Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer.

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

Generalizability of established prostate cancer risk variants in men of African ancestry.

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

8q24 risk alleles and prostate cancer in African-Barbadian men.

BACKGROUND: African American men (AA) exhibit a disproportionate share of prostate cancer (PRCA) incidence, morbidity, and mortality. Several genetic association studies have implicated select 8q24 loci in PRCA risk in AA. The objective of this investigation is to evaluate the association between previously reported 8q24 risk alleles and PRCA in African-Barbadian (AB) men known to have high rates of PRCA. METHODS: Ten previously reported candidate tag SNPs were genotyped and/or imputed in the 8q24 region in 532 AB men with PRCA and 513 AB controls from the Prostate Cancer in a Black Population (PCBP) study. RESULTS: Rs2124036 was significant in AB men, (OR = 2.7, 95% CI (1.3-5.3), P = 0.005, Empirical (max (T), corrected for multiple testing) P = 0.03) for the homozygous C/C genotype. Only a single SNP from this region remained statistically significant in our analysis of our AB population. These results may indicate the presence of a founder effect or due to the chosen SNPs not tagging an ancestral haplotype bearing the 8q24 risk allele(s) in this population or could reflect inadequate power to detect an association. We conducted a meta-analysis including our AB population along with two additional African Caribbean populations from Tobago and Jamaica for SNPs rs16901979 and rs1447295. Meta-analysis results were most significant for rs16901979 A allele (Z score 2.73; P = 0.006) with a summary OR = 1.31 (95% CI: 1.09-1.58). CONCLUSIONS: Additional studies are needed to provide deeper genotype coverage to further interrogate the 8q24 region to understand its contribution to PRCA in this population.

A genome-wide association study of breast cancer in women of African ancestry.

Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.

Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry.

Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.

Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados.

Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Although a number of genetic loci have shown association or genetic linkage to monogenic forms of POAG, the identified genes and loci do not appear to have a major role in the common POAG phenotype. We seek to identify genetic loci that appear to be major risk factors for POAG in the Afro-Caribbean population of Barbados, West Indies. We performed linkage analyses in 146 multiplex families ascertained through the Barbados Family Study of Glaucoma (BFSG) and identified a strong linkage signal on chromosome 2p (logarithm of odds score = 6.64 at = 0 with marker D2S2156). We subsequently performed case-control analyses using unrelated affected individuals and unaffected controls. A set of SNPs on chromosome 2p was evaluated in two independent groups of BFSG participants, a discovery group (130 POAG cases, 65 controls) and a replication group (122 POAG cases, 65 controls), and a strong association was identified with POAG and rs12994401 in both groups (P < 3.34 E-09 and P < 1.21E-12, respectively). The associated SNPs form a common disease haplotype. In summary, we have identified a locus with a major impact on susceptibility to the common POAG phenotype in an Afro-Caribbean population in Barbados. Our approach illustrates the merit of using an isolated population enriched with common disease variants as an efficient method to identify genetic underpinning of POAG.

Validation of a quantitative FFQ for the Barbados National Cancer Study.

OBJECTIVE: To assess the validity of a 148-item quantitative FFQ (QFFQ) that was developed for the Barbados National Cancer Study (BNCS) to determine dietary intake over 12 months and examine the dietary risk factors. DESIGN: A cross-sectional validation study of the QFFQ against 4 d food diaries. Spearman's rank correlations (ρ), intra-class correlation coefficients (ICC) and weighted κ were computed as measures of concordance, adjusting for daily variations in the food diaries. Cross-classification tables and Bland-Altman plots were created for further assessment. SETTING: BNCS is a case-control study of environmental risk factors for breast and prostate cancer in a predominantly African-origin population in Barbados. SUBJECTS: Fifty-four individuals (21 years and older) were recruited among controls in the BNCS who were frequency-matched on sex and age group to breast and prostate cancer cases. RESULTS: Similar mean daily energy intake was derived from the food diary (8201 kJ (1960 kcal)) and QFFQ (7774 kJ (1858 kcal)). Rho for energy and macronutrients ranged from 0·66 (energy) to 0·17 (dietary fibre). The percentage of energy from carbohydrates and protein showed the highest and lowest ICC among macronutrients (0·63 and 0·27, respectively). The highest weighted κ was observed for energy (0·45). When the nutrient intake was divided into quartiles, approximately 34 % of the observations were in the same quartile. CONCLUSIONS: This investigation supports the validity of the QFFQ as a method for assessing long-term dietary intake except for dietary fibre, folate, vitamins A, E and B12. The instrument will be a useful tool in the analysis of diet-cancer associations in the BNCS.

