Beaver Dam Eye Study Research Articles

The safety of ranibizumab and bevacizumab on senescent retinal pigment epithelial cells

AbstractPurpose: Retinal pigment epithelial (RPE) cells in patients with age‐related macular degeneration are presumably senescent. This study investigated the effects of ranibizumab and bevacizumab on the viability of senescent RPE cells.Methods: Premature senescence of human RPE (ARPE‐19) cells was induced by exposure to low‐dose pulsed H2O2 stress for 5 days and confirmed with senescence‐associated 𝛽‐galactosidase (SA‐𝛽‐gal) staining. After treatment with clinical doses of ranibizumab and bevacizumab, the MTT [3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐Diphenyltetrazolium Bromide] assay and flow cytometry were used to determine cell viability. A caspase 3/7 assay, cell cycle analysis, SA‐𝛽‐gal staining, and in vitro wound healing assay were also performed to investigate the effects of the drugs on senescent ARPE‐19 cells.Results: Ranibizumab and bevacizumab did not have deleterious effects on apoptosis, cell viability, additional senescence, or the migration capacity of senescent RPE cells.Conclusions: Clinical dosages of ranibizumab and bevacizumab do not produce significant cytotoxicity in senescent RPE cells.Reference1. Klein R, Klein BE, Jensen SC, Meuer SM. The five‐year incidence and progression of age‐related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997; 104: 7–21.

Generational Differences in the 10-year Incidence of Impaired Contrast Sensitivity

ABSTRACT Purpose To determine if incidence of contrast sensitivity (CS) impairment differs by generation and identify factors to explain these differences. Methods The Beaver Dam Eye Study (BDES) and Beaver Dam Offspring Study (BOSS) are cohort studies of aging adults in Beaver Dam, Wisconsin. Baseline examinations occurred from 1993 to 1995 (BDES) and 2005–2008 (BOSS). Follow-up examinations occurred in five-year intervals. CS testing was conducted with Pelli-Robson letter sensitivity charts; Incident impairment was a log CS score <1.55 in either eye at follow-up. Associations of incidence with generation were investigated using estimated hazard ratios (HR) with 95% confidence intervals (CI). Results Participants (N = 3185) had a mean age of 51.9 years at baseline (standard deviation = 9.9) and 51.9% were female. Ten-year cumulative incidence of CS impairment was 40.1%, was higher among women (41.7%) than men (38.8%), and increased by age group. The risk of incident CS impairment decreased by 39% per generation. In multivariable models, the Baby Boom Generation (HR = 0.42, 95%CI = 0.31, 0.58) and Generation X (HR = 0.56, 95%CI = 0.34, 0.91) had a significantly decreased risk of CS impairment compared to the Greatest Generation. Results were similar in sensitivity analyses excluding those with cataract, age-related macular degeneration, or visual acuity impairment. Conclusion The risk of incident CS impairment decreased by birth cohort, with the greatest reduction in the Baby Boom Generation. The difference in risk suggests that there are unknown modifiable risk factors that may help to further explain the etiology of CS impairment and provide potential pathways for prevention in the future.

Prevalence of Age-related Maculopathy: The Beaver Dam Eye Study

The relationships of retinal drusen, retinal pigmentary abnormalities, and macular degeneration to age and sex were studied in 4926 people between the ages of 43 and 86 years who participated in the Beaver Dam Eye Study. The presence and severity of various characteristics of drusen and other lesions typical of age-related maculopathy were determined by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. One or more drusen were present in the macular area of at least 1 eye in 95.5% of the population. People 75 years of age or older had significantly higher frequencies (P < 0.01) of the following characteristics than people 43 to 54 years of age: larger sized drusen (>125 /μm, 24.0% versus 1.9%), soft indistinct drusen (23.0% versus 2.1%), retinal pigment abnormalities (26.6% versus 7.3%), exudative macular degeneration (5.2% versus 0.1%), and geographic atrophy (2.0% versus 0%). These data indicate signs of age-related maculopathy are common in people 75 years of age or older and may pose a substantial public health problem.

