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Consensus Genotyper for Exome Sequencing (CGES): improving the quality of exome variant genotypes.
Trubetskoy V, Rodriguez A, Dave U, Campbell N, Crawford EL, Cook EH, Sutcliffe JS, Foster I, Madduri R, Cox NJ, Davis LK
(2015) Bioinformatics 31: 187-93
MeSH Terms: Algorithms, Autistic Disorder, Consensus Sequence, Data Interpretation, Statistical, Exome, Genetic Testing, Genotype, High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Single Nucleotide, Software
Show Abstract · Added February 22, 2016
MOTIVATION - The development of cost-effective next-generation sequencing methods has spurred the development of high-throughput bioinformatics tools for detection of sequence variation. With many disparate variant-calling algorithms available, investigators must ask, 'Which method is best for my data?' Machine learning research has shown that so-called ensemble methods that combine the output of multiple models can dramatically improve classifier performance. Here we describe a novel variant-calling approach based on an ensemble of variant-calling algorithms, which we term the Consensus Genotyper for Exome Sequencing (CGES). CGES uses a two-stage voting scheme among four algorithm implementations. While our ensemble method can accept variants generated by any variant-calling algorithm, we used GATK2.8, SAMtools, FreeBayes and Atlas-SNP2 in building CGES because of their performance, widespread adoption and diverse but complementary algorithms.
RESULTS - We apply CGES to 132 samples sequenced at the Hudson Alpha Institute for Biotechnology (HAIB, Huntsville, AL) using the Nimblegen Exome Capture and Illumina sequencing technology. Our sample set consisted of 40 complete trios, two families of four, one parent-child duo and two unrelated individuals. CGES yielded the fewest total variant calls (N(CGES) = 139° 897), the highest Ts/Tv ratio (3.02), the lowest Mendelian error rate across all genotypes (0.028%), the highest rediscovery rate from the Exome Variant Server (EVS; 89.3%) and 1000 Genomes (1KG; 84.1%) and the highest positive predictive value (PPV; 96.1%) for a random sample of previously validated de novo variants. We describe these and other quality control (QC) metrics from consensus data and explain how the CGES pipeline can be used to generate call sets of varying quality stringency, including consensus calls present across all four algorithms, calls that are consistent across any three out of four algorithms, calls that are consistent across any two out of four algorithms or a more liberal set of all calls made by any algorithm.
AVAILABILITY AND IMPLEMENTATION - To enable accessible, efficient and reproducible analysis, we implement CGES both as a stand-alone command line tool available for download in GitHub and as a set of Galaxy tools and workflows configured to execute on parallel computers.
SUPPLEMENTARY INFORMATION - Supplementary data are available at Bioinformatics online.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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11 MeSH Terms
Genetics of pulmonary hypertension.
Best DH, Austin ED, Chung WK, Elliott CG
(2014) Curr Opin Cardiol 29: 520-7
MeSH Terms: Bone Morphogenetic Protein Receptors, Type II, Familial Primary Pulmonary Hypertension, Genetic Predisposition to Disease, Genetic Testing, Humans, Mutation
Show Abstract · Added February 12, 2015
PURPOSE OF REVIEW - The identification of the genetic basis for heritable predisposition to pulmonary arterial hypertension (PAH) has altered the clinical and research landscape for PAH patients and their care providers. This review aims to describe the genetic discoveries and their impact on clinical medicine.
RECENT FINDINGS - Since the landmark discovery that bone morphogenetic protein receptor type II (BMPR2) mutations cause the majority of cases of familial PAH, investigators have discovered mutations in genes that cause PAH in families without BMPR2 mutations, including the type I receptor ACVRL1 and the type III receptor ENG (both associated with hereditary hemorrhagic telangiectasia), caveolin-1 (CAV1), and a gene (KCNK3) encoding a two-pore potassium channel. Mutations in these genes cause an autosomal-dominant predisposition to PAH in which a fraction of mutation carriers develop PAH (incomplete penetrance). In 2014, scientists discovered mutations in eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) that cause pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease, an autosomal recessively inherited disorder.
SUMMARY - The discovery that some forms of pulmonary hypertension are heritable and can be genetically defined adds important opportunities for physicians to educate their patients and their families to understand the potential risks and benefits of genetic testing.
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6 MeSH Terms
The genetics of pulmonary arterial hypertension.
Austin ED, Loyd JE
(2014) Circ Res 115: 189-202
MeSH Terms: Alleles, Animals, Bone Morphogenetic Protein Receptors, Type II, Caveolin 1, Epigenesis, Genetic, Familial Primary Pulmonary Hypertension, Genetic Testing, Gonadal Steroid Hormones, Humans, Hypertension, Pulmonary, Mutation, Nerve Tissue Proteins, Potassium Channels, Tandem Pore Domain, Protein Precursors, Protein-Serine-Threonine Kinases
Show Abstract · Added February 12, 2015
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease.
© 2014 American Heart Association, Inc.
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15 MeSH Terms
Discordance between self-report and genetic confirmation of sickle cell disease status in African-American adults.
Bean CJ, Hooper WC, Ellingsen D, DeBaun MR, Sonderman J, Blot WJ
(2014) Public Health Genomics 17: 169-72
MeSH Terms: Adult, African Americans, Aged, Anemia, Sickle Cell, Cohort Studies, Data Collection, Female, Genetic Testing, Health Education, Health Knowledge, Attitudes, Practice, Hemoglobin C, Hemoglobin, Sickle, Heterozygote, Humans, Male, Middle Aged, Self Report, Sickle Cell Trait, Southeastern United States, beta-Globins
Show Abstract · Added October 7, 2014
BACKGROUND - Sickle cell disease (SCD) is an autosomal recessive genetic disorder, with persons heterozygous for the mutation said to have the sickle cell trait (SCT). Serious adverse effects are mainly limited to those with SCD, but the distinction between disease and trait is not always clear to the general population. We sought to determine the accuracy of self-reported SCD when compared to genetic confirmation.