Causes of visual loss and their risk factors: an incidence summary from the Barbados Eye Studies.

OBJECTIVES: To summarize incidence and risk factors for each main cause of visual loss in an African-Caribbean population and discuss the implications of these data from a public health perspective. METHODS: A nationally representative cohort (n = 4 709; ages 40-84 years at baseline) had ophthalmic and other examinations over 9 years. Incidence rates were estimated by the product-limit approach. Risk factors were evaluated from Cox regression models. RESULTS: Average incidence was ~ 0.1% per year for blindness (< 6/120) and 0.7% per year for low vision (< 6/18 to 6/120), increasing steeply with age (P < 0.05) and affecting related quality of life (P < 0.05). Age-related cataract and open-angle glaucoma (OAG) accounted for 73.2% of blindness and diabetic retinopathy (DR) for 8.9%; cataract caused two-thirds of low vision. Average incidence was 5.1% per year for all lens changes (gradable/ungradable opacities or aphakia) and 0.4% per year for cataract surgery. Incidence of definite OAG was 0.5% per year (0.9% for suspect or probable); 53% of the affected were unaware. Persons with diabetes mellitus (DM) had a DR incidence of 4.4% per year. Age-related macular degeneration was rare (0.08% per year). Main cataract risk factors were age and DM. OAG incidence increased with age, intraocular pressure, family history, low ocular perfusion pressures, and thinner corneas. DR risk increased with early DM onset, DM duration, oral/insulin treatment, increased systolic and diastolic blood pressures, and hyperglycemia. Antihypertensive treatment halved DR risk. CONCLUSIONS: Incidence of visual impairment was high and significantly affected quality of life. Age-related cataract and OAG caused ~ 75% of blindness, indicating the need for public health action to increase appropriate cataract surgery and early OAG detection and treatment. Controlling DM and hypertension would help prevent DR-related complications and could lower cataract risk, further decreasing visual loss.

Risk factors for breast cancer in a black population--the Barbados National Cancer Study.

The Barbados National Cancer Study (BNCS) is a nationwide case-control study investigating environmental and genetic factors for breast cancer (BC) in a predominantly African-origin population with similar ancestry as African-Americans. This report evaluates associations of incident BC in the BNCS to various factors, including demographic, anthropometric, reproductive and family history variables, not investigated previously in this population. The BNCS included 241 incident BC cases and 481 age-matched female controls, with mean ages of 57 and 56 years, respectively. In addition to a reported family history of BC in a close relative [odds ratios (OR) = 3.74, 95% CI (1.41, 9.90) in a parent; OR = 3.26 (1.47, 7.21) in a sibling], other factors associated with BC were older age at first full-term pregnancy [OR = 1.04 (1.00, 1.07)] and having a history of benign breast disease [OR = 1.88 (1.19, 2.99)]. Increased parity reduced the risk of BC [OR = 0.34 (0.15, 0.77) among those with >or=3 children]. The reproductive patterns of African-Barbadian (AB) women tended to differ from those of African-American (AA) women (later age of menarche, earlier age at first pregnancy, higher frequency of lactation and infrequent use of exogenous hormones) and could help to explain their considerably lower postmenopausal incidence of BC. The relationship between reported family history and BC, combined with the associations noted for several reproductive and other variables, supports the genetic and environmental contributions to BC, which may vary in populations across the African diaspora. Further investigations of other populations may clarify these issues.