Oxidized Low-density Lipoprotein and the Incidence of Age-related Macular Degeneration

To examine the relationship between serum oxidized low-density lipoprotein (ox-LDL) cholesterol and the incidence of age-related macular degeneration (AMD) over a 25-year period in a sample of persons from the population-based Beaver Dam Eye Study (BDES). Observational prospective cohort study. A total of 4972 people from the BDES (aged 43-84 years and living in Beaver Dam, Wisconsin in 1988) seen during at least 1 of 6 examination phases at approximately 5-year intervals between 1988 and2016. A 50% random sample of participants (N= 2468) was selected for ox-LDL measurements. Stored frozen specimens from every examination phase were processed using an enzyme-linked immunosorbent assay from a single batch. All available intervals were included for a person, resulting in 6586 person-visits. Age-related macular degeneration was assessed using the Wisconsin Age-related Maculopathy Grading System, and severity was defined using a 5-step severity scale. The severity of the worse eye at each examination was used for analyses. A multi-state Markov (MSM) model was fit to simultaneously assess the ox-LDL relationship to all AMD transitions, including incidence of any AMD, incidence of late AMD, and worsening and improvement of AMD over the 25 years of the study. The mean (standard deviation) level of ox-LDL was 75.3 (23.1) U/L at the baseline examination. When adjusting for age, sex, ARMS2 and CFH risk alleles, and examination phase, the ox-LDL at the beginning of a period was not statistically significantly associated with the incidence of any AMD (hazard ratio per 10 U/L ox-LDL was 1.03, 95% confidence interval 0.98,1.09). Furthermore, ox-LDL was not associated with worsening anywhere along the AMD severity scale, nor with incidence of late AMD. The lack of relationships of ox-LDL to the incidence of any AMD or worsening of AMD remained after adjustment for history of statin use, smoking status, body mass index, and history of cardiovascular disease (data not shown). Our findings do not provide evidence for statistically significant relationships between ox-LDL and AMD disease development or worsening of AMD.

Refraction and Change in Refraction Over a 20-Year Period in the Beaver Dam Eye Study.

PurposeHyperopic shifts in refraction have been consistently reported in adults over 40, followed by myopic shifts after age 70. Although potential factors underlying these changes in refraction in older adults have been investigated previously, the studies were restricted by the limited longitudinal data available. The authors of this study sought to better characterize the long-term trajectory of refraction in older adults using 20 years of prospective data.MethodsThe impact of cohort effects on refraction over 20 years was examined. Generalized estimating equations were used to evaluate the etiologic factors underlying refraction and changes in refraction measured over a 20-year period (1988–2010) among adults over age 40 from the Beaver Dam Eye Study.ResultsOnly individuals with nuclear cataract experienced a myopic shift in refraction, showing a 0.25 diopter (D) decrease (95% confidence interval [CI]: −0.44 D to −0.07 D) over a five-year period. Individuals with mild and moderate nuclear sclerosis showed varying degrees of hyperopic shifts over five years (0.22 D: 95% CI: 0.20 D–0.25 D; 0.23 D: 95% CI: 0.20 D–0.27 D, respectively).ConclusionsNuclear cataract is the primary contributor to the myopic shift among older individuals. Birth cohort effects on baseline refraction but not change in refraction were observed.

Association analysis of exome variants and refraction, axial length, and corneal curvature in a European-American population.

