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Search Results: 1 - 10 of 203718 matches for " Craig P. Hersh "
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Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery
Craig P Hersh, Dawn L DeMeo, John J Reilly, Edwin K Silverman
Respiratory Research , 2007, DOI: 10.1186/1465-9921-8-59
Abstract: In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV1, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs) were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution.A SNP upstream from glutathione S-transferase pi (GSTP1; p = 0.003) and a coding SNP in microsomal epoxide hydrolase (EPHX1; p = 0.02) were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in EPHX1 was associated with change in BODE score (p = 0.008), with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in GSTP1 and three additional SNPs in EPHX1 were associated (p < 0.05) with additional LVRS outcomes. None of these SNP effects were seen in 166 patients randomized to medical therapy.Genetic variants in GSTP1 and EPHX1, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.The National Emphysema Treatment Trial, a multicenter randomized trial of lung volume reduction surgery (LVRS) versus medical management for emphysema, found that on average, LVRS led to improved functional status, but not increased survival in patients with emphysema and severe chronic airflow obstruction [1]. However, substantial variability in response to LVRS was observed. Based on pulmonary function testing and emphysema distribution on chest computed tomography (CT), a patient population with a high risk of death was identified [2]. Among non-high risk patients, baseline exercise ca
The clinical features of the overlap between COPD and asthma
Megan Hardin, Edwin K Silverman, R Graham Barr, Nadia N Hansel, Joyce D Schroeder, Barry J Make, James D Crapo, Craig P Hersh, the COPDGene Investigators
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-127
Abstract: We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.ClinicalTrials.gov: NCT00608764Chronic Obstructive Pulmonary Disease (COPD) affects over 10 million Americans. In the United States, COPD is the third leading cause of death [1] and is responsible for over $15 billion in annual healthcare costs [2]. World-wide, COPD is one of the few conditions in which mortality is rising, and it is estimated to become the third leading cause of death by 2020[3,4]. More than 40% of patients with COPD will additionally report a history of asthma, and this dual-diagnosis increases with age [5,6].There is increasing evidence that patients who have COPD and asthma experience more rapid disease progression than those with either disease alone. Airway hyperresponsiveness (AHR) and the diagnosis of asthma have been associated with greater decline in FEV1 in both smokers and nonsmokers [7-9] and asthma has been recognized as a risk factor for COPD [10]. The pre
Epidemiology, radiology, and genetics of nicotine dependence in COPD
Deog Kyeom Kim, Craig P Hersh, George R Washko, John E Hokanson, David A Lynch, John D Newell, James R Murphy, James D Crapo, Edwin K Silverman, the COPD Gene Investigators
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-9
Abstract: Current smokers with COPD (GOLD stage ≥ 2) or normal spirometry were analyzed from the COPDGene Study, a prospective observational study. Nicotine dependence was determined by the Fagerstrom test for nicotine dependence (FTND). Volumetric CT acquisitions measuring the percent of emphysema on inspiratory CT (% of lung <-950 HU) and gas trapping on expiratory CT (% of lung <-856 HU) were obtained. Genotypes for two SNPs in the CHRNA3/5 region (rs8034191, rs1051730) previously associated with nicotine dependence and COPD were analyzed for association to COPD and nicotine dependence phenotypes.Among 842 currently smoking subjects (335 COPD cases and 507 controls), 329 subjects (39.1%) showed high nicotine dependence. Subjects with high nicotine dependence had greater cumulative and current amounts of smoking. However, emphysema severity was negatively correlated with the FTND score in controls (ρ = -0.19, p < .0001) as well as in COPD cases (ρ = -0.18, p = 0.0008). Lower FTND score, male gender, lower body mass index, and lower FEV1 were independent risk factors for emphysema severity in COPD cases. Both CHRNA3/5 SNPs were associated with FTND in current smokers. An association of genetic variants in CHRNA3/5 with severity of emphysema was only found in former smokers, but not in current smokers.Nicotine dependence was a negative predictor for emphysema on CT in COPD and control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution, which may influence genetic association studies of emphysema phenotypes.ClinicalTrials (NCT): NCT00608764Cigarette smoking is the most important environmental risk factor for the development of COPD [1-3]. Cigarette smoking intensity is known to be associated with clinical features of COPD such as the rate of lung function decline [2,4] and COPD exacerbation frequency [5,6]. In addition, it is correlated with symptoms of chronic bronchitis even in healthy smokers [7]. However
A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci
Sreekumar G. Pillai ,Dongliang Ge equal contributor,Guohua Zhu equal contributor,Xiangyang Kong equal contributor,Kevin V. Shianna,Anna C. Need,Sheng Feng,Craig P. Hersh,Per Bakke,Amund Gulsvik,Andreas Ruppert,Karin C. L?drup Carlsen,Allen Roses,Wayne Anderson,ICGN Investigators,Stephen I. Rennard,David A. Lomas,Edwin K. Silverman,David B. Goldstein
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000421
Abstract: There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10?10, (rs8034191) and 5.74×10?10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease
Weiliang Qiu, Michael H. Cho, John H. Riley, Wayne H. Anderson, Dave Singh, Per Bakke, Amund Gulsvik, Augusto A. Litonjua, David A. Lomas, James D. Crapo, Terri H. Beaty, Bartolome R. Celli, Stephen Rennard, Ruth Tal-Singer, Steven M. Fox, Edwin K. Silverman, Craig P. Hersh, and the ECLIPSE Investigators
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024395
Abstract: Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.