Body size and breast cancer in a black population--the Barbados National Cancer Study.

OBJECTIVE: To evaluate the relationship between body size and incident breast cancer in an African-origin Caribbean population. METHODS: This investigation is based on 222 incident breast cancer cases and 454 controls from the Barbados National Cancer Study (BNCS) in whom body size variables that included height, weight, body-mass index (BMI), waist and hip circumferences (WC, HC), and waist-hip ratio (WHR) were compared. Multivariate-adjusted logistic regression analyses were performed and the findings are presented as odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: Although 33% of cases and 39% of controls were obese (BMI > or = 30 kg/m(2)), BMI was not found to be a significant predictor of breast cancer in the multivariate analyses. Tall stature increased risk among women > or =50 years (OR = 2.16, 95% CI (1.02, 4.58)), and a dual effect with age was suggested for both WC and WHR (decreased risk for those aged < or =50 years; increased risk among those > or =50 years). CONCLUSIONS: Body size appears to influence the risk of breast cancer in this population of African origin. The BNCS data suggest that a few, but not all body size factors play a role in breast cancer risk, and that age may affect these relationships.

Natural history of open-angle glaucoma.

OBJECTIVE: This article, based on the Early Manifest Glaucoma Trial (EMGT), provides prospective natural history data on progression of glaucomatous field defects in 3 of the most common glaucoma types. DESIGN: Cohort of EMGT patients randomized to the untreated control group and followed up to the time of progression, when treatment could be initiated. PARTICIPANTS: We evaluated 118 control patients: 46 with high-tension glaucoma (HTG), 57 with normal-tension glaucoma (NTG), and 15 with pseudoexfoliation glaucoma (PEXG). METHODS: Visual fields were tested every 3 months with the Humphrey 30-2 Full Threshold test program. MAIN OUTCOME MEASURES: Linear regression analyses of the perimetric mean deviation (MD) values were performed, and the rate of progression was defined as the regression coefficient in decibels per year. Percentages of progressed eyes and time to progression were determined using EMGT event-based predetermined progression criteria derived from Glaucoma Change Probability Maps. RESULTS: The median and interquartile rates of visual function loss were -0.40 (1.05) dB/year overall and -0.46 (1.61) in HTG, -0.22 (0.65) in NTG, and -1.13 (6.13) in PEXG. Thus, interpatient variability was large. Mean rates were considerably higher than medians: -1.08 dB/year overall, -1.31 in HTG, -0.36 in NTG, and -3.13 in PEXG. Differences in median visual function progression rates among groups were statistically significant (NTG vs. HTG, P = 0.003; PEXG vs. non-PEXG, P<0.001). Progression was considerably and significantly faster in older than in younger patients (P = 0.002). By 6 years, 68% of patients had progressed overall, 74% of those with HTG, 56% of those with NTG, and 93% of those with PEXG (P = 0.012). Median time to progression also differed considerably among groups: 19.5 months in PEXG, 44.8 months in HTG, and particularly 61.1 months in NTG (P<0.0001). CONCLUSIONS: In this 6-year follow-up study, the median untreated rate of progression corresponded to advancing from normal visual function to blindness in approximately 70 years, whereas on the basis of the mean rate, visual function would show the same deterioration in approximately 25 years. Large differences existed among patients and different glaucoma types, with PEXG progressing considerably faster than HTG, and NTG progressing at the lowest rate.

Nine-year incidence of visual impairment in the Barbados Eye Studies.

