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Jamie R Robinson, Vanessa E Kennedy, Youssef Doss, Lisa Bastarache, Joshua Denny, Jeremy L Warner
OBJECTIVE: Systemic loxoscelism is a rare illness resulting from the bite of the recluse spider and, in its most severe form, can lead to widespread hemolysis, coagulopathy, and death. We aim to describe the clinical features and outcomes of the largest known cohort of individuals with moderate to severe loxoscelism. METHODS: We performed a retrospective, cross sectional study from January 1, 1995, to December 31, 2015, at a tertiary-care academic medical center, to determine individuals with clinical records consistent with moderate to severe loxoscelism...
2017: PloS One
Dan M Roden
In experimental physiological research, a common study design for examining the functional role of a gene or a genetic variant is to introduce that genetic variant into a model organism (such as yeast or mouse) and then to search for phenotypic consequences. The development of DNA biobanks linked to dense phenotypic information enables such an experiment to be applied to human subjects in the form of a phenome-wide association study (PheWAS). The PheWAS paradigm takes advantage of a curated medical phenome, often derived from electronic health records, to search for associations between 'input functions' and phenotypes in an unbiased fashion...
February 23, 2017: Journal of Physiology
Kelly Regan, Soheil Moosavinasab, Philip Payne, Simon Lin
The promise of drug repurposing is that existing drugs may be used for new disease indications in order to curb the high costs and time for approval. The goal of computational methods for drug repurposing is to enable solutions for safer, cheaper and faster drug discovery. Towards this end, we developed a novel method that integrates genetic and clinical phenotype data from large-scale GWAS and PheWAS studies with detailed drug information on the concept of transitive Drug-Gene-Disease triads. We created "RE:fine Drugs," a freely available, interactive dashboard that automates gene, disease and drug-based searches to identify drug repurposing candidates...
December 11, 2016: Journal of Visualized Experiments: JoVE
Tao Zheng, Wei Xie, Liling Xu, Xiaoying He, Ya Zhang, Mingrong You, Gong Yang, You Chen
OBJECTIVE: To discover diverse genotype-phenotype associations affiliated with Type 2 Diabetes Mellitus (T2DM) via genome-wide association study (GWAS) and phenome-wide association study (PheWAS), more cases (T2DM subjects) and controls (subjects without T2DM) are required to be identified (e.g., via Electronic Health Records (EHR)). However, existing expert based identification algorithms often suffer in a low recall rate and could miss a large number of valuable samples under conservative filtering standards...
January 2017: International Journal of Medical Informatics
Shefali S Verma, Anastasia M Lucas, Daniel R Lavage, Joseph B Leader, Raghu Metpally, Sarathbabu Krishnamurthy, Frederick Dewey, Ingrid Borecki, Alexander Lopez, John Overton, John Penn, Jeffrey Reid, Sarah A Pendergrass, Gerda Breitwieser, Marylyn D Ritchie
A wide range of patient health data is recorded in Electronic Health Records (EHR). This data includes diagnosis, surgical procedures, clinical laboratory measurements, and medication information. Together this information reflects the patient's medical history. Many studies have efficiently used this data from the EHR to find associations that are clinically relevant, either by utilizing International Classification of Diseases, version 9 (ICD-9) codes or laboratory measurements, or by designing phenotype algorithms to extract case and control status with accuracy from the EHR...
2016: Pacific Symposium on Biocomputing
Katherine P Liao, Jeffrey A Sparks, Boris P Hejblum, I-Hsin Kuo, Jing Cui, Lauren J Lahey, Andrew Cagan, Vivian S Gainer, Weidong Liu, T Tony Cai, Jeremy Sokolove, Tianxi Cai
OBJECTIVE: Patients with rheumatoid arthritis (RA) develop autoantibodies against a spectrum of antigens, but the clinical significance of these autoantibodies is unclear. Using a phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA. METHODS: This study was conducted in a cohort of RA patients identified from the electronic medical records (EMRs) of 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA...
April 2017: Arthritis & Rheumatology
Jayanth Doss, Huan Mo, Robert J Carroll, Leslie J Crofford, Joshua C Denny
OBJECTIVE: The differences between seronegative and seropositive rheumatoid arthritis (RA) have not been widely reported. We performed electronic health record (EHR)-based phenome-wide association studies (PheWAS) to identify disease associations in seropositive and seronegative RA. METHODS: A validated algorithm identified RA subjects from the de-identified version of the Vanderbilt University Medical Center EHR. Serotypes were determined by rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) values...