Refractive errors, myopia, and hyperopia are common visual disorders greatly affecting older individuals. Refraction is determined by genetic factors but only a small percentage of its variation has been explained. We performed a genetic association analysis with three ocular phenotypes: spherical equivalent (a continous measure of refraction), axial length, and corneal curvature in 1,871 European-Americans from the Beaver Dam Eye Study. Individuals were genotyped on the Illumina exome array and imputed to the Haplotype Reference Consortium reference panel. After increasing the number of analyzed variants in targeted protein-coding regions 10-fold via imputation, we confirmed associations for two previously known loci with corneal curvature (chr4q12, rs2114039; g.55092626T>C, β=-0.03 (95% confidence interval [CI]): -0.06, -0.01, P value=0.01) and spherical equivalent (chr15q14, rs634990; g.35006073T>C, β=-0.27, 95% CI: -0.45, -0.09, P value=3.79×10-3 ). Despite increased single nucleotide polymorphism (SNP) density, we did not detect any novel significant variants after correction for multiple comparisons. In summary, we confirmed two previous loci associated with corneal curvature and spherical equivalent in a European-American population highlighting the potential biological role of those regions in these traits.

Skin Intrinsic Fluorescence and Age-Related Macular Degeneration: The Beaver Dam Eye Study.

PurposeTo determine if skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin is associated with AMD.MethodsSIF was measured with the SCOUT DS skin fluorescence spectrometer in a cross-sectional cohort study of 969 persons aged 68 to 102 years from the 1181 who participated in the 25-year follow-up examination in the Beaver Dam Eye Study (BDES) in 2014 to 2016. The SCOUT DS skin fluorescence spectrometer uses five light-emitting diodes, centered at 375 nm to 456 nm. AMD was assessed by grading of digital color 45° stereoscopic fundus photographs of the macula using the Wisconsin Age-Related Maculopathy grading scheme. Analyses included logistic regression with generalized estimating equations to account for correlation between the eyes of a person.ResultsThere were data for 1827 eyes for analyses. Early AMD was present in 22% and late AMD in 4% of the eyes. While adjusting for age, sex, smoking status, and history of cardiovascular disease, there were no significant associations of any SIF measure with any AMD or exudative AMD. SIF01 (odds ratio per 1 SD difference on the log scale, 95% confidence interval) (1.66, 1.00–2.74, P = 0.05) and SIF03 (1.81, 1.16–2.81, P = 0.008) were associated with geographic atrophy.ConclusionsThere was a suggestive relationship of two SIF measures, SIF01 and SIF03, using different correction factors from the excitation centered at 375 nm, with the prevalence of geographic atrophy in the BDES. Longitudinal follow-up is indicated to assess a temporal relationship.

Exome Array Analysis of Nuclear Lens Opacity

ABSTRACTPurpose: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data.Methods: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status.Results: No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10–6; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10–5). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10–6) and among never smokers (N = 790, p = 2.67 × 10–6).Conclusions: This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.

Generational Differences in the 5-Year Incidence of Age-Related Macular Degeneration