OBJECTIVE: To describe the 9-year incidence of visual impairment and primary causes of blindness among black participants of the Barbados Eye Studies (BES). DESIGN: Population-based prospective cohort study. PARTICIPANTS: The BES followed a nationally representative cohort selected by simple random sampling, aged 40 to 84 years at baseline, with reexaminations after 4 years (Barbados Incidence Study of Eye Diseases [BISED]) and 9 years (BISED II). BISED II included 2793 (81%) of those eligible. METHODS: Cumulative 9-year incidence rates were estimated by the Product-Limit approach. The study was reviewed and approved by the institutional review boards of collaborating institutions. MAIN OUTCOME MEASURES: Best-corrected visual acuity (VA) was assessed by the Ferris-Bailey chart, following a modified Early Treatment of Diabetic Retinopathy Study protocol. Low vision and blindness were defined by World Health Organization (WHO) criteria as VA <6/18 to 6/120, and <6/120, respectively, in the better eye, and by U.S. criteria as VA < or =20/40 and < or =20/200, respectively. Vision loss was defined as a decrease of 15 letters or more read correctly in the better eye between baseline and follow-up examinations. RESULTS: The 9-year incidence was 1.0% and 2.1% for blindness and 6.0% and 9.0% for low vision, by WHO and U.S. criteria, respectively. Older age at baseline was associated with higher incidence of low vision and blindness, reaching 23.0% (95% confidence interval [CI], 18.8-28.0) and 4.3% (95% CI, 2.7-6.9) at age 70 years or more, based on WHO criteria. The primary causes of incident bilateral blindness (U.S. criteria) in 126 eyes were age-related cataract (48.3%), open-angle glaucoma (OAG) (14.3%), combined cataract and OAG (6.3%), diabetic retinopathy (8.7%), and optic atrophy (7.1%). Age-related macular degeneration (2.4%) rarely caused blindness. CONCLUSIONS: Incident visual impairment is exceedingly high in this population. Cataract, OAG, and diabetic retinopathy remain the major causes of blindness, underpinning the clinical and public health significance of these conditions in this and similar populations.

Ocular perfusion pressure and glaucoma: clinical trial and epidemiologic findings.

PURPOSE OF REVIEW: A possible connection between ocular perfusion pressure and open-angle glaucoma (OAG) has been hypothesized. This review summarizes the scientific rationale for the proposed relationship, presents recent data, and outlines potential implications. RECENT FINDINGS: Population-based epidemiologic studies found strong relationships between low ocular perfusion pressure and OAG prevalence, as well as OAG incidence. Clinical studies report similar associations between low perfusion pressure and OAG progression. These consistent findings suggest that altered blood flow in the optic disc increases both the risk of OAG development and the progression of established OAG. An underlying factor would be impaired vascular autoregulation, which may lead to poor perfusion in OAG. In contrast, there is conflicting evidence on the possible link of glaucoma to blood pressure/hypertension. SUMMARY: Current evidence supports the role of vascular factors as part of the multifactorial cause of OAG. As ocular perfusion pressure reflects the vascular status at the optic disc, it may be more relevant than systemic blood pressure alone. Although the associations of OAG to perfusion pressure are strong, consistent, and biologically plausible, they require careful interpretation. The evidence implicating a vascular cause in OAG is mounting, but the clinical implications for patient management are still uncertain.

Impact of glaucoma, lens opacities, and cataract surgery on visual functioning and related quality of life: the Barbados Eye Studies.

PURPOSE: To determine the relationship of open-angle glaucoma (OAG) and lens opacities to visual functioning and related quality of life (QOL), by using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) in a population of African origin. METHODS: The study included 962 black participants of the Barbados Eye Studies with known glaucoma, prior cataract surgery, visual acuity (VA)

Estimating the rate of progressive visual field damage in those with open-angle glaucoma, from cross-sectional data.

