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Background Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p  = 1.70 × 10 − 20 ). This effect was consistent in both pediatric ( p  = 9.92 × 10 − 6 ) and adult ( p  = 9.73 × 10 − 15 ) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) ( p  = 3.94 × 10 − 8 , beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout ( p  = 1.09 × 10 − 4 ). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p  = 3.80 × 10 − 8 ), and another near ZFP90-CDH1 for fibrosis (rs698718, p  = 2.74 × 10 − 11 ). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. Conclusions In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.

Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate (“A-by-G” grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.

Introduction Currently, one of the commonly used methods for disseminating electronic health record (EHR)-based phenotype algorithms is providing a narrative description of the algorithm logic, often accompanied by flowcharts. A challenge with this mode of dissemination is the potential for under-specification in the algorithm definition, which leads to ambiguity and vagueness. Methods This study examines incidents of under-specification that occurred during the implementation of 34 narrative phenotyping algorithms in the electronic Medical Record and Genomics (eMERGE) network. We reviewed the online communication history between algorithm developers and implementers within the Phenotype Knowledge Base (PheKB) platform, where questions could be raised and answered regarding the intended implementation of a phenotype algorithm. Results We developed a taxonomy of under-specification categories via an iterative review process between two groups of annotators. Under-specifications that lead to ambiguity and vagueness were consistently found across narrative phenotype algorithms developed by all involved eMERGE sites. Discussion and conclusion Our findings highlight that under-specification is an impediment to the accuracy and efficiency of the implementation of current narrative phenotyping algorithms, and we propose approaches for mitigating these issues and improved methods for disseminating EHR phenotyping algorithms.

Background Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. Methods We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. Results The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5–4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. Conclusions By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

Background/ObjectivesMelanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus.Subjects/MethodsThe sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping.ResultsTargeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m2. In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10−25, Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10−08, Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI.ConclusionsMC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.

Abstract With the burgeoning development of computational phenotypes, it is increasingly difficult to identify the right phenotype for the right tasks. This study uses a mixed-methods approach to develop and evaluate a novel metadata framework for retrieval of and reusing computational phenotypes. Twenty active phenotyping researchers from 2 large research networks, Electronic Medical Records and Genomics and Observational Health Data Sciences and Informatics, were recruited to suggest metadata elements. Once consensus was reached on 39 metadata elements, 47 new researchers were surveyed to evaluate the utility of the metadata framework. The survey consisted of 5-Likert multiple-choice questions and open-ended questions. Two more researchers were asked to use the metadata framework to annotate 8 type-2 diabetes mellitus phenotypes. More than 90% of the survey respondents rated metadata elements regarding phenotype definition and validation methods and metrics positively with a score of 4 or 5. Both researchers completed annotation of each phenotype within 60 min. Our thematic analysis of the narrative feedback indicates that the metadata framework was effective in capturing rich and explicit descriptions and enabling the search for phenotypes, compliance with data standards, and comprehensive validation metrics. Current limitations were its complexity for data collection and the entailed human costs. Lay Summary Computational phenotypes are essential to scale precision medicine and observational healthcare research. More comprehensive and explicitly defined phenotype metadata could improve phenotype retrieval, reuse, and sharing. However, few studies have focused directly on phenotype metadata explicitness or validation methods and metrics. We designed a phenotype metadata framework as part of ongoing research with the Electronic Medical Records and Genomics (eMERGE) network phenotyping working group. We identified 39 metadata elements based on group consensus. We distributed a survey to 47 new researchers that rated the usefulness of each metadata element on a scale of 1–5, and conducted a thematic analysis of the free-text survey questions. Two researchers annotated 8 type-2 diabetes mellitus phenotypes with the framework. More than 90% of respondents assigned a rating of 4–5 to metadata framework elements regarding phenotype definition and validation metrics. In our thematic analysis, explicit descriptions, compliance with data standards, and comprehensive validation methods were strengths of the framework. Using a mixed-methods approach, we have developed a comprehensive framework for defining computational clinical phenotypes. Use of this framework may help curate patient data used for both observational and prospective healthcare research.

I also can't imagine the corporate profile obtained from the Ministry of Consumer and Corporate Affairs regarding the status of the WNEDC wasn't properly researched by these lawyers before Weyerhaeuser offered to purchase from the municipality all of its supposed rights and interests in the limited partnership for $1. My question is, are the politicians who represent our interests and manage our natural resources on our behalf up for the challenge? It's time they stood up to this resource-based, for-profit company and gently remind them that they are able to exist and earn a healthy profit by being allowed to exploit our natural resources. In effect, we are also a partnership. By our good graces they are allowed to exist. There is a covenant between the province of Ontario and these resource-based companies to ensure economic development and job creation in exchange for the use of our natural resources which includes the water. When Weyerhaeuser ceased operation and company spokeswoman Jayne Murray publicly proclaimed there was very little money to be made with the dams, as a stakeholder in this province and community, I feel they relinquished their part of the covenant and the licence to use the water that flows over the dams should have been rescinded with a proviso.

A reasonable condition for allowing Russia to maintain an embassy in Ottawa would be zero tolerance for alcohol consumption by its staff who drive, with the provision that any Russian diplomat stopped by police would be obliged to submit to a breathalyser and would be removed immediately from his car and sent home the next day if he registered any degree of intoxication.

The 1979 refugee crisis as a result of conflicts in Southeast Asia brought out the very best in Ottawa and our Ottawa Valley communities. When the buses pulled into Ottawa, the sponsors were there to greet the refugees and take them to the varyious locations around the city and throughout the countryside. Black & White Photo: Bryce Flynn, The Ottawa Citizen / In 1979, Project 4000 showed the way for Canadians to open homes to refugees from war-torn countries, writes [Barbara Benoit O'Rourke]. ; Black & White Photo: Bryce Flynn, The Ottawa Citizen / In 1979, Project 4000 showed the way for Canadians to open homes to refugees from war- torn countries, writes Barbara Benoit O'Rourke. ;