A method for gene-based pathway analysis using genomewide association study summary statistics reveals nine new type 1 diabetes associations.

Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty-one of the 1,583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication P-values were skewed (P=9.85×10-11) with 12 of the 22 SNPs showing P<0.05. Support, including replication evidence, was obtained for nine T1D associated variants in genes ITGB7 (rs11170466, P=7.86×10-9), NRP1 (rs722988, 4.88×10-8), BAD (rs694739, 2.37×10-7), CTSB (rs1296023, 2.79×10-7), FYN (rs11964650, P=5.60×10-7), UBE2G1 (rs9906760, 5.08×10-7), MAP3K14 (rs17759555, 9.67×10-7), ITGB1 (rs1557150, 1.93×10-6), and IL7R (rs1445898, 2.76×10-6). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available.This is the final version. It was first published by Wiley at http://onlinelibrary.wiley.com/doi/10.1002/gepi.21853/abstract

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. We acknowledge use of DNA samples from the NIHR Cambridge BioResource. We thank volunteers for their support and participation in the Cambridge BioResource and members of the Cambridge BioResource Scientific Advisory Board (SAB) and Management Committee for their support of our study. We acknowledge the NIHR Cambridge Biomedical Research Centre for funding. Access to Cambridge BioResource volunteers and to their data and samples are governed by the Cambridge BioResource SAB. Documents describing access arrangements and contact details are available at http://www.cambridgebioresource.org.uk/. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol, UK, and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton, for preparing and providing the control DNA samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113; a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/.This is the author accepted manuscript. The final version is available via NPG at http://www.nature.com/ng/journal/v47/n4/full/ng.3245.html

The GIN-McMaster Guideline Development Checklist extension for engagement

Objectives: Better engagement of diverse groups of interest-holders in the development of health guidelines has been proposed to improve their usefulness, implementability, and acceptability. Guidelines shape clinical or public health practice decision-making. Trustworthy guidelines are systematically developed documents that include actionable statements based on evidence and a formal, structured and transparent decision process. This paper describes the Guidelines International Network (GIN)-McMaster Guideline Development Checklist (GDC) Extension for Engagement to assist developers with engaging multiple interest-holders throughout all topics of guideline development. Study Design and Setting: To produce this checklist extension, we conducted a 3-phase mixed methods study. First, we identified 10 groups of interest-holders to be engaged in health guideline development: patients, the public, providers, program managers, principal investigators, payers/purchasers of health services, payers/funders of health research, policymakers, peer-reviewed journal editors, and product makers identified in previous work and recruited coleads to represent these groups (n = 26 total). Results: We conducted a series of reviews to identify existing methods and barriers/facilitators for engagement, approaches to managing conflicts of interest, and describe the impacts of engagement on the guideline development process. The results of these reviews informed the development of an online survey for which we received 195 responses. We clarified these results through 43 key informant interviews with interest-holders. The final GDC extension checklist was determined based on consensus methods with our coleads. Conclusion: This paper presents the GIN-McMaster GDC Extension for Engagement. This checklist provides interest-holder–informed recommendations for providing advice/feedback or participating in decision-making in guideline development. Plain Language Summary: Health-care guidelines are formal recommendations for diagnosing and managing medical conditions or public health concerns. The steps involved in developing guidelines include from planning the process, defining the focus of the guideline and the questions it should answer, and summarizing the evidence. The Guidelines International Network-McMaster Guideline Development checklist includes 146 steps of guideline development grouped into 18 topics. Our work extends this checklist to provide guidance on how to engage with people from different groups of ‘interest-holders’ throughout guideline development. These interest-holders include (1) patients, (2) members of the public, (3) health-care providers, (4) people who manage and operate health programs, (5) researchers, (6) people who pay for or purchase health services, (7) policymakers, (8) people who pay for health research, (9) people who publish research and guidelines, and (10) people who develop and sell health-care devices or products. We engaged with people from each of the groups to develop this guidance. Twenty-six people coled our interest-holder groups. We conducted a series or systematic reviews on (a) how to engage people in guidelines, (b) identifying the barriers and facilitators to engagement, (c) assessing the impacts of engagement, and (d) describing how to manage conflicts of interest related to engagement. These reviews were used to create a first draft of guidance. Then we conducted an online survey and gathered the opinions from 195 people from each of our interest-holder groups. We interviewed 43 interest-holders for additional information to revise the guidance and then finalized the guidance with our interest-holder coleads. This checklist provides guidance for engaging interest-holder groups throughout guideline development.</p

Sustainable Investment - The New Heart of EU Financial Market Regulation

Contemporary Challenges in American & Global Law concluded its winter line-up of events on Wednesday, March 24 with a program entitled, “Sustainable Investment - The New Heart of EU Financial Market Regulation.” Gaspar Kot (LL.M. 2012) who works for UBS—a Swiss multinational investment bank and financial services company—in Kraków, Poland provided opening remarks on the topic. Chris Concannon ’94, President and Chief Operating Officer of MarketAxess, in New York City, New York, provided comments for the discussion

Android™ App Forensic Evidence Database

Posted with permission of CSAFE.</p

Treatment of Carbapenem-Resistant Enterobacteriaceae (CRE) in 6 US communities

Background. Antibiotic resistance profiles of CRE infections pose a substantial treatment challenge. We described the antibiotics being used to treat CRE infections and assessed effective antibiotic use. Methods. CDC's Emerging Infections Program performs active population-based laboratory surveillance for CRE. CRE cases are defined by isolation, from urine or a normally-sterile site, of Escherichia coli, Klebsiella spp., or Enterobacter spp. non-susceptible to carbapenems (except ertapenem) and resistant to all third-generation cephalosporins tested. Six EIP sites piloted an assessment of antibiotic therapy for 3 months in 2014 to evaluate treatment in the 14 days after specimen collection. Antibiotic class, timing of antibiotic relative to specimen collection date, and effective antibiotic use (based on susceptibility documented in the medical record) were evaluated. Results. Of the 105 incident cases, 11 (10%) were invasive infections and 94 (90%) had positive urinary cultures alone. Klebsiella pneumoniae was the most common organism (59%). Most patients (80%) received an antibiotic within 14 days after specimen collection, most commonly fluoroquinolones (21%). Of the 71 patients assessed for effective antibiotic use, 48 (68%) received an effective antibiotic within 14 days of specimen collection, most commonly aminoglycosides (26%). Median time to any antibiotic was 0 days (range: 0–11 days), whereas median time to first effective antibiotic was 3 days (range: 0–12 days). Effective therapy was similar in invasive infections (75%) and urinary isolates (66%). 19 patients (42%) received an effective antibiotic as initial therapy, most commonly fluoroquinolones. 26 patients (58%) received their effective antibiotic after sensitivities became available, most commonly aminoglycosides. Conclusion. Nearly a third of patients with CRE who received antibiotics did not receive an effective antibiotic within 14 days of their specimen collection date. Although most patients received an antibiotic on the date of specimen collection, the median time to first effective antibiotic was 3 days after specimen collection. For patients with CRE infections, rapid susceptibility testing may help guide prompt, effective treatment. Disclosures. All authors: No reported disclosureshttps://academic.oup.com/ofid/article/3/suppl_1/2021/263628