PURPOSE: To estimate the rate of visual field progression in open-angle glaucoma (OAG) subjects, by using data from population-based cross-sectional studies. METHODS: Subjects with OAG were identified in nine surveys of randomly sampled populations using standard criteria for glaucomatous optic neuropathy. Subjects were of European, African, Chinese, and Hispanic ethnicity. The measure of OAG damage was the mean deviation (MD) of an automated visual field test (Humphrey Field Analyzer; Carl Zeiss Meditec, Inc., Dublin, CA). The rate of progression was the mean of all subjects' damage in the worse eye divided by an average time since onset. Time since onset was estimated from age-specific prevalence rates. RESULTS: A total of 1066 subjects with OAG contributed visual field data. The mean worsening in decibels per year was: European-derived, -1.12; Hispanic, -1.26; African-derived, -1.33; and Chinese -1.56 (difference among ethnicities, P = 0.16). The mean duration of disease was lowest among Chinese persons at 10.5 years (95% CI: 8.8-12.6) and was highest in African-derived subjects at 15.4 years (95% CI: 14.6-15.9). The progression rate was not consistently related to age or gender. By combining disease duration and progression rate, the model predicted that 15% or fewer of the worse eyes would reach the end of the field damage scale in the patient's lifetime. CONCLUSIONS: The estimates of typical worsening per year in the worse eye among subjects with OAG suggested slightly more rapid progression than in some clinic-based studies. The rate did not differ significantly by ethnicity or gender, but was worse in those with known, treated OAG and in pseudophakic subjects.

Nine-year incidence and risk factors for pterygium in the barbados eye studies.

PURPOSE: To present 9-year incidence data and associated risk factors for pterygium among black participants in the Barbados Eye Studies. DESIGN: Population-based incidence study. PARTICIPANTS: A total of 1888 black participants, aged 40 to 84 years, who were free of pterygium at baseline and received an ophthalmologic study examination at the 9-year follow-up. METHODS: Age and sex-specific 9-year incidence of pterygium is presented. Risk factors were initially identified using Mantel-Haenszel analyses, and significant factors (P<0.10) were subsequently included in multivariate logistic regression models. Odds ratios (OR) and 95% confidence intervals (CI) are provided. MAIN OUTCOME MEASURES: Development of pterygium, defined as the presence of a raised fleshy growth that crosses the limbus and encroaches onto the clear cornea. RESULTS: The 9-year incidence of pterygium was 11.6% (95% CI, 10.1-13.1), with no clear pattern with increasing age and no statistically significant differences between genders. Multivariate logistic regression analyses indicated that having a lifetime outdoor job location was positively associated with the development of pterygium (OR = 1.51; 95% CI, 1.05-2.16), whereas darker skin color (OR = 0.67; 95% CI, 0.46-0.97) and use of any prescription lenses (OR = 0.58; 95% CI, 0.42-0.81) were found to be protective factors. CONCLUSIONS: The incidence of pterygium was high in this population, for an average of 1.3% per year. Working outdoors increased the risk 1.5-fold, whereas having a darker skin complexion and using eyewear for either reading or distance substantially decreased the risk of developing pterygium. These data suggest that absorption of ultraviolet light plays a role in this condition and that preventive strategies are needed to decrease the burden of pterygium development in this and other populations. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Disc hemorrhages and treatment in the early manifest glaucoma trial.

