Return of genomic results to research participants: the floor, the ceiling, and the choices in between.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Ethical and practical challenges of sharing data from genome-wide association studies: the eMERGE Consortium experience.

In 2007, the National Human Genome Research Institute (NHGRI) established the Electronic MEdical Records and GEnomics (eMERGE) Consortium (www.gwas.net) to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic medical record (EMR) systems for large-scale, high-throughput genetic research. One of the major ethical and administrative challenges for the eMERGE Consortium has been complying with existing data-sharing policies. This paper discusses the challenges of sharing genomic data linked to health information in the electronic medical record (EMR) and explores the issues as they relate to sharing both within a large consortium and in compliance with the National Institutes of Health (NIH) data-sharing policy. We use the eMERGE Consortium experience to explore data-sharing challenges from the perspective of multiple stakeholders (i.e., research participants, investigators, and research institutions), provide recommendations for researchers and institutions, and call for clearer guidance from the NIH regarding ethical implementation of its data-sharing policy.

Intersectionality and COVID-19: Academic Medicine Faculty's Lived Experiences of Well-Being, Workload, and Productivity During the Pandemic.

Purpose: The aim of this study was to utilize an intersectional framework to examine academic faculty's lived experiences during COVID-19. Specifically, we set out to: (1) describe the multiple intersectional identities (e.g., gender, race/ethnicity, rank, caregiver status, disability status) represented by the faculty, (2) examine potential disparities in well-being, workload, and productivity linked to these intersectional factors, and (3) identify qualitative themes endorsed by faculty as they relate to lived experiences during COVID-19. Methods: This was a cross-sectional mixed-methods research study. The Center for Women in Medicine and Science (CWIMS) at the University of Minnesota developed and implemented a survey between February-June of 2021 in response to national reports of disparities in the impacts of COVID-19 on faculty with lived experiences from multiple intersections. Results: There were 291 full-time faculty who participated in the study. Quantitative findings indicated that faculty with multiple intersectional identities (e.g., woman+assistant professor+caregiver+underrepresented in medicine) reported greater depression symptoms, work/family conflict, and stress in contrast to faculty with fewer intersectional identities. Furthermore, faculty with more intersectional identities reported higher clinical workloads and service responsibilities and lower productivity with regard to research article submissions, publications, and grant submissions in contrast to faculty with fewer intersectional identities. Qualitative findings supported quantitative findings and broadened understanding of potential underlying reasons. Conclusions: Findings confirm anecdotal evidence that faculty with lived experiences from multiple intersections may be disproportionately experiencing negative outcomes from the pandemic. These findings can inform decisions about how to address these disparities moving into the next several years with regard to promotion and tenure, burnout and well-being, and faculty retention in academic medical settings. Given these findings, it is also important to intentionally plan responses for future public health crises to prevent continued disparities for faculty with multiple intersectional identities.

PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies.

Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized. We provide the PLatform for the Analysis, Translation, and Organization of large-scale data (PLATO), a software tool equipped to handle multi-omic data for hundreds of thousands of samples to explore complexity using genetic interactions, environment-wide association studies and gene-environment interactions, phenome-wide association studies, as well as copy number and rare variant analyses. Using the data from the Marshfield Personalized Medicine Research Project, a site in the electronic Medical Records and Genomics Network, we apply each feature of PLATO to type 2 diabetes and demonstrate how PLATO can be used to uncover the complex etiology of common traits.

Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS 1): study design and research methodology.

PURPOSE: To describe the methodology of the Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS 1), an ongoing population-based study to estimate the prevalence of diabetes and diabetic retinopathy in urban Chennai, Tamil Nadu, South India, and also to elucidate the clinical, anthropometric, biochemical and genetic risk factors associated with diabetic retinopathy. METHODS: In this ongoing study, we anticipate recruiting a total of 5830 participants. Eligible patients, over the age of 40 years, are enumerated using the multistage random sampling method. Demographic data, socioeconomic status, physical activity, risk of sleep apnea, dietary habits, and anthropometric measurements are collected. A detailed medical and ocular history and a comprehensive eye examination, including stereo fundus photographs, are taken at the base hospital. Biochemical investigations (total serum cholesterol, high-density lipoproteins, serum triglycerides, hemoglobin, glycosylated hemoglobin HbA1c) and genetic studies of eligible subjects are conducted. A computerized database is created for the records. CONCLUSION: The study is expected to result in an estimate of the prevalence of diabetes and diabetic retinopathy and a better understanding of biochemical and genetic risk factors associated with diabetic retinopathy in an urban South Indian population. Worldwide, the prevalence of diabetes mellitus, in particular type II diabetes, is rising at an alarming rate. The World Health Organization (WHO) and International Diabetes Federation (IDF) have predicted that the number of cases of adult-onset diabetes would more than double by 2030 from the present level of 171 million to 366 million-an increase of 214%.1 In developed countries, this increase in diabetic population would be around 42% and in developing countries, particularly in India, it is even higher; i.e. 150%.1 In India, the prevalence of diabetes mellitus in the urban population is around 12.1%, as reported by the national urban diabetes study2 conducted in six major cities. Studies have shown the prevalence of diabetes to be higher among the high-income groups (25.5%) as compared to low-income groups (12.6%).3,4,5 The assessment of socioeconomic status was based on income,6, 7 education,2, 7 occupation2 or caste6-which are not representative of the actual socioeconomic status. In the present study, however, the sample was stratified on socioeconomic scoring. This scoring was calculated on the basis of several parameters such as the residence being rented or owned, the number of rooms in the house, the highest educational status, the highest salary, the highest occupation, material possessions (cycle, TV, audio, car, etc.) and house/land value. To the best of our knowledge, this kind of comprehensive socioeconomic scoring has not been done before for prevalence studies on diabetic retinopathy in the general population.

