular AMD. CONCLUSIONS: Extramacular drusen are commonly observed in eyes with AMD and are more frequent with an increasing drusen burden within the macula. In eyes with intermediate AMD, extramacular drusen do not confer additional risk to previously identified risk factors in progression to late AMD.

Machine learning OCT predictors of progression from intermediate age-related macular degeneration to geographic atrophy and vision loss.

Objective: To describe optical coherence tomography (SD-OCT) features, age, gender, and systemic variables that may be used in machine/deep learning studies to identify high-risk patient subpopulations with high risk of progression to geographic atrophy (GA) and visual acuity (VA) loss in the short term. Design: prospective, longitudinal study. Subjects: We analyzed imaging data from patients with iAMD (N= 316) enrolled in Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT with adequate SD-OCT imaging for repeated measures. Methods: Qualitative and quantitative multimodal variables from the database were derived at each yearly visit over 5 years. Based on statistical analyses developed in the field of cardiology, an algorithm was developed and used to select person-years without GA on colour fundus photography or SD-OCT at baseline. The analysis employed machine learning approaches to generate classification trees. Eyes were stratified as low, average, above average and high risk in 1 or 2 years, based on OCT and demographic features by the risk of GA development or decreased VA by 5+ and 10+ letters. Main outcome measures: new onset of SD-OCT-determined GA and VA loss. Results: We identified multiple retinal and subretinal SD-OCT and demographic features from the baseline visit, each of which independently conveyed low to high risk of new-onset GA or VA loss on each of the follow-up visits at 1 or 2 years. Conclusion: We propose a risk-stratified classification of iAMD based on the combination of OCT-derived retinal features, age, gender and systemic variables for progression to OCT-determined GA and/or VA loss. After external validation, the composite early endpoints may be used as exclusion or inclusion criteria for future clinical studies of iAMD focused on prevention of GA progression or VA loss.

Long-term Outcomes of Adding Lutein/Zeaxanthin and ω-3 Fatty Acids to the AREDS Supplements on Age-Related Macular Degeneration Progression: AREDS2 Report 28.

Importance: After the Age-Related Eye Disease Study 2 (AREDS2) study, the beta carotene component was replaced by lutein/zeaxanthin for the development of the revised AREDS supplement. However, it is unknown if the increased risk of lung cancer observed in those assigned beta carotene persists beyond the conclusion of the AREDS2 trial and if there is a benefit of adding lutein/zeaxanthin to the original AREDS supplement that can be observed with long-term follow-up. Objective: To assess 10-year risk of developing lung cancer and late age-related macular degeneration (AMD). Design, Setting, and Participants: This was a multicenter epidemiologic follow-up study of the AREDS2 clinical trial, conducted from December 1, 2012, to December 31, 2018. Included in the analysis were participants with bilateral or unilateral intermediate AMD for an additional 5 years after clinical trial. Eyes/participants were censored at the time of late AMD development, death, or loss to follow-up. Data were analyzed from November 2019 to March 2022. Interventions: During the clinical trial, participants were randomly assigned primarily to lutein/zeaxanthin and/or ω-3 fatty acids or placebo and secondarily to no beta carotene vs beta carotene and low vs high doses of zinc. In the epidemiologic follow-up study, all participants received AREDS2 supplements with lutein/zeaxanthin, vitamins C and E, and zinc plus copper. Outcomes were assessed at 6-month telephone calls. Analyses of AMD progression and lung cancer development were conducted using proportional hazards regression and logistic regression, respectively. Main Outcomes and Measures: Self-reported lung cancer and late AMD validated with medical records. Results: This study included 3882 participants (mean [SD] baseline age, 72.0 [7.7] years; 2240 women [57.7%]) and 6351 eyes. At 10 years, the odds ratio (OR) of having lung cancer was 1.82 (95% CI, 1.06-3.12; P = .02) for those randomly assigned to beta carotene and 1.15 (95% CI, 0.79-1.66; P = .46) for lutein/zeaxanthin. The hazard ratio (HR) for progression to late AMD comparing lutein/zeaxanthin with no lutein/zeaxanthin was 0.91 (95% CI, 0.84-0.99; P = .02) and comparing ω-3 fatty acids with no ω-3 fatty acids was 1.01 (95% CI, 0.93-1.09; P = .91). When the lutein/zeaxanthin main effects analysis was restricted to those randomly assigned to beta carotene, the HR was 0.80 (95% CI, 0.68-0.92; P = .002). A direct analysis of lutein/zeaxanthin vs beta carotene showed the HR for late AMD was 0.85 (95% CI, 0.73-0.98; P = .02). The HR for low vs high zinc was 1.04 (95% CI, 0.94-1.14; P = .49), and the HR for no beta carotene vs beta carotene was 1.04 (95% CI, 0.94-1.15; P = .48). Conclusions and Relevance: Results of this long-term epidemiologic follow-up study of the AREDS2 cohort suggest that lutein/zeaxanthin was an appropriate replacement for beta carotene in AREDS2 supplements. Beta carotene usage nearly doubled the risk of lung cancer, whereas there was no statistically significant increased risk with lutein/zeaxanthin. When compared with beta carotene, lutein/zeaxanthin had a potential beneficial association with late AMD progression.

