Catherine A. McCarty

Prevalence of age-related macular degeneration in the United States

OBJECTIVE To estimate the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender. METHODS Summary prevalence estimates of drusen 125 microm or larger, neovascular AMD, and geographic atrophy were prepared separately for black and white persons in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US Census data and to projected US population figures for 2020 to estimate the number of the US population with drusen and AMD. RESULTS The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy. More than 7 million individuals had drusen measuring 125 microm or larger and were, therefore, at substantial risk of developing AMD. Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020. Age-related macular degeneration was far more prevalent among white than among black persons. CONCLUSION Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to almost 3 million by 2020.

A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP (rs1219648) = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

The Epidemiology of Dry Eye in Melbourne, Australia

OBJECTIVE To describe the epidemiology of dry eye in the adult population of Melbourne, Australia. DESIGN A cross-sectional prevalence study. PARTICIPANTS Participants were recruited by a household census from two of nine clusters of the Melbourne Visual Impairment Project, a population-based study of age-related eye disease in the 40 and older age group of Melbourne, Australia. Nine hundred and twenty-six (82.3% of eligible) people participated; 433 (46.8%) were male. They ranged in age from 40 to 97 years, with a mean of 59.2 years. MAIN OUTCOME MEASURES Self-reported symptoms of dry eye were elicited by an interviewer-administered questionnaire. Four objective assessments of dry eye were made: Schirmers test, tear film breakup time, rose bengal staining, and fluorescein corneal staining. A standardized clinical slit-lamp examination was performed on all participants. Dry eye for the individual signs or symptoms was defined as: rose bengal > 3, Schirmers < 8, tear film breakup time < 8, > 1/3 fluorescein staining, and severe symptoms (3 on a scale of 0 to 3). RESULTS Dry eye was diagnosed as follows: 10.8% by rose bengal, 16.3% by Schirmers test, 8.6% by tear film breakup time, 1.5% by fluorescein staining, 7.4% with two or more signs, and 5.5% with any severe symptom not attributed to hay fever. Women were more likely to report severe symptoms of dry eye (odds ratio [OR] = 1.85; 95% confidence limits [CL] = 1.01, 3.41). Risk factors for two or more signs of dry eye include age (OR = 1.04; 95% CL = 1.01, 1.06), and self-report of arthritis (OR = 3.27; 95% CL = 1.74, 6.17). These results were not changed after excluding the 21 people (2.27%) who wore contact lenses. CONCLUSIONS These are the first reported population-based data of dry eye in Australia. The prevalence of dry eye varies by sign and symptom.

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 × 10−10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor–positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 × 10−7) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies.

IntroductionThe eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors.OrganizationThe five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel.Current progressThe primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ≈2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site.Future activitiesPlans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care.SummaryBy combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.

Angle-closure glaucoma in an urban population in southern india: The andhra pradesh eye disease study

