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https://www.readbyqxmd.com/read/29746339/comorbidities-in-childhood-celiac-disease-a-phenome-wide-association-study-using-the-electronic-health-record
#1
Ariana Prinzbach, Soheil Moosavinasab, Steve Rust, Brendan Boyle, John A Barnard, Yungui Huang, Simon Lin
OBJECTIVES: Celiac disease (CD) is associated with a variety of extraintestinal autoimmune and inflammatory findings that manifest clinically as symptoms and comorbidities. Understanding these comorbidities may improve identification of the disease and prevent sequelae. In this study, we use an unbiased electronic health record (EHR)-based Phenome Wide Association Study (PheWAS) method to confirm known comorbidities, discover novel associations and enhance characterization of the clinical presentation of CD in children...
May 9, 2018: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/29703846/-lpa-variants-are-associated-with-residual-cardiovascular-risk-in-patients-receiving-statins
#2
Wei-Qi Wei, Xiaohui Li, Qiping Feng, Michiaki Kubo, Iftikhar J Kullo, Peggy L Peissig, Elizabeth W Karlson, Gail P Jarvik, Ming Ta Michael Lee, Ning Shang, Eric A Larson, Todd Edwards, Christian Shaffer, Jonathan D Mosley, Shiro Maeda, Momoko Horikoshi, Marylyn Ritchie, Marc S Williams, Eric B Larson, David R Crosslin, Sarah T Bland, Jennifer A Pacheco, Laura J Rasmussen-Torvik, David Cronkite, George Hripcsak, Nancy J Cox, Russell A Wilke, C Michael Stein, Jerome I Rotter, Yukihide Momozawa, Dan M Roden, Ronald M Krauss, Joshua C Denny
Background -Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods -We performed a two-stage genome-wide association study (GWAS) of CHD events during statin therapy. We first identified 3,099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7,681 controls without CHD events during comparable intensity and duration of statin therapy from four sites in the Electronic Medical Records and Genomics (eMERGE) Network...
April 27, 2018: Circulation
https://www.readbyqxmd.com/read/29659871/rare-variants-in-the-gene-alpl-that-cause-hypophosphatasia-are-strongly-associated-with-ovarian-and-uterine-disorders
#3
Kathryn M Dahir, Daniel R Tilden, Jeremy L Warner, Lisa Bastarache, Derek K Smith, Aliya Gifford, Andrea H Ramirez, Jill Simmons, Margo M Black, John H Newman, Josh C Denny
Background: Mutations in ALPL, which encodes tissue-nonspecific isozyme alkaline phosphatase (TNSALP), cause hypophosphatasia (HPP). HPP is suspected by a low serum alkaline phosphatase (AlkP). We hypothesized that some patients with bone or dental disease have undiagnosed HPP caused by ALPL variants. Our objective was to discover the prevalence of these gene variants in the Vanderbilt DNA biobank (BioVU) and to assess phenotypic associations. Methods: We identified subjects in BioVU, a repository of DNA, that had at least one of three known rare HPP disease-causing variants in ALPL: rs199669988, rs121918007, rs121918002...
April 6, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29618318/a-simulation-study-investigating-power-estimates-in-phenome-wide-association-studies
#4
Anurag Verma, Yuki Bradford, Scott Dudek, Anastasia M Lucas, Shefali S Verma, Sarah A Pendergrass, Marylyn D Ritchie
BACKGROUND: Phenome-wide association studies (PheWAS) are a high-throughput approach to evaluate comprehensive associations between genetic variants and a wide range of phenotypic measures. PheWAS has varying sample sizes for quantitative traits, and variable numbers of cases and controls for binary traits across the many phenotypes of interest, which can affect the statistical power to detect associations. The motivation of this study is to investigate the various parameters which affect the estimation of statistical power in PheWAS, including sample size, case-control ratio, minor allele frequency, and disease penetrance...
