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.

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.

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.

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 x 10(-18)), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87 x 10(-11)). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% Cl 0.50-0.67], p = 1.17 x 10(-12)) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% Cl 0.53-0.72], p = 8.88 x 10(-10)). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% Cl 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% Cl 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 TGFbeta signaling could be effective for multiple forms of glaucoma.

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.

The purpose of this study was to investigate the effect of presbyopic correction on changes in visual fields caused by an alteration in outflow of aqueous humour. Visual fields were compared before and after introduction of presbyopic correction in participants of the Melbourne Visual Impairment Project. Height and slope of the 'Hill of Vision' were assessed by calculating median thresholds in the four sets of three eccentric points. Analysis of 101 eyes in the study group and 101 eyes in the control group shows higher decrease of the 'Hill of Vision' height in the group of participants who started wearing presbyopic correction, than in the group without presbyopic correction (P = 0.02). Intraocular pressure measured irrespectively of participant's accommodative activity was not significantly different between the two groups at both time points. These data suggest that the use of presbyopic correction is associated with changes in the visual field.

Background: Primary chronic canaliculitis is an uncommon disease usually caused by Actinomyces israelii (streptothrix). Actinomyces israelii is a cast-forming Gram-positive anaerobe that is difficult to isolate and identify. We present a case that demonstrates the typical clinicopathological presentation of this unusual condition and discuss management options. Methods and Results: A 10-year-old girl presented with a 6 month history of intermittent ‘conjunctivitis’ and discharge from her ‘pouted’ left lower punctum. Microbiology confirmed probable A. israelii infection, but topical treatment failed. Exploration under anaesthesia revealed a canalicular diverticulum and three canaliculiths. Histological examination of the canaliculiths demonstrated that they consisted of solid casts of Actinomyces. Punctoplasty, removal of the casts, and adjunct antibiotic therapy resulted in resolution of the canaliculitis. Conclusions: Primary chronic canaliculitis should be considered in any patient who presents with chronic or recurrent conjunctivitis and the eyelid should be inspected for a discharging and ‘pouting’ punctum. Failure of the condition to resolve on topical treatment requires surgical exploration of the canalicular system and removal of any casts. Extensive surgery is not always required.