Maximum Likelihood Estimation in Latent Class Models For Contingency Table Data
S. E. Fienberg,P. Hersh,A. Rinaldo,Y. Zhou
Mathematics , 2007,
Abstract: Statistical models with latent structure have a history going back to the 1950s and have seen widespread use in the social sciences and, more recently, in computational biology and in machine learning. Here we study the basic latent class model proposed originally by the sociologist Paul F. Lazarfeld for categorical variables, and we explain its geometric structure. We draw parallels between the statistical and geometric properties of latent class models and we illustrate geometrically the causes of many problems associated with maximum likelihood estimation and related statistical inference. In particular, we focus on issues of non-identifiability and determination of the model dimension, of maximization of the likelihood function and on the effect of symmetric data. We illustrate these phenomena with a variety of synthetic and real-life tables, of different dimension and complexity. Much of the motivation for this work stems from the "100 Swiss Francs" problem, which we introduce and describe in detail.
A stimulus to define informatics and health information technology
William Hersh
BMC Medical Informatics and Decision Making , 2009, DOI: 10.1186/1472-6947-9-24
Abstract: The paper, presented as a Debate to encourage further discussion and disagreement, provides definitions of the major terminology used in biomedical and health informatics and health information technology. For informatics, it focuses on the words that modify the term as well as individuals who practice the discipline. Other categories of related terms are covered as well, from the associated disciplines of computer science, information technolog and health information management to the major application categories of applications used. The discussion closes with a classification of individuals who work in the largest segment of the field, namely clinical informatics.The goal of presenting in Debate format is to provide a starting point for discussion to reach a documented consensus on the definition and use of these terms."We have the most inefficient health care system imaginable. We're still using paper. Nurses can't read the prescriptions that doctors have written out. Why wouldn't we want to put that on an electronic medical record that will reduce error rates, reduce our long-term costs of health care, and create jobs right now?"- US President Barack Obama, February 9, 2009Health information technology (HIT) has achieved a new prominence in the United States (US) with its inclusion in the American Recovery and Reinvestment Act (ARRA) of 2009, the federal economic stimulus package signed into law by President Barack Obama on February 17, 2009. The promise of HIT for improving quality and safety of health care while reducing costs has caught the eye of policy makers and other leaders in health care. I had the opportunity to be involved in commenting on some of the draft versions of the legislation, and it became apparent during this process that most people outside HIT do not understand our terminology. As such, this led to confusion that could have had dire consequences for language written into such prominent law, such as its funding of workforce initiatives no
Connectivity of h-complexes
Patricia Hersh
Mathematics , 2003,
Abstract: This paper verifies a conjecture of Edelman and Reiner regarding the homology of the $h$-complex of a Boolean algebra. A discrete Morse function with no low-dimensional critical cells is constructed, implying a lower bound on connectivity. This together with an Alexander duality result of Edelman and Reiner implies homology-vanishing also in high dimensions. Finally, possible generalizations to certain classes of supersolvable lattices are suggested.
Lexicographic shellability for balanced complexes
Patricia Hersh
Mathematics , 2003,
Abstract: We introduce a notion of lexicographic shellability for pure, balanced boolean cell complexes, modelled after the $CL$-shellability criterion of Bj\"orner and Wachs for posets and its generalization by Kozlov called $CC$-shellability. We give a lexicographic shelling for the quotient of the order complex of a Boolean algebra of rank $2n$ by the action of the wreath product $S_2\wr S_n$ of symmetric groups, and we provide a partitioning for the quotient complex $\Delta (\Pi_n)/S_n $. Stanley asked for a description of the symmetric group representation $\beta_S $ on the homology of the rank-selected partition lattice $\Pi_n^S $ in [St2], and in particular he asked when the multiplicity $b_S(n)$ of the trivial representation in $\beta_S$ is 0. One consequence of the partitioning for $\dps $ is a (fairly complicated) combinatorial interpretation for $b_S(n) $; another is a simple proof of Hanlon's result that $b_{1,..., i}(n)=0$. Using a result of Garsia and Stanton, we deduce from our shelling for $\Delta (B_{2n})/S_2 \wr S_n$ that the ring of invariants $k[x_1,..., x_{2n}]^{S_2\wr S_n}$ is Cohen-Macaulay over any field $k$.
A partitioning and related properties for the quotient complex $Δ (B_{lm})/S_l \wr S_m$
Patricia Hersh
Mathematics , 2003,
Abstract: We study the quotient complex $\Delta (B_{lm})/S_l\wr S_m$ as a means of deducing facts about the ring $k[x_1,..., x_{lm}]^{S_l\wr S_m}$. It is shown in [He] that this quotient complex is shellable when $l=2$, implying Cohen-Macaulayness of $k[x_1,..., x_{2m}]^{S_2\wr S_m}$ for any field $k$. We now confirm for all pairs $(l,m)$ with $l>2$ and $m>1$ that this quotient complex is not Cohen