April 4, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29606303/phewas-and-beyond-the-landscape-of-associations-with-medical-diagnoses-and-clinical-measures-across-38-662-individuals-from-geisinger
#5
Anurag Verma, Anastasia Lucas, Shefali S Verma, Yu Zhang, Navya Josyula, Anqa Khan, Dustin N Hartzel, Daniel R Lavage, Joseph Leader, Marylyn D Ritchie, Sarah A Pendergrass
Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We calculated associations between these diagnoses and traits with ∼630,000 common frequency SNPs with minor allele frequency > 0...
March 19, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29547983/electronic-health-records-the-next-wave-of-complex-disease-genetics
#6
Brooke N Wolford, Cristen J Willer, Ida Surakka
The combination of Electronic Health Records (EHRs) with genetic data has ushered in the next wave of complex disease genetics. Population-based biobanks and other large cohorts provide sufficient sample sizes to identify novel genetic associations across the hundreds to thousands of phenotypes gleaned from EHRs. In this review we summarize the current state of these EHR-linked biobanks, explore ongoing methods development in the field, and highlight recent discoveries of genetic associations. We enumerate the many existing biobanks with EHRs linked to genetic data, many of which are available to researchers via application and contain sample sizes > 50,000...
March 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29545989/current-scope-and-challenges-in-phenome-wide-association-studies
#7
Anurag Verma, Marylyn D Ritchie
Purpose of Review: Over many decades, researchers have been designing studies to investigate the relationship between genotypes and phenotypes to gain an understanding about the effect of genetics on disease. Recently, a high-throughput approach called phenome-wide associations studies (PheWAS) have been extensively used to identify associations between genetic variants and many diseases and traits simultaneously. In this review, we describe the value of PheWAS along with methodological issues and challenges in interpretation for current applications of PheWAS...
December 2017: Current Epidemiology Reports
https://www.readbyqxmd.com/read/29545597/rare-variants-in-drug-target-genes-contributing-to-complex-diseases-phenome-wide
#8
Shefali Setia Verma, Navya Josyula, Anurag Verma, Xinyuan Zhang, Yogasudha Veturi, Frederick E Dewey, Dustin N Hartzel, Daniel R Lavage, Joe Leader, Marylyn D Ritchie, Sarah A Pendergrass
The DrugBank database consists of ~800 genes that are well characterized drug targets. This list of genes is a useful resource for association testing. For example, loss of function (LOF) genetic variation has the potential to mimic the effect of drugs, and high impact variation in these genes can impact downstream traits. Identifying novel associations between genetic variation in these genes and a range of diseases can also uncover new uses for the drugs that target these genes. Phenome Wide Association Studies (PheWAS) have been successful in identifying genetic associations across hundreds of thousands of diseases...
March 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29481723/phenome-wide-association-studies-uncover-a-novel-association-of-increased-atrial-fibrillation-in-males-with-systemic-lupus-erythematosus
#9
April Barnado, Robert J Carroll, Carolyn Casey, Lee Wheless, Joshua C Denny, Leslie J Crofford
OBJECTIVE: Phenome-wide association studies (PheWAS) scan across billing codes in the electronic health record (EHR) and re-purpose clinical EHR data for research. We examined if PheWAS could function as an EHR discovery tool for SLE and uncover novel clinical associations in male versus female SLE patients. METHODS: We used a de-identified version of the Vanderbilt University Medical Center EHR with over 2.8 million subjects. We performed PheWAS comparing 1) SLE cases vs...
February 26, 2018: Arthritis Care & Research
https://www.readbyqxmd.com/read/29437585/mr-phewas-exploring-the-causal-effect-of-sua-level-on-multiple-disease-outcomes-by-using-genetic-instruments-in-uk-biobank
#10
Xue Li, Xiangrui Meng, Athina Spiliopoulou, Maria Timofeeva, Wei-Qi Wei, Aliya Gifford, Xia Shen, Yazhou He, Tim Varley, Paul McKeigue, Ioanna Tzoulaki, Alan F Wright, Peter Joshi, Joshua C Denny, Harry Campbell, Evropi Theodoratou
OBJECTIVES: We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank. METHODS: We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelian randomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS...