Whether a reported decline in the risk of developing age-related macular degeneration (AMD) continued for people born during the Baby Boom years (1946-1964) or later is unknown. These data are important to plan for ocular health care needs in the 21st century. To determine whether the 5-year risk for AMD declined by generation and to identify factors that contributed to improvement in risk. Data came from the longitudinal cohort Beaver Dam Eye Study (March 1, 1988, through September 15, 1990, and March 1, 1993, through June 15, 1995) and the Beaver Dam Offspring Study (June 8, 2005, through August 4, 2008, and July 12, 2010, through March 21, 2013). These population-based studies examined residents of Beaver Dam, Wisconsin, aged 43 to 84 years in 1987 through 1988 and their adult offspring aged 21 to 84 years in 2005 through 2008. A total of 4819 participants were at risk for developing AMD based on fundus images obtained at baseline visits. Data were analyzed from February 18, 2016, through June 22, 2017, with additional analyses ending September 22, 2017. Fundus images were graded for AMD using the Wisconsin Age-related Maculopathy Grading System. The incidence of AMD was defined as the presence at the 5-year follow-up examination of pure geographic atrophy or exudative macular degeneration, any type of drusen with pigmentary abnormalities, or soft indistinct drusen without pigmentary abnormalities. Among the 4819 participants, the mean (SD) baseline age of the cohort was 54 (11) years; 2117 were men (43.9%) and 2702 were women (56.1%). The 5-year age- and sex-adjusted incidence of AMD was 8.8% in the Greatest Generation (born during 1901-1924), 3.0% in the Silent Generation (born during 1925-1945), 1.0% in the Baby Boom Generation (born during 1946-1964), and 0.3% in Generation X (born during 1965-1984). Adjusting for age and sex, each generation was more than 60% less likely to develop AMD than the previous generation (relative risk, 0.34; 95% CI, 0.24-0.46). The generational association (relative risk, 0.40; 95% CI, 0.28 to 0.57) remained significant after adjusting for age, sex, smoking, educational attainment, exercise, levels of non–high-density lipoprotein cholesterol and high-sensitivity C-reactive protein, and use of nonsteroidal anti-inflammatory drugs, statins, and multivitamins. The 5-year risk for AMD declined by birth cohorts throughout the 20th century. Factors that explain this decline in risk are not known. However, this pattern is consistent with reported declines in risks for cardiovascular disease and dementia, suggesting that aging Baby Boomers may experience better retinal health at older ages than did previous generations.

Gene therapy for the long term treatment of wet AMD

Age-related macular degeneration (AMD) is the most common cause of visual impairment in elderly populations of the developed world, 1 Klein R Klein BE Linton KL Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992; 99: 933-943 Summary Full Text PDF PubMed Scopus (1614) Google Scholar and neovascular AMD (wet AMD) accounts for 90% of severe vision loss in patients with AMD. Wet AMD is associated with the upregulation of vascular endothelial growth factor (VEGF), which promotes angiogenesis and vascular permeability. 2 Kwak N Okamoto N Wood JM Campochiaro PA VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2000; 41: 3158-3164 PubMed Google Scholar Recently, therapies using recombinant anti-VEGF antibody fragments (eg, ranibizumab, bevacizumab, and aflibercept) 3 Lynch SS Cheng CM Bevacizumab for neovascular ocular diseases. Ann Pharmacother. 2007; 41: 614-625 Crossref PubMed Scopus (139) Google Scholar , 4 Rosenfeld PJ Rich RM Lalwani GA Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am. 2006; 19: 361-372 PubMed Scopus (287) Google Scholar , 5 Schmidt-Erfurth U Kaiser PK Korobelnik JF et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014; 121: 193-201 Summary Full Text Full Text PDF PubMed Scopus (602) Google Scholar to inhibit VEGF activity have shown that wet AMD can be treated successfully. However, the necessity for frequent intravitreal injections at 4–8 week intervals is expensive, 6 Levison D Medicare payments for drugs used to treat wet age-related macular degeneration. Department of Health and Human Services, Washington, DC2012 Google Scholar inconvenient for the patient, and carries the risk of infections such as endophthalmitis. 7 Day S Acquah K Mruthyunjaya P Grossman DS Lee PP Sloan FA Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular degeneration. Am J Ophthalmol. 2011; 152: 266-272 Summary Full Text Full Text PDF PubMed Scopus (129) Google Scholar Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trialIntravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies. Full-Text PDF

Six-Year Incidence of Age-Related Macular Degeneration in Asian Malays: The Singapore Malay Eye Study