METHODS - From stratified random samples of Southern Community Cohort Study participants, we sequenced the β- globin gene in 51 individuals reporting SCD and 75 individuals reporting no SCD.
RESULTS - The median age of the group selected was 53 years (range 40-69) with 29% male. Only 5.9% of the 51 individuals reporting SCD were confirmed by sequencing, with the remaining 62.7% having SCT, 5.9% having hemoglobin C trait, and 25.5% having neither SCD nor trait. Sequencing results of the 75 individuals reporting no SCD by contrast were 100% concordant with self-report.
CONCLUSIONS - Misreporting of SCD is common in an older adult population, with most persons reporting SCD in this study being carriers of the trait and a sizeable minority completely unaffected. The results from this pilot survey support the need for increased efforts to raise community awareness and knowledge of SCD.
© 2014 S. Karger AG, Basel.
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20 MeSH Terms
Response to "clinically actionable genotypes among Brazilians".
Van Driest SL, Roden DM
(2014) Clin Pharmacol Ther 96: 26
MeSH Terms: Female, Gene Frequency, Genetic Testing, Genetic Variation, Humans, Male, Pharmacogenetics
Added January 23, 2015
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7 MeSH Terms
Beyond histology: translating tumor genotypes into clinically effective targeted therapies.
Meador CB, Micheel CM, Levy MA, Lovly CM, Horn L, Warner JL, Johnson DB, Zhao Z, Anderson IA, Sosman JA, Vnencak-Jones CL, Dahlman KB, Pao W
(2014) Clin Cancer Res 20: 2264-75
MeSH Terms: Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Genetic Testing, Genetic Variation, Genomics, Genotype, Humans, Lung Neoplasms, Melanoma, Molecular Targeted Therapy, Mutation, Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Receptor Protein-Tyrosine Kinases
Show Abstract · Added March 10, 2014
Increased understanding of intertumoral heterogeneity at the genomic level has led to significant advancements in the treatment of solid tumors. Functional genomic alterations conferring sensitivity to targeted therapies can take many forms, and appropriate methods and tools are needed to detect these alterations. This review provides an update on genetic variability among solid tumors of similar histologic classification, using non-small cell lung cancer and melanoma as examples. We also discuss relevant technological platforms for discovery and diagnosis of clinically actionable variants and highlight the implications of specific genomic alterations for response to targeted therapy.
©2014 AACR.
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6 Members
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19 MeSH Terms
Biomarkers to the rescue in a lung nodule epidemic.
Massion PP
(2014) J Clin Oncol 32: 725-6
MeSH Terms: Biomarkers, Tumor, Female, Gene Expression Profiling, Genetic Testing, Humans, Lung Neoplasms, Male, Mass Screening, MicroRNAs, Tomography, X-Ray Computed
Added March 10, 2014
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10 MeSH Terms
Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process.
Caudle KE, Klein TE, Hoffman JM, Muller DJ, Whirl-Carrillo M, Gong L, McDonagh EM, Sangkuhl K, Thorn CF, Schwab M, Agundez JA, Freimuth RR, Huser V, Lee MT, Iwuchukwu OF, Crews KR, Scott SA, Wadelius M, Swen JJ, Tyndale RF, Stein CM, Roden D, Relling MV, Williams MS, Johnson SG
(2014) Curr Drug Metab 15: 209-17
MeSH Terms: Genetic Testing, Genotype, Humans, Pharmaceutical Preparations, Pharmacogenetics, Phenotype, Practice Guidelines as Topic, Practice Patterns, Physicians'
Show Abstract · Added June 26, 2014
The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
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8 MeSH Terms
Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing.
Van Driest SL, Shi Y, Bowton EA, Schildcrout JS, Peterson JF, Pulley J, Denny JC, Roden DM
(2014) Clin Pharmacol Ther 95: 423-31
MeSH Terms: African Americans, Aged, Female, Gene Frequency, Genetic Testing, Genetic Variation, Genotype, Humans, Male, Middle Aged, Pharmacogenetics
Show Abstract · Added May 19, 2014
Since September 2010, more than 10,000 patients have undergone preemptive, panel-based pharmacogenomic testing through the Vanderbilt Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment program. Analysis of the genetic data from the first 9,589 individuals reveals that the frequency of genetic variants is concordant with published allele frequencies. Based on five currently implemented drug-gene interactions, the multiplexed test identified one or more actionable variants in 91% of the genotyped patients and in 96% of African American patients. Using medication exposure data from electronic medical records, we compared a theoretical "reactive," prescription-triggered, serial single-gene testing strategy with our preemptive, multiplexed genotyping approach. Reactive genotyping would have generated 14,656 genetic tests. These data highlight three advantages of preemptive genotyping: (i) the vast majority of patients carry at least one pharmacogenetic variant; (ii) data are available at the point of care; and (iii) there is a substantial reduction in testing burden compared with a reactive strategy.
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5 Members
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11 MeSH Terms
Novel SCN3A variants associated with focal epilepsy in children.
Vanoye CG, Gurnett CA, Holland KD, George AL, Kearney JA
(2014) Neurobiol Dis 62: 313-22
MeSH Terms: Cells, Cultured, Child, Child, Preschool, Epilepsies, Partial, Female, Genetic Testing, HEK293 Cells, Humans, Male, Mutation, Missense, NAV1.3 Voltage-Gated Sodium Channel, Sodium Channels
Show Abstract · Added March 7, 2014
Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.
© 2013.
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12 MeSH Terms