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.

Assessing bidirectional associations between cognitive impairment and late age-related macular degeneration in the Age-Related Eye Disease Study 2.

INTRODUCTION: We aimed to investigate bidirectional associations between cognitive impairment and late age-related macular degeneration (AMD). METHODS: Participants in the Age-Related Eye Disease Study 2 (AREDS2) received annual eye examinations and cognitive function testing (e.g., Modified Telephone Interview for Cognitive Status [TICS-M]). We examined bidirectional associations between cognitive impairment (e.g., a TICS-M score < 30) and late AMD at 5 and 10 years. RESULTS: Five thousand one hundred eighty-nine eyes (3157 participants; mean age 72.7 years) were analyzed and followed for a median of 10.4 years. Eyes of participants with cognitive impairment at baseline were more likely to progress to late AMD at 5 years (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.08-1.43) and 10 years (HR, 1.20; 95% CI, 1.05-1.37) than eyes of participants without cognitive impairment. Worse baseline AMD severity was not associated with developing cognitive impairment. DISCUSSION: Cognitive impairment is associated with late AMD progression in AREDS2. Our finding highlights the importance of eyecare for people with cognitive impairment.

Cataract Surgery and the Risk of Developing Late Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 Report Number 27.

PURPOSE: To evaluate the risk of developing late age-related macular degeneration (AMD) after incident cataract surgery. DESIGN: 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). PARTICIPANTS: AREDS2 participants aged 50 to 85 years with bilateral large drusen or unilateral late AMD. METHODS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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). CONCLUSIONS: 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.

The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).

OBJECTIVE: To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN: A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING: Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01857310.

The Use of Cost-Effectiveness Analysis in Sickle Cell Disease: A Critical Review of the Literature.

Novel interventions for sickle cell disease (SCD) bring hope to patients, yet concern about the associated economic costs exists. Cost-effectiveness analysis (CEA) uses standardized methods, with robust underpinnings in health economics, to estimate the value of these interventions compared with usual care. However, because of the complexity and lifetime trajectory of SCD, CEAs are challenging to conduct. The objectives of this rapid review were to summarize the main characteristics, components, and results of published CEAs of existing interventions for SCD, identify research gaps, and provide directions for future analyses. We identified records through searches of bibliographic databases, from reference lists of relevant review articles, and through consultation with experts. A total of 13 CEAs met our inclusion criteria and were qualitatively synthesized. These evaluated blood transfusions (n = 2), hematopoietic stem cell transplantation (n = 1), pharmaceuticals (n = 2), hypothetical cell or genetic therapy (n = 1), screening programs (n = 4), and interventions for SCD treatment complications (n = 3). A limited number of potential SCD and treatment complications were evaluated. No study adopted a societal perspective in the base case, six studies examined lifetime cost-effectiveness, seven studies employed a Markov or discrete-event simulation model, and eight studies used an outcome metric that captured both quality and length of life. To better compare the value of emerging and current therapies, future CEAs should adopt a societal perspective incorporating both medical and nonmedical costs, comprehensively model SCD complexity using robust health economic simulation models over the patient's entire lifespan, and capture the intervention's effect on both survival and quality of life.

Cluster Analysis and Genotype-Phenotype Assessment of Geographic Atrophy in Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 25.

PURPOSE: To explore whether phenotypes in geographic atrophy (GA) secondary to age-related macular degeneration can be separated into 2 or more partially distinct subtypes and if these have different genetic associations. This is important because distinct GA subtypes associated with different genetic factors might require customized therapeutic approaches. DESIGN: Cluster analysis of participants within a controlled clinical trial, followed by assessment of phenotype-genotype associations. PARTICIPANTS: Age-Related Eye Disease Study 2 participants with incident GA during study follow-up: 598 eyes of 598 participants. METHODS: Phenotypic features from reading center grading of fundus photographs were subjected to cluster analysis, by k-means and hierarchical methods, in cross-sectional analyses (using 15 phenotypic features) and longitudinal analyses (using 14 phenotypic features). The identified clusters were compared by 4 pathway-based genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). The analyses were repeated in reverse (clustering by genotype and comparison by phenotype). MAIN OUTCOME MEASURES: Characteristics and quality of cluster solutions, assessed by Calinski-Harabasz scores, unexplained variance, and consistency; and genotype-phenotype associations, assessed by t test. RESULTS: In cross-sectional phenotypic analyses, k-means identified 2 clusters (labeled A and B), whereas hierarchical clustering identified 4 clusters (C-F); cluster membership differed principally by GA configuration but in few other ways. In longitudinal phenotypic analyses, k-means identified 2 clusters (G and H) that differed principally by smoking status but in few other ways. These 3 sets of cluster divisions were not similar to each other (r ≤ 0.20). Despite adequate power, pairwise cluster comparison by the 4 genetic risk scores demonstrated no significant differences (P > 0.05 for all). In clustering by genotype, k-means identified 2 clusters (I and J). These differed principally at ARMS2, but no significant genotype-phenotype associations were observed (P > 0.05 for all). CONCLUSIONS: Phenotypic clustering resulted in GA subtypes defined principally by GA configuration in cross-sectional analyses, but these were not replicated in longitudinal analyses. These negative findings, together with the absence of significant phenotype-genotype associations, indicate that GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic causes.