To determine the 6-year incidence of early and late age-related macular degeneration (AMD) in a Singaporean Malay population and to validate the Age-Related Eye Disease Study (AREDS) simplified severity scale in Asians. Prospective, population cohort study. The Singapore Malay Eye Study baseline participants (age, ≥40 years; 2006-2008) were followed up in 2011 through 2013, and 1901 of 3280 of eligible participants (72.1%) took part. Fundus photographs were graded using the Wisconsin AMD grading system. Incidence of early and late AMD. Gradable fundus photographs were available for 1809 participants who attended both baseline and 6-year follow-up examinations. The age-standardized incidences of early and late AMD were 5.89% (95% confidence interval [CI], 4.81-7.16) and 0.76% (95% CI, 0.42-1.29), respectively. The 5-year age-standardized incidence of early AMD (calculated based on the 6-year incidence) was lower in our population (5.58%; 95% CI, 4.43-7.01) compared with the Beaver Dam Eye Study population (8.19%). The incidence of late AMD in our population was similar to that of the Beaver Dam Eye Study population (0.98% [95% CI, 0.49-1.86] vs. 0.91%), the Blue Mountains Eye Study population (1.10% [95% CI, 0.52-9.56] vs. 1.10%), and the Hisayama Study population (1.09% [95% CI, 0.54-4.25] vs. 0.84%). The incidence of late AMD increased markedly with increasing baseline AREDS score (step 0, 0.23%; step 4, 9.09%). This study documented the incidence of early and late AMD in a Malay population. The AREDS simplified severity scale is useful in predicting the risk of late AMD development in Asians.

Serum Phosphate and Retinal Microvascular Changes: The Multi-Ethnic Study of Atherosclerosis and the Beaver Dam Eye Study

ABSTRACTPurpose: Higher levels of serum phosphate are strongly linked to increased risk of cardiovascular disease and therapies aimed to lower serum phosphate are employed in the management of patients with chronic kidney disease (CKD). Data are limited, however, on serum phosphate as a risk factor for microvascular disease in community-based populations. It is important to determine the impact of novel risk factors, such as phosphate, on the microvasculature.Methods: We conducted a prospective study of 3919 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and 3544 individuals in the Beaver Dam Eye Study (BDES) to test the associations of serum phosphate with retinopathy and retinal vessel caliber, and change in retinopathy severity and change in retinal vessel caliber.Results: Mean (standard deviation) serum phosphate was 3.66 (0.52) mg/dl in the MESA and 3.77 (0.55) mg/dl in the BDES. In multivariable adjusted models, phosphate was significantly associated with prevalent retinopathy in the MESA (Odds Ratio [OR] per 1 mg/dl increase in phosphate, 1.22; Confidence Interval [CI] 1.02–1.47) and the BDES (OR 1.06; CI 1.01–1.11). In stratified analyses, these relationships were even stronger and only seen in individuals with diabetes in both the MESA (OR 1.81; CI 1.30–2.53) and the BDES (OR 1.16; CI 1.05–1.29). Phosphate was not associated with incident or change in retinopathy severity, nor any retinal caliber outcome.Conclusions: Among community-living individuals with low prevalence of CKD, higher serum phosphate was associated with prevalent retinopathy in individuals with diabetes. Further longitudinal assessments in patients with diabetes necessitate further investigation.

Five-year progression of unilateral age-related macular degeneration to bilateral involvement: the Three Continent AMD Consortium report

PurposeTo assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors.DesignPooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver...

Nerve Fiber Layer Thickness and Characteristics Associated with Glaucoma in Community Living Older Adults: Prelude to a Screening Trial?

ABSTRACTPurpose: To examine the associations of nerve fiber layer (NFL) thickness with other ocular characteristics in older adults.Methods: Participants in the Beaver Dam Eye Study (2008–2010) underwent spectral domain optical coherence tomography (SD-OCT) scans of the optic nerve head, imaging of optic discs, frequency doubling technology (FDT) perimetry, measurement of intraocular pressure (IOP), and an interview concerning their history of glaucoma and use of drops to lower eye pressure. Self-reported histories of glaucoma and the use of drops to lower eye pressure were obtained at follow-up examinations (2014–2016).Results: NFL thickness measured on OCTs varied by location around the optic nerve. Age was associated with mean NFL thickness. Mean NFL was thinnest in eyes with larger cup/disc (C/D) ratios. Horizontal hemifield defects or other optic nerve-field defects were associated with thinner NFL. NFL in persons who reported taking eye drops for high intraocular pressure was thinner compared to those not taking drops. After accounting for the presence of high intraocular pressure, large C/D ratios or hemifield defects, eyes with thinner NFL in the arcades were more likely (OR = 2.3 for 30 micron thinner NFL, p = 0.04) to have incident glaucoma at examination 5 years later.Conclusion: Retinal NFL thickness was associated with a new history of self-reported glaucoma 5 years later. A trial testing the usefulness of NFL as part of a screening battery for predicting glaucoma in those previously undiagnosed might lead to improved case finding and, ultimately, to diminishing the risk of visual field loss.