OBJECTIVE To assess the prevalence and features of angle-closure glaucoma (ACG) in an urban population in southern India. DESIGN A population-based, cross-sectional study. PARTICIPANTS A total of 2522 (85.4% of those eligible) persons of all ages, including 1399 persons 30 years of age or older, from 24 clusters representative of the population of Hyderabad city. TESTING The participants underwent an interview and detailed eye examination that included logarithm of minimum angle of resolution visual acuity, refraction, slit-lamp biomicroscopy, applanation tonometry, and gonioscopy; pupil dilatation and stereoscopic fundus evaluation was performed if the risk of angle-closure as a result of dilatation was not believed to be imminent. Humphrey threshold 24-2 visual fields (Humphrey Instruments Inc., San Leandro, CA) were performed when indicated by standardized criteria for disc damage or if intraocular pressure (IOP) was 22 mmHg or more. MAIN OUTCOME MEASURES An occludable angle was defined as pigmented posterior trabecular meshwork not visible by gonioscopy in three quarters or more of the angle circumference. Manifest primary angle-closure glaucoma (PACG) was defined as IOP of 22 mmHg or more or glaucomatous optic disc damage with visual field loss in the presence of an occludable angle. An IOP of 22 mmHg or more or glaucomatous optic disc damage in the presence of an occludable angle secondary to an obvious cause was defined as secondary ACG. RESULTS Manifest PACG and occludable angles without ACG were present in 12 and 24 participants, respectively, with age- and gender-adjusted prevalence (95% confidence interval [CI]) of 0.71% (0.34%-1.31%) and 1.41% (0.73%-2.09%) in participants 30 years of age or older, and 1.08% (0.36%-1.80%) and 2.21% (1.15%-3.27%) in participants 40 years of age or older, respectively. With multivariate analysis, the prevalence of these two conditions considered together increased significantly with age (P < 0.001); although not statistically significant, these were more common in females (odds ratio 1.70; 95% CI, 0.82-3.54) and in those belonging to lower socioeconomic strata as compared with middle and upper strata (odds ratio, 1.82; 95% CI, 0.88-3.74). The odds of manifest PACG were higher in the presence of hyperopia of more than 2 diopters ([D]; odds ratio, 3.69; 95% CI, 0.89-15.2). Only four of 12 participants (33.3%) with manifest PACG had been previously diagnosed, and one of 12 (8.3%) had peripheral iridotomy performed previously. Manifest PACG had caused blindness in one or both eyes in five of these 12 participants (41.7%); best-corrected distance visual acuity less than 20/400 in one or both eyes in four patients, and acuity less than 20/200 in one eye in another patient. Most (83.3%) of those with manifest PACG could be classified as having chronic form of the disease. We may have underestimated manifest PACG because visual fields were per- formed only on those with clinical suspicion of optic disc damage. Secondary ACG was present in two participants. CONCLUSIONS The prevalence of PACG in this urban population in southern India is close to that reported recently in a Mongolian population. A large proportion of the PACG in this population was undiagnosed and untreated. Because visual loss resulting from PACG is potentially preventable if peripheral iridotomy or iridectomy is performed in the early stage, strategies for early detection of PACG could reduce the high risk of blindness resulting from PACG seen in this urban population in India.

The prevalence of glaucoma in the Melbourne Visual Impairment Project

PURPOSE The purpose of the study was to determine the prevalence of glaucoma in Melbourne, Australia. METHODS All subjects were participants in the Melbourne Visual Impairment Project (Melbourne VIP), a population-based prevalence study of eye disease that included residential and nursing home populations. Each participant underwent a standardized eye examination, which included a Humphrey Visual Field test, applanation tonometry, fundus examination including fundal photographs, and a medical history interview. Glaucoma status was determined by a masked assessment and consensus adjudication of visual fields, optic disc photographs, intraocular pressure, and glaucoma history. RESULTS A total of 3271 persons (83% response rate) participated in the residential Melbourne VIP. The overall prevalence rate of definite primary open-angle glaucoma in the residential population was 1.7% (95% confidence limits = 1.21, 2.21). Of these, 50% had not been diagnosed previously. Only two persons (0.1%) had primary angle-closure glaucoma and six persons (0.2%) had secondary glaucoma. The prevalence of glaucoma increased steadily with age from 0.1% at ages 40 to 49 years to 9.7% in persons aged 80 to 89 years. There was no relationship with gender. The authors examined 403 (90.2% response rate) nursing home residents. The age standardized rate for this component was 2.36% (95% confidence limits = 0, 4.88). CONCLUSION The rate of glaucoma in Melbourne rises significantly with age. With only half of patients being diagnosed, glaucoma is a major eye health problem and will become increasingly important as the population ages.

Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data

Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.

The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future

The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute–funded consortium engaged in the development of methods and best practices for using the electronic medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype–phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine.Genet Med 15 10, 761–771.Genetics in Medicine (2013); 15 10, 761–771. doi:10.1038/gim.2013.72

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

Background Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). Conclusions Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.