PURPOSE: To evaluate the effect of intraocular pressure (IOP)-reducing treatment on the development of disc hemorrhages in patients with glaucoma. DESIGN: Prospective cohort study of patients in the Early Manifest Glaucoma Trial, followed up to 11 years (median = 8 years). PARTICIPANTS: Patients with newly detected glaucoma randomized to argon laser trabeculoplasty plus betaxolol (n = 129) or no initial treatment (n = 126), followed with tonometry, perimetry, and ophthalmoscopy every 3 months, and fundus photography every 6 months. METHODS: Logistic regression expressed as odds ratios (OR) and 95% confidence intervals (CIs), analysis of variance, and Cox time-dependent models, expressed as hazard ratios (HRs) and CIs. MAIN OUTCOME MEASURES: Presence (yes/no) and frequency of disc hemorrhages. RESULTS: Disc hemorrhages were identified in approximately 55% of all patients, whether by ophthalmoscopy or review of photographs. In analyses including data up to the time of progression, disc hemorrhages were equally common among treated and control patients: 51.2% versus 45.2%, respectively (P = 0.34), based on ophthalmoscopy, and 50.4% versus 44.4%, respectively (P = 0.34), based on photographs. Gender was the only factor related to the presence of disc hemorrhages detected by both ophthalmoscopy (OR = 0.48; CI, 0.26-0.88; P = 0.022) and photographs (OR = 0.64; CI, 0.38-1.09; P = 0.099) for male patients. The frequency of disc hemorrhages over time did not differ between treated and control patients: 8.4% versus 8.5%, respectively (P = 0.93), based on ophthalmoscopy, and 12.4% versus 11.2%, respectively (P = 0.36), based on photographs. Disc hemorrhages were significantly associated with time to progression (HR = 1.02; CI, 1.01-1.04), and there was no evidence of interaction between treatment group and disc hemorrhages. CONCLUSIONS: IOP-reducing treatment was unrelated to the presence or frequency of disc hemorrhages. The results may suggest that disc hemorrhages cannot be considered an indication of insufficient IOP-lowering treatment, and that glaucoma progression in eyes with disc hemorrhages cannot be totally halted by IOP reduction. The results also suggest that disc hemorrhages do not occur in all patients with glaucoma.

Risk factors for incident open-angle glaucoma: the Barbados Eye Studies.

PURPOSE: To evaluate risk factors for definite open-angle glaucoma (OAG), based on African-descent participants of the Barbados Eye Studies. DESIGN: Cohort study with 81% to 85% participation over 9 years' follow-up. PARTICIPANTS: We evaluated 3222 persons at risk, 40 to 84 years old, who did not have definite OAG at baseline. METHODS: Participants had standardized study visits at baseline and after 4 and 9 years, with structured interviews, blood pressure (BP), and other measurements. The ophthalmic protocol included automated perimetry, applanation tonometry, fundus photography, and comprehensive ophthalmologic examinations for those referred. Central corneal thickness (CCT) was measured in a subset at the 9-year examination. Incidence was estimated by the product-limit approach; relative risk ratios (RRs) with 95% confidence intervals (CIs) were based on Cox regression models with discrete time. MAIN OUTCOME MEASURE: Nine-year incidence of definite OAG. RESULTS: Over 9 years, 125 persons developed definite OAG (incidence, 4.4%; 95% CI, 3.7-5.2). Baseline factors influencing risk were age (RR, 1.04; 95% CI, 1.02-1.05 per year); family history of glaucoma (RR, 2.4; 95% CI, 1.3-4.6); higher intraocular pressure (IOP) (RR, 1.12; 95% CI, 1.08-1.16 per mmHg); lower systolic BP (RR, 0.91; 95% CI, 0.84-1.00 per 10 mmHg); and lower ocular systolic, diastolic, and mean perfusion pressures (RR, 0.66; 95% CI, 0.54-0.80 per 10 mmHg higher mean perfusion pressure) (RR, 2.6; 95% CI, 1.4-4.6 for low mean perfusion pressure [<40 mmHg]). Thinner CCT was also associated with OAG incidence (odds ratio, 1.41; 95% CI, 1.01-1.96 per 40 mum lower). CONCLUSIONS: This is the first report of risk factors for long-term OAG incidence; it is also based on a sizable number of new cases. Incidence was high in this African-descent population, where the established factors of older age, higher IOP, and family history contributed to risk. Additional predictors were vascular factors, including lower systolic BP, and particularly lower ocular perfusion pressures, which more than doubled risk. Thinner CCT was also a factor. These findings indicate a multifactorial etiology of OAG and suggest that similar risk factors apply across populations. Results are relevant for understanding OAG causation and identifying groups at high risk.