The Incidence and Progression of Age-Related Macular Degeneration over 15 Years: The Blue Mountains Eye Study

Purpose To assess the 15-year incidence and progression of age-related macular degeneration (AMD) in an older Australian population. Design Population-based cohort study. Participants Blue Mountains Eye Study (BMES) participants (n = 3654) aged 49+ years were examined during 1992–1994. Of these, 2334 (75.8% of survivors) were reexamined after 5 years (1997–1999), 1952 (76.7% of survivors) after 10 years (2002–2004), and 1149 (56.1% of survivors) after 15 years (2007–2010). Methods Color retinal photographs were taken, and comprehensive questionnaires were administered at each visit and DNA was genotyped. Retinal photographic grading was performed by the same graders following the Wisconsin AMD grading protocol. Side-by-side comparisons were used to confirm newly developed AMD lesions. Incidence was estimated using Kaplan–Meier estimates. Associations of AMD incidence with age, sex, smoking status, presence of the complement factor H (CFH)-rs1061170 and age-related maculopathy susceptibility 2 (ARMS2)-rs10490924 polymorphisms, and fish consumption were analyzed using discrete logistic regression models. Generalized estimation equation models were used to assess the risk of incident late AMD associated with baseline AMD lesion characteristics. Main Outcome Measures The 15-year incidence and progression of AMD, and associated factors. Results The 15-year incidence was 22.7% for early AMD and 6.8% for late AMD. After adjusting for competing risks, early and late AMD incidence were 15.1% and 4.1%, respectively. Age was strongly associated with early and late AMD incidence (both P 0.0001). After age standardization to the Beaver Dam Eye Study (BDES) population, early and late AMD incidence in the BMES were 13.1% and 3.3%, respectively. Female sex and the presence of both risk alleles of CFH-rs1061170 or ARMS2-rs10490924 were independently associated with early AMD incidence, whereas current smoking and presence of ≥1 risk allele of CFH-rs1061170 or ARMS2-rs10490924 were associated with late AMD incidence. Fish consumption was inversely associated with late but not early AMD incidence. Severity of early AMD lesion characteristics was a strong predictor of progression to late AMD. Conclusions We documented the 15-year incidence of early and late AMD in an older Australian population that were comparable to BDES observations. Risk of progression to late AMD was strongly associated with severity of early AMD lesions.

Smoking, central adiposity, and poor glycemic control increase risk of hearing impairment.

To determine associations between smoking, adiposity, diabetes mellitus, and other risk factors for cardiovascular disease (CVD) and the 15-year incidence of hearing impairment (HI). A longitudinal population-based cohort study (1993-95 to 2009-10), the Epidemiology of Hearing Loss Study (EHLS). Beaver Dam, Wisconsin. Participants in the Beaver Dam Eye Study (1988-90; residents of Beaver Dam, WI, aged 43-84 in 1987-88) were eligible for the EHLS. There were 1,925 participants with normal hearing at baseline. Fifteen-year cumulative incidence of HI (pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz greater than 25 decibels hearing level in either ear). Cigarette smoking, exercise, and other factors were ascertained according to questionnaire. Blood pressure, waist circumference, body mass index, and glycosylated hemoglobin were measured. Follow-up examinations (≥1) were obtained from 87.2% (n=1,678; mean baseline age 61). The 15-year cumulative incidence of HI was 56.8%. Adjusting for age and sex, current smoking (hazard ratio (HR)=1.31, P=.048), education (<16 years; HR=1.35, P=.01), waist circumference (HR=1.08 per 10 cm, P=.02), and poorly controlled diabetes mellitus (HR=2.03, P=.048) were associated with greater risk of HI. Former smokers and people with better-controlled diabetes mellitus were not at greater risk. Smoking, central adiposity, and poorly controlled diabetes mellitus predicted incident HI. These well-known risk factors for CVD suggest that vascular changes may contribute to HI in aging. Interventions targeting reductions in smoking and adiposity and better glycemic control in people with diabetes mellitus may help prevent or delay the onset of HI.

