Traci E Clemons’s research while affiliated with The EMMES Corporation and other places

Purpose To determine whether reticular pseudodrusen (RPD) status and/or ARMS2/HTRA1 genotype 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 a cohort within the Age-Related Eye Disease Study 2 (AREDS2) controlled clinical trial. Participants 771 eyes (563 participants, mean age 74.8 years) with GA. Methods GA area was measured by planimetry from color fundus photographs at annual visits. RPD presence was graded from fundus autofluorescence images. Mixed-model regression of square root GA area was performed according to RPD status and/or ARMS2 genotype, including mediation analysis. Main outcome measures Change in square root GA area over time. Results GA enlargement was significantly faster in eyes with RPD (P<0.0001), at 0.379 (95% CI 0.329-0.430) versus 0.273 mm/year (0.256-0.289). The rate was also significantly faster in individuals carrying ARMS2 risk alleles (P<0.0001), at 0.224 (95% CI 0.198-0.250), 0.287 (0.263-0.310), and 0.307 mm/year (0.273-0.341), in those with 0-2 risk alleles, respectively. In mediation analysis, the direct effect of ARMS2 genotype on GA enlargement was 0.074 mm/year (95% CI 0.009-0.139, P=0.025), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI -0.006-0.009, P=0.64). In eyes with incident GA, RPD presence was not associated with altered likelihood of central involvement (P=0.29) or multifocality (P=0.16) at incidence. In eyes with incident non-central GA, RPD presence was associated with faster GA progression to the central macula (P=0.009), at 157 (95% CI 126-188) versus 111 μm/year (97-125). Similar findings were observed in the AREDS, as a validation dataset. Conclusions GA enlargement is faster in eyes with RPD and in individuals carrying ARMS2 risk alleles. However, RPD status does not mediate the association between ARMS2 genotype and faster enlargement. RPD presence and ARMS2 genotype are relatively independent risk factors and must lead to faster enlargement by distinct mechanisms. RPD presence does not predict central involvement or multifocality at GA incidence, but is associated with faster progression towards the central macula. These findings have implications for clinical trials and clinical practice; RPD status should be considered for improved predictions of enlargement rate.

Purpose To develop a severity classification for macular telangiectasia type2 (MacTel) disease using multi-modal imaging Design An algorithm was used on data from a prospective natural history study of MacTel for classification development. Subjects A total of 1,733 participants enrolled in an international natural history study of MacTel. Methods The Classification and Regression Trees (CART), a predictive non-parametric algorithm used in machine learning, analyzed the features of the multi-modal 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 optical coherence tomography (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 at baseline for the right eye and then for the left eye. These analyses using the algorithm were repeated for the best-corrected visual acuity obtained at the last study visit of the natural history study for the right eye and then for the left eye. Results The CART analyses demonstrated 3 important features from the multi-modal imaging for the classification: OCT hyperreflectivity, pigment and ellipsoid zone loss. By combining these 3 features (as absent, present, non-central involvement and central involvement of the macula), a seven-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 General 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 spectral domain OCT. This classification is designed to provide better communications to other clinicians, researchers, and patients.

Purpose To identify the prevalence of drusen outside the macula and their role in progression of age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study Participants 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 were included. Method 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 to drusen within the macula. Main Outcome Measures Progression rates to late AMD Results Extramacular drusen were seen in 3624 (86.9% eyes) but represented a small area (< 0.5mm2) in 50.3% of eyes with only 17.5% having an area > 1 disc area (DA). Eyes with extramacular drusen had larger macular drusen size and larger macular drusen area compared to eyes without (p < 0.001). Extramacular drusen were not associated with progression to late AMD; hazard ratio adjusted for baseline age, gender, 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. Conclusion Drusen outside the macula are commonly seen in eyes with AMD and are more frequent with 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.

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.

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 two clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. Participants Eyes with no late AMD at baseline in AREDS (n=6959 eyes, 3780 participants; mean age 69.4y) and AREDS2 (n=3355 eyes, 2056 participants; mean age 72.3y). Methods Color fundus photographs (CFP) from annual study visits were graded for soft drusen, pigmentary abnormalities, and late AMD. RPD presence was determined by grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFP (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 (NV). Results In AREDS, for late AMD analyses by person, in a model considering the modified simplified severity scale simultaneously, RPD presence was associated with higher risk of progression: hazard ratio (HR) 2.15 (95% CI 1.75-2.64). However, the risk associated with RPD presence differed significantly at different simplified severity scale levels: HR 3.23 (1.60-6.51), 3.81 (2.38-6.10), 2.28 (1.59-3.27), and 1.64 (1.20-2.24), at levels 0-1/2/3/4, respectively. Considering the 9-step scale (by eye), RPD presence was also associated with higher risk: HR 2.54 (2.07-3.13). The HRs were 5.11 (3.93-6.66) at levels 1-6 and 1.78 (1.43-2.22) at 7-8. In AREDS2, by person, RPD presence was not associated with higher risk: HR 1.18 (0.90-1.56); by eye, it was: HR 1.57 (1.31-1.89). No significant differences in risk were observed at different severity levels, for the limited spectrum in AREDS2. In both cohorts, RPD presence carried higher risk for GA than NV. Conclusions RPD represent an important anatomical risk factor for progression to late AMD, particularly GA. However, the added risk associated with RPD varies markedly by severity level. It carries highly increased risk at lower/moderate levels and less increased risk at higher levels. RPD status should be included in updated AMD classification systems, risk calculators, and clinical trials.

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 sub-populations 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.

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.

Purpose To evaluate the risk of developing late age-related macular degeneration (AMD) following 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 either bilateral large drusen or unilateral late AMD. Methods In eyes that were free of cataract surgery and late AMD at baseline, two 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 the study completion. Eyes that had 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 baseline 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 and 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 ratios (Confidence Interval [CI]): 0.96 (0.8,1.13; p = 0.60) for the right eye and 1.05 (0.89,1.25; p = 0.56) for the left eye. Of the matched pairs, late AMD was identified in 412 eyes that received cataract surgery and in 433 phakic controls, resulting in an odds ratio (95% CI) of 0.92 (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 [95%CI]: 0.92 [0.56,1.49], p = 0.73). Conclusions Cataract surgery did not increase the risk of developing late AMD among the AREDS2 participants with up to 10 years of follow-up. This study provides data for counselling AMD patients who might benefit from cataract surgery.

Eyecare professionals should be aware of Charles Bonnet Syndrome (CBS), a phenomenon involving visual hallucinations in people with visual impairments. We examined prevalence of CBS among AREDS2 participants and its associations with age-related eye diseases.

Purpose To explore whether phenotypes in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) can be separable into two or more partially distinct subtypes and if these have different genetic associations. This is important since the discovery of 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 AREDS2 participants with incident GA during study follow-up: 598 eyes of 598 participants (median age 75.7y). Methods Phenotypic features from reading center grading of fundus photographs were subjected to cluster analysis, by both k-means and hierarchical methods, in cross-sectional analyses (using 15 phenotypic features assessed principally at GA emergence) and longitudinal analyses (using 14 phenotypic features). In pre-specified hypothesis tests, identified clusters were compared by four pathway-based genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). The analyses were repeated in reverse, i.e., 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; genotype-phenotype associations, assessed by t test. Results In cross-sectional phenotypic analyses, k-means identified two clusters (labeled A, B), while hierarchical clustering identified four (C-F); A-E membership differed principally by GA configuration but in relatively few other ways. In longitudinal phenotypic analyses, k-means identified two clusters (G, H), which differed principally by smoking status but in relatively few other ways. These three sets of cluster divisions were not similar to each other (r ≤ 0.20). Despite adequate power, pairwise cluster comparison by the four genetic risk scores demonstrated no significant differences (p>0.05 for all). In clustering by genotype, k-means identified two clusters (I/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 etiologies.