Fundus Autofluorescence Imaging in Macular Telangiectasia Type 2: MacTel Study Report Number 9.

PURPOSE: To investigate the role of fundus autofluorescence (FAF) imaging in the diagnosis of macular telangiectasia type 2 (MacTel) and to describe disease-associated FAF patterns and their origin. DESIGN: Cross-sectional multicenter study METHODS: FAF images were collected from the multicenter MacTel Natural History Observation and Registry Study. In a first qualitative approach, common FAF phenotypes were defined and correlated with multimodal imaging. We then evaluated how many eyes showed FAF changes, and temporal vs nasal asymmetry of FAF changes was graded. Finally, 100 eyes of MacTel patients and 100 control eyes (50 normal eyes and 50 eyes with other macular diseases) were combined and 2 masked graders assessed the presence of MacTel based on FAF images alone. RESULTS: The study included 807 eyes of 420 patients (33 eyes were excluded owing to poor image quality). Loss of macular pigment, cystoid spaces, pigment plaques, neovascular membranes, and ectatic vascular changes commonly caused characteristic changes on FAF images. All MacTel patients had macular FAF changes in at least 1 eye. In 95% of eyes, these changes were more pronounced temporally than nasally. Common FAF patterns were increased (60%) and mixed/decreased FAF (38%) and/or visibility of vascular changes such as blunted vessels or ectatic capillaries (79%). Based on those features, high diagnostic performance was achieved for detection of the disease based on FAF alone (Youden index up to 0.91). CONCLUSIONS: The study demonstrates that MacTel is consistently associated with disease-specific changes on FAF imaging. Those changes are typically more pronounced in the temporal parafovea.

Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression.

BACKGROUND: Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. METHODS: We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. RESULTS: Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. CONCLUSIONS: Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.

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.

Dietary Nutrient Intake and Progression to Late Age-Related Macular Degeneration in the Age-Related Eye Disease Studies 1 and 2.

PURPOSE: 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. DESIGN: Post hoc analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: 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. METHODS: 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. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), neovascular AMD, and (separate analyses) large drusen. RESULTS: 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, ß-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, ß-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. CONCLUSIONS: 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.

Macular Telangiectasia Type 2: Visual Acuity, Disease End Stage, and the MacTel Area: MacTel Project Report Number 8.

PURPOSE: To report the visual acuity measures from the macular telangiectasia type 2 (MacTel) registry and to investigate and describe phenotypic findings in eyes with substantial vision loss resulting from MacTel. DESIGN: Cross-sectional multicenter study. PARTICIPANTS: Participants in the MacTel Natural History Observation Registration Study. METHODS: Best-corrected visual acuity (BCVA) data, retinal imaging data, and clinical data were accessed from the MacTel Study databases in May 2019. MAIN OUTCOME MEASURES: Frequency distribution of BCVA and its relationship to age; morphologic changes in eyes with very late disease stages, defined by a BCVA of 20/200 or worse; average retinal thickness of macular subfields on OCT; and dimensions of the area affected by MacTel (i.e., the MacTel area). RESULTS: Best-corrected visual acuity was 20/50 or worse in 37.3% and 20/200 or worse in 3.8% of 4449 eyes of 2248 patients; 18.4% and 0.7% of all patients showed bilateral BCVA of 20/50 or worse and 20/200 or worse, respectively. Asymmetry between right and left eyes was present (median BCVA, 71 letters vs. 74 letters), a finding supported by more advanced morphologic changes in right eyes. Participant age correlated with BCVA, but the effect size was small. If a neovascularization or macular hole were present, bilateral occurrence was frequent (33% or 17%, respectively), and BCVA was better than 20/200 (79% or 78%, respectively) or 20/50 or better (26% or 13%, respectively). Eyes with advanced disease (BCVA, ≤20/200) showed the following characteristics: (1) atrophy of the foveal photoreceptor layer with or without associated subretinal fibrosis; (2) an affected area, termed MacTel area, limited to a horizontal diameter not exceeding the distance between the temporal optic disc margin and foveal center, and the vertical diameter not exceeding approximately 0.8 times this distance (exceptions were eyes with large active or inactive neovascular membranes); (3) reduced retinal thickness measures within the MacTel area; and (4) less frequent retinal greying and more frequent hyperpigmentations compared with eyes that have better BCVA. CONCLUSIONS: Severe vision loss is rare in MacTel and is related to photoreceptor atrophy in most people. Results indicate disease asymmetry with slightly worse vision and more advanced disease manifestation in right eyes. MacTel-related neurodegeneration does not spread beyond the limits of the MacTel area.