February 2017: Arthritis & Rheumatology
Anurag Verma, Shefali S Verma, Sarah A Pendergrass, Dana C Crawford, David R Crosslin, Helena Kuivaniemi, William S Bush, Yuki Bradford, Iftikhar Kullo, Suzette J Bielinski, Rongling Li, Joshua C Denny, Peggy Peissig, Scott Hebbring, Mariza De Andrade, Marylyn D Ritchie, Gerard Tromp
BACKGROUND: We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy...
August 12, 2016: BMC Medical Genomics
Anurag Verma, Anna O Basile, Yuki Bradford, Helena Kuivaniemi, Gerard Tromp, David Carey, Glenn S Gerhard, James E Crowe, Marylyn D Ritchie, Sarah A Pendergrass
We performed a Phenome-Wide Association Study (PheWAS) to identify interrelationships between the immune system genetic architecture and a wide array of phenotypes from two de-identified electronic health record (EHR) biorepositories. We selected variants within genes encoding critical factors in the immune system and variants with known associations with autoimmunity. To define case/control status for EHR diagnoses, we used International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes from 3,024 Geisinger Clinic MyCode® subjects (470 diagnoses) and 2,899 Vanderbilt University Medical Center BioVU biorepository subjects (380 diagnoses)...
2016: PloS One
Soheil Moosavinasab, Jeremy Patterson, Robert Strouse, Majid Rastegar-Mojarad, Kelly Regan, Philip R O Payne, Yungui Huang, Simon M Lin
The process of discovering new drugs has been extremely costly and slow in the last decades despite enormous investment in pharmaceutical research. Drug repurposing enables researchers to speed up the process of discovering other conditions that existing drugs can effectively treat, with low cost and fast FDA approval. Here, we introduce 'RE:fine Drugs', a freely available interactive website for integrated search and discovery of drug repurposing candidates from GWAS and PheWAS repurposing datasets constructed using previously reported methods in Nature Biotechnology...
2016: Database: the Journal of Biological Databases and Curation
Renato Polimanti, Henry R Kranzler, Joel Gelernter
To identify novel traits associated with alleles known to predispose to alcohol and nicotine use, we conducted a phenome-wide association study (PheWAS) in a large multi-population cohort. We investigated 7688 African-Americans, 1133 Asian-Americans, 14 081 European-Americans, and 3492 Hispanic-Americans from the Women's Health Initiative, analyzing alleles at the CHRNA3-CHRNA5 locus, ADH1B, and ALDH2 with respect to phenotypic traits related to anthropometric characteristics, dietary habits, social status, psychological traits, reproductive history, health conditions, and nicotine/alcohol use...
October 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Joshua C Denny, Lisa Bastarache, Dan M Roden
Beginning in the early 2000s, the accumulation of biospecimens linked to electronic health records (EHRs) made possible genome-phenome studies (i.e., comparative analyses of genetic variants and phenotypes) using only data collected as a by-product of typical health care. In addition to disease and trait genetics, EHRs proved a valuable resource for analyzing pharmacogenetic traits and developing reverse genetics approaches such as phenome-wide association studies (PheWASs). PheWASs are designed to survey which of many phenotypes may be associated with a given genetic variant...
August 31, 2016: Annual Review of Genomics and Human Genetics
Lyubov E Salnikova, Maryam B Khadzhieva, Dmitry S Kolobkov
Pelvic floor dysfunction, specifically genital prolapse (GP) and stress urinary inconsistency (SUI) presumably co-occur with other connective tissue disorders such as hernia, hemorrhoids, and varicose veins. Observations on non-random coexistence of these disorders have never been summarized in a meta-analysis. The performed meta-analysis demonstrated that varicose veins and hernia are associated with GP. Disease connections on the molecular level may be partially based on shared genetic susceptibility. A unique opportunity to estimate shared genetic susceptibility to disorders is provided by a PheWAS (phenome-wide association study) designed to utilize GWAS data concurrently to many phenotypes...
July 2016: Human Genetics
Ryan B Shartau, Dane A Crossley, Zachary F Kohl, Colin J Brauner
The nests of embryonic turtles naturally experience elevated CO2 (hypercarbia), which leads to increased blood PCO2  and a respiratory acidosis, resulting in reduced blood pH [extracellular pH (pHe)]. Some fishes preferentially regulate tissue pH [intracellular pH (pHi)] against changes in pHe; this has been proposed to be associated with exceptional CO2 tolerance and has never been identified in amniotes. As embryonic turtles may be CO2 tolerant based on nesting strategy, we hypothesized that they preferentially regulate pHi, conferring tolerance to severe acute acid-base challenges...