February 6, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29378629/an-integrative-functional-genomics-framework-for-effective-identification-of-novel-regulatory-variants-in-genome-phenome-studies
#11
Junfei Zhao, Feixiong Cheng, Peilin Jia, Nancy Cox, Joshua C Denny, Zhongming Zhao
BACKGROUND: Genome-phenome studies have identified thousands of variants that are statistically associated with disease or traits; however, their functional roles are largely unclear. A comprehensive investigation of regulatory mechanisms and the gene regulatory networks between phenome-wide association study (PheWAS) and genome-wide association study (GWAS) is needed to identify novel regulatory variants contributing to risk for human diseases. METHODS: In this study, we developed an integrative functional genomics framework that maps 215,107 significant single nucleotide polymorphism (SNP) traits generated from the PheWAS Catalog and 28,870 genome-wide significant SNP traits collected from the GWAS Catalog into a global human genome regulatory map via incorporating various functional annotation data, including transcription factor (TF)-based motifs, promoters, enhancers, and expression quantitative trait loci (eQTLs) generated from four major functional genomics databases: FANTOM5, ENCODE, NIH Roadmap, and Genotype-Tissue Expression (GTEx)...
January 29, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29361760/using-y-chromosomal-haplogroups-in-genetic-association-studies-and-suggested-implications
#12
A Mesut Erzurumluoglu, Denis Baird, Tom G Richardson, Nicholas J Timpson, Santiago Rodriguez
Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association...
January 22, 2018: Genes
https://www.readbyqxmd.com/read/29279060/heterogeneity-of-asthma-and-the-risk-of-celiac-disease-in-children
#13
Bhavisha Patel, Chung-Il Wi, M Earth Hasassri, Rohit Divekar, Imad Absah, Eyad Almallouhi, Euijung Ryu, Katherine King, Young J Juhn
BACKGROUND: Although human leukocyte antigen (HLA)-DR and HLA-DQ genes and gluten play crucial roles in developing celiac disease (CD), most patients with these risk factors still do not develop CD, which indicates additional unrecognized risk factors. OBJECTIVE: To determine the association between asthma and the risk of CD in children. METHODS: We conducted a population-based retrospective case-control study in children who resided in Olmsted County, Minnesota...
January 1, 2018: Allergy and Asthma Proceedings:
https://www.readbyqxmd.com/read/29185237/using-human-experiments-of-nature-to-predict-drug-safety-issues-an-example-with-pcsk9-inhibitors
#14
Rebecca N Jerome, Jill M Pulley, Dan M Roden, Jana K Shirey-Rice, Lisa A Bastarache, Gordon R Bernard, Leeland B Ekstrom, William J Lancaster, Joshua C Denny
INTRODUCTION: When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities. OBJECTIVE: We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9)...
March 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/29166900/association-between-borderline-dysnatremia-and-mortality-insight-into-a-new-data-mining-approach
#15
Yannick Girardeau, Anne-Sophie Jannot, Gilles Chatellier, Olivier Saint-Jean
BACKGROUND: Even small variations of serum sodium concentration may be associated with mortality. Our objective was to confirm the impact of borderline dysnatremia for patients admitted to hospital on in-hospital mortality using real life care data from our electronic health record (EHR) and a phenome-wide association analysis (PheWAS). METHODS: Retrospective observational study based on patient data admitted to Hôpital Européen George Pompidou, between 01/01/2008 and 31/06/2014; including 45,834 patients with serum sodium determinations on admission...