Small Drusen and Age-Related Macular Degeneration: The Beaver Dam Eye Study.

We tested the hypothesis that large areas of small hard drusen (diameter <63 µm) and intermediate drusen (diameter 63–124 µm) are associated with the incidence of age-related macular degeneration (AMD). Eyes of 3344 older adults with at least two consecutive visits spaced five years apart over a 20-year period were included. A 6-level severity scale, including no drusen, four levels of increasing area (from minimal (<2596 µm²) to large (>9086 µm²)) of only small hard drusen, and intermediate drusen, was used. The five-year incidence of AMD was 3% in eyes at the start of the interval with no, minimal, small, and moderate areas of only small drusen and 5% and 25% for eyes with large area of only small drusen and intermediate drusen, respectively. Compared to eyes with a moderate area of small drusen, the odds ratio (OR) of developing AMD in eyes with a large area of only small drusen was 1.8 (p < 0.001). Compared to eyes with large area of only small drusen, eyes with intermediate drusen had an OR of 5.5 (p < 0.001) of developing AMD. Our results are consistent with our hypothesis that large areas of only small drusen are associated with the incidence of AMD.

Severity of age-related macular degeneration in 1 eye and the incidence and progression of age-related macular degeneration in the fellow eye: the Beaver Dam Eye Study.

Previous studies regarding the severity of age-related macular degeneration (AMD) in 1 eye and its prognostic implications for the fellow eye have focused on the incidence of neovascular AMD in the fellow eye of participants with neovascular AMD in the other eye. It is unclear to what extent the severity of AMD in 1 eye affects the incidence, progression, and regression of AMD in its fellow eye across the entire range of AMD severity. To investigate the effect of the severity of AMD in 1 eye on the incidence, progression, and regression of AMD in the fellow eye. The Beaver Dam Eye Study is a longitudinal population-based study of age-related eye diseases conducted in the city and township of Beaver Dam, Wisconsin. Examinations were performed every 5 years over a 20-year period (from the baseline examination in 1988-1990 to 2008-2010). Study participants (n = 4379) were 43 to 86 years of age at the baseline examination. At baseline and in up to 4 subsequent examinations, retinal photographs were taken. Incidence, progression, and regression of AMD (assessed by use of the Wisconsin Age-Related Maculopathy Grading System on retinal photographs and adjusted for age, sex, and the Y402H polymorphism in the complement factor H gene on chromosome 1q) and mortality. More severe AMD in 1 eye was associated with increased incidence of AMD and accelerated progression in its fellow eye (levels 1-2: hazard ratio [HR], 4.90 [95% CI, 4.26-5.63]; levels 2-3: HR, 2.09 [95% CI, 1.42-3.06]; levels 3-4: HR, 2.38 [95% CI, 1.74-3.25]; levels 4-5: HR, 2.46 [95% CI, 1.65-3.66]). Less severe AMD in 1 eye was associated with less progression of AMD in its fellow eye (levels 2-3: HR, 0.42 [95% CI, 0.33-0.55]; levels 3-4: HR, 0.50 [95% CI, 0.34-0.83]). We estimate that 51% of participants who develop any AMD always maintain AMD severity states within 1 step of each other between eyes; 90% of participants stay within 2 steps. Using multistate models, we show that AMD severity in 1 eye tracks AMD severity in its fellow eye.