Localization of cortical cataract in subjects of diverse races and latitude.

PURPOSE: To compare the characteristics of early cortical cataract localization in three groups in cataract epidemiologic surveys performed in Reykjavík, Melbourne, and Singapore. METHODS: Individuals who had right eyes with an area of cortical opacity less than 20% of the pupil when dilated 7 mm or more were selected as subjects. This included 197 subjects from the Reykjavík Eye Study, 231 from the Vitamin E, Cataract, and Age-Related Maculopathy (VECAT) study in Melbourne, and 92 from the Singapore-Japan Cooperative Cataract Study, all showing early-stage cataract in pupils dilated to 7 mm or more. Scheimpflug and retroilluminated photographs were used to locate opacities. Localization of cortical cataract was determined by dividing the retroillumination image into seven concentric circles with diameters of 1 through 7 mm, and eight sections of 45 degrees radial octants. The positive rate of opacification was then calculated for each quadrant. RESULTS: The highest positive rate of opacification was observed in the lower nasal quadrant in all groups. The relative risk of the prevalence of cortical opacity in the lower nasal oblique hemisphere to the upper temporal oblique hemisphere was the highest in the Singaporean subjects followed by those of Melbourne and then of Reykjavík. CONCLUSIONS: The prevalence of cortical cataract was higher in the lower nasal quadrant than in the other quadrants for all subjects of diverse race in three climatically different locations. This higher prevalence was most pronounced in subjects living at low latitude. These results support the view that solar UV exposure is a possible risk factor for development of human cortical cataract.

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.

Utilisation of eye care services by urban and rural Australians.

AIM: To investigate factors related to the use of eye care services in Australia. METHODS: Health, eye care service use, and sociodemographic data were collected in a structured interview of participants in a population based study. All participants had a standard eye examination. RESULTS: Men (OR 1.3 CL 1.02, 1.7), those who spoke Greek (OR 2.1 CL 1.1, 3.8) or Italian (OR 1.9 CL 1.0, 3.3), and those without private health insurance (OR 1.59 CL 1.22, 2.04) were more likely to have not used eye care services. Ophthalmology services were utilised at lower rates in rural areas (OR 0.14 CL 0.09, 0.2). Approximately 40% of participants with undercorrected refractive error, cataract, and undiagnosed glaucoma had seen either an ophthalmologist, optometrist, or both within the last year. CONCLUSION: Despite the similarity in prevalence of eye disease in urban and rural areas, significant differences exist in the utilisation of eye care services. Sex, private health insurance, urban residence, and the ability to converse in English were significant factors associated with eye healthcare service use. Many participants had undiagnosed eye disease despite having seen an eye care provider in the last year.

The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables.

Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls, and the rationale for the GWAS study design.

Projected prevalence of age-related cataract and cataract surgery in Australia for the years 2001 and 2021: pooled data from two population-based surveys.

This study aimed to estimate the number of Australians over 50 with cataract in the years 2001 and 2021. Data from two population-based studies were pooled: the Blue Mountains Eye Study and Melbourne Visual Impairment Project and Australian Bureau of Statistics population projections were used. Similar definitions for the three cataract types were used in the two studies (nuclear >/= grade 4, posterior sub-capsular >/= 1 mm, cortical >/= 10% lens area or >/= 25% circumference). Combining the three types and prior surgery, it was estimated that in 2001, 1.7 million Australians had clinically significant cataract in either eye and 320,000 had previously undergone cataract surgery. It was estimated that the number of persons with cataract will rise to 2.7 million by 2021 (over 500,000 will have had cataract surgery). The number of Australians with cataract will grow by two-thirds during the next 20 years, reflecting continued population ageing. Health care delivery systems will need to develop methods to handle this increased workload.