July 1, 2016: Journal of Experimental Biology
Joseph B Leader, Sarah A Pendergrass, Anurag Verma, David J Carey, Dustin N Hartzel, Marylyn D Ritchie, H Lester Kirchner
Phenome-Wide Association Studies (PheWAS) comprehensively investigate the association between genetic variation and a wide array of outcome traits. Electronic health record (EHR) based PheWAS uses various abstractions of International Classification of Diseases, Ninth Revision (ICD-9) codes to identify case/control status for diagnoses that are used as the phenotypic variables. However, there have not been comparisons within a PheWAS between results from high quality derived phenotypes and high-throughput but potentially inaccurate use of ICD-9 codes for case/control definition...
2015: AMIA ... Annual Symposium Proceedings
William S Bush, Matthew T Oetjens, Dana C Crawford
Advances in genotyping technology have, over the past decade, enabled the focused search for common genetic variation associated with human diseases and traits. With the recently increased availability of detailed phenotypic data from electronic health records and epidemiological studies, the impact of one or more genetic variants on the phenome is starting to be characterized both in clinical and population-based settings using phenome-wide association studies (PheWAS). These studies reveal a number of challenges that will need to be overcome to unlock the full potential of PheWAS for the characterization of the complex human genome-phenome relationship...
March 2016: Nature Reviews. Genetics
Anna O Basile, John R Wallace, Peggy Peissig, Catherine A McCarty, Murray Brilliant, Marylyn D Ritchie
Next-generation sequencing technology has presented an opportunity for rare variant discovery and association of these variants with disease. To address the challenges of rare variant analysis, multiple statistical methods have been developed for combining rare variants to increase statistical power for detecting associations. BioBin is an automated tool that expands on collapsing/binning methods by performing multi-level variant aggregation with a flexible, biologically informed binning strategy using an internal biorepository, the Library of Knowledge (LOKI)...
2016: Pacific Symposium on Biocomputing
Anurag Verma, Joseph B Leader, Shefali S Verma, Alex Frase, John Wallace, Scott Dudek, Daniel R Lavage, Cristopher V Van Hout, Frederick E Dewey, John Penn, Alex Lopez, John D Overton, David J Carey, David H Ledbetter, H Lester Kirchner, Marylyn D Ritchie, Sarah A Pendergrass
Electronic health records (EHR) provide a comprehensive resource for discovery, allowing unprecedented exploration of the impact of genetic architecture on health and disease. The data of EHRs also allow for exploration of the complex interactions between health measures across health and disease. The discoveries arising from EHR based research provide important information for the identification of genetic variation for clinical decision-making. Due to the breadth of information collected within the EHR, a challenge for discovery using EHR based data is the development of high-throughput tools that expose important areas of further research, from genetic variants to phenotypes...
2016: Pacific Symposium on Biocomputing
Shefali S Verma, Alex T Frase, Anurag Verma, Sarah A Pendergrass, Shaun Mahony, David W Haas, Marylyn D Ritchie
Association studies have shown and continue to show a substantial amount of success in identifying links between multiple single nucleotide polymorphisms (SNPs) and phenotypes. These studies are also believed to provide insights toward identification of new drug targets and therapies. Albeit of all the success, challenges still remain for applying and prioritizing these associations based on available biological knowledge. Along with single variant association analysis, genetic interactions also play an important role in uncovering the etiology and progression of complex traits...
2016: Pacific Symposium on Biocomputing
Yaping Lu, Yemao Liu, Xiaohui Niu, Qingyong Yang, Xuehai Hu, Hong-Yu Zhang, Jingbo Xia
In the post-GWAS (Genome-Wide Association Scan) era, the interpretation of GWAS results is crucial to screen for highly relevant phenotype-genotype association pairs. Based on the single genotype-phenotype association test and a pathway enrichment analysis, we propose a Metabolite-pathway-based Phenome-Wide Association Scan (M-PheWAS) to analyze the key metabolite-SNP pairs in rice and determine the regulatory relationship by assessing similarities in the changes of enzymes and downstream products in a pathway...
2015: Frontiers in Plant Science
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