A comparison of visual field progression criteria of 3 major glaucoma trials in early manifest glaucoma trial patients.

PURPOSE: Three major glaucoma trials, all using the same Humphrey visual field tests, specified different criteria to define visual field progression. This article compares the performance of these criteria with a reference standard of unanimous classifications by 3 independent glaucoma experts. DESIGN: Longitudinal, comparative study of diagnostic criteria. PARTICIPANTS AND CONTROLS: Two hundred forty-five patients with manifest glaucoma in the Early Manifest Glaucoma Trial (EMGT). METHODS: Visual field series of 1 eye of each of 245 EMGT patients were classified by 3 independent glaucoma specialists as definitely progressing, definitely nonprogressing, or neither. Field series that were classified in the first 2 categories by all 3 experts met the reference standards for the progressing and nonprogressing groups and were analyzed according to the progression criteria of the Advanced Glaucoma Intervention Study (AGIS), the Collaborative Initial Glaucoma Treatment Study (CIGTS), and the EMGT. Sensitivity, specificity, time to progression, and sustainability were calculated. MAIN OUTCOME MEASURES: Progression, nonprogression, sensitivity, specificity, time to progression, and sustainability. RESULTS: Seventy-seven field series were definitely progressing, and 95 series were definitely nonprogressing. Among progressing eyes, 45 (58%) of 77 were identified using AGIS criteria, 58 (75%) of 77 were identified with CIGTS criteria, and 74 (96%) of 77 were identified with EMGT criteria; all comparisons of sensitivities were significant, simultaneous (P<0.001), and pairwise (P<0.01). The specificity for EMGT criteria was 89%, lower (P<0.05) than that of AGIS (98%) and CIGTS (99%) criteria. Median time to progression was considerably shorter with EMGT criteria (33 months; 95% confidence interval [CI], 30-36 months) than with AGIS (66 months; 95% CI, 57-78 months) and CIGTS (55 months; 95% CI, 48-66 months) criteria. Sustainability increased with time after progression; it averaged 79%, 84%, and 81%, respectively, for AGIS, CIGTS, and EMGT criteria during the first year after the first progression and 95%, 100%, and 93% during the fourth year after progression. CONCLUSIONS: The EMGT criteria identified progression earlier and more often than AGIS and CIGTS criteria. Specificity was good for all criteria but was better with AGIS and CIGTS than with EMGT criteria. Sustainability was high for all 3 sets of criteria and best for CIGTS criteria and increased with time after progression.

Open-angle glaucoma and mortality: The Barbados Eye Studies.

OBJECTIVE: To evaluate the relationship between open-angle glaucoma (OAG) and mortality in a black population at 9-years' follow-up. DESIGN: Population-based cohort study of 4092 black participants (aged 40-84 years at baseline) in the Barbados Eye Studies. Open-angle glaucoma was defined by visual field defects and optic disc damage, based on standardized examinations and photograph gradings. Ocular hypertension was defined by an intraocular pressure greater than 21 mm Hg or treatment, without OAG damage. Mortality was ascertained from death certificates. Cox proportional hazards regression analyses determined associations with mortality. RESULTS: After 9 years, 764 (19%) participants were deceased. Mortality was unrelated to overall OAG at baseline (n = 300) after adjustment for confounders. However, cardiovascular mortality tended to increase in persons with previously diagnosed/treated OAG (n = 141; relative risk [RR], 1.38, P = .07) and was significantly higher with treatment involving timolol maleate (RR, 1.91, P = .04). Cardiovascular deaths also tended to increase in persons with ocular hypertension at baseline (n = 498; RR, 1.28, P = .06). CONCLUSIONS: In this black population, cardiovascular mortality tended to increase in persons with previously diagnosed/treated OAG and ocular hypertension. The excess mortality associated with timolol maleate treatment of OAG, also found in a white population, warrants further investigation.