The Epidemiology of Vitreoretinal Interface Abnormalities as Detected by Spectral-Domain Optical Coherence Tomography: The Beaver Dam Eye Study

To describe the prevalence and interrelationships of epiretinal membranes (ERMs), vitreomacular traction (VMT), macular cysts, paravascular cysts (PVCs), lamellar macular holes (LMHs), full-thickness macular holes (FTMHs), and visual impairment in a population-based study of older adults. Cross-sectional study. There were 1913 participants aged 63 to 102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008-2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD OCT) scans of the macula in at least 1 eye. The presence of ERMs and other retinal lesions was determined by standardized grading of macular SD OCT scans and photographs of 3 standard fields. Epiretinal membranes, VMT, macular cysts, PVCs, LMHs, FTMHs, and visual impairment. By using SD OCT, the prevalence of ERMs (34.1%), VMT (1.6%), macular cysts (5.6%), PVCs (20.0%), LMHs (3.6%), and FTMHs (0.4%) was estimated. The prevalence of macular cysts (P < 0.001), ERMs (P < 0.001), and VMT (P = 0.005) increased with age; the prevalence of PVCs (P = 0.05) decreased with age; and the prevalence of LMHs was not associated with age (P = 0.70). The prevalence of macular cysts, LMHs, and ERMs was higher in eyes with a history of cataract surgery. Macular cysts and ERMs were more common in eyes with retinal diseases, such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment, than in eyes without these conditions. Macular cysts, ERMs, and FTMHs were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR], 3.96; P < 0.0001), PVCs (OR, 1.45, P = 0.007), LMHs (OR, 10.62; P < 0.001), VMT (OR, 2.72, P = 0.01), and visual impairment (OR, 3.23; P < 0.001) were more frequent in eyes with ERMs compared with eyes without ERMs. Epiretinal membranes are associated with macular cysts, PVCs, LMHs, VMT, and visual impairment. Further follow-up will allow better understanding of the natural history of ERMs and VMT and their relationships to the development of macular cysts and LMHs in the aging population.

Exome array analysis identifies CAV1/CAV2 as a susceptibility locus for intraocular pressure.

Intraocular pressure (IOP) is an important clinical parameter in the evaluation of ocular health. Elevated IOP is a major risk factor for primary open-angle glaucoma (POAG). The goal of this study was to identify rare and less common variants that influence IOP. We performed an exome array analysis in a subset of 1660 individuals from a population-based cohort, the Beaver Dam Eye Study. Associations with IOP were tested on 45,849 single nucleotide variants and 12,390 autosomal genes across the genome. Intraocular pressure was suggestively associated with novel variants located in FAR2 at 12p11.22 (rs4931170, P = 1.2 × 10(-5)), in GGA3 at 17q25.1 (rs52809447, P = 6.7 × 10(-5)), and in PKDREJ at 22q13.31 (rs7291444, P = 7.4 × 10(-5)). Gene-based analysis found suggestive associations between IOP and the genes HAP1, MTBP, FREM3, and PHF12. We successfully replicated the associations with GAS7 (P = 7.4 × 10(-3)) for IOP, and also identified a previously reported POAG locus in the CAV1/CAV2 region to be associated with IOP (P = 3.3 × 10(-3)). This association was confirmed in a meta-analysis with three published genome-wide association studies (Pcombined = 4.0 × 10(-11)). Our results suggest that novel genetic variants and genes with multiple, less common variants may play a role in the control of IOP. The implication of the caveolin genes, CAV1/CAV2, as a common genetic factor influencing both IOP variations and POAG may provide new insights of the underlying mechanism leading to glaucoma and glaucomatous visual field loss.