November 22, 2017: BMC Medical Informatics and Decision Making
https://www.readbyqxmd.com/read/29023970/phenotype-validation-in-electronic-health-records-based-genetic-association-studies
#16
Lu Wang, Scott M Damrauer, Hong Zhang, Alan X Zhang, Rui Xiao, Jason H Moore, Jinbo Chen
The linkage between electronic health records (EHRs) and genotype data makes it plausible to study the genetic susceptibility of a wide range of disease phenotypes. Despite that EHR-derived phenotype data are subjected to misclassification, it has been shown useful for discovering susceptible genes, particularly in the setting of phenome-wide association studies (PheWAS). It is essential to characterize discovered associations using gold standard phenotype data by chart review. In this work, we propose a genotype stratified case-control sampling strategy to select subjects for phenotype validation...
December 2017: Genetic Epidemiology
https://www.readbyqxmd.com/read/28867356/relationship-of-sult1a1-copy-number-variation-with-estrogen-metabolism-and-human-health
#17
Jixia Liu, Ran Zhao, Zhan Ye, Alexander J Frey, Emily R Schriver, Nathaniel W Snyder, Scott J Hebbring
Human cytosolic sulfotransferase 1A1 (SULT1A1) is considered to be one of the most important SULT isoforms for metabolism, detoxification, and carcinogenesis. This theory is driven by observations that SULT1A1 is widely expressed in multiple tissues and acts on a wide range of phenolic substrates. SULT1A1 is subject to functional common copy number variation (CNV) including deletions or duplications. However, it is less clear how SULT1A1 CNV impacts health and disease. To better understand the biological role of SULT1A1 in human health, we genotyped CNV in 14,275 Marshfield Clinic patients linked to an extensive electronic health record...
November 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28736474/phenotype-analysis-of-early-risk-factors-from-electronic-medical-records-improves-image-derived-diagnostic-classifiers-for-optic-nerve-pathology
#18
Shikha Chaganti, Kunal P Nabar, Katrina M Nelson, Louise A Mawn, Bennett A Landman
We examine imaging and electronic medical records (EMR) of 588 subjects over five major disease groups that affect optic nerve function. An objective evaluation of the role of imaging and EMR data in diagnosis of these conditions would improve understanding of these diseases and help in early intervention. We developed an automated image-processing pipeline that identifies the orbital structures within the human eyes from computed tomography (CT) scans, calculates structural size, and performs volume measurements...
February 11, 2017: Proceedings of SPIE
https://www.readbyqxmd.com/read/28711146/drug-repositioning-strategies-for-the-identification-of-novel-therapies-for-rheumatic-autoimmune-inflammatory-diseases
#19
REVIEW
Amrie C Grammer, Peter E Lipsky
Rheumatic Autoimmune Inflammatory Diseases such as Sjögren's and lupus lack modern treatments. Less than 5% of drugs approved by the FDA from 2014 to mid-2016 had a RAID indication. Many RAID standard-of-care drugs were repurposed based on serendipitous observations, similarity-of-disease categorization, and/or off-target effects. Recently, drug repurposing has become more intentional, relying on an evolving awareness of molecular underpinnings, as well as a better understanding of drug-target interactions by computational modeling...
August 2017: Rheumatic Diseases Clinics of North America
https://www.readbyqxmd.com/read/28686612/evaluating-phecodes-clinical-classification-software-and-icd-9-cm-codes-for-phenome-wide-association-studies-in-the-electronic-health-record
#20
Wei-Qi Wei, Lisa A Bastarache, Robert J Carroll, Joy E Marlo, Travis J Osterman, Eric R Gamazon, Nancy J Cox, Dan M Roden, Joshua C Denny
OBJECTIVE: To compare three groupings of Electronic Health Record (EHR) billing codes for their ability to represent clinically meaningful phenotypes and to replicate known genetic associations. The three tested coding systems were the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, the Agency for Healthcare Research and Quality Clinical Classification Software for ICD-9-CM (CCS), and manually curated "phecodes" designed to facilitate phenome-wide association studies (PheWAS) in EHRs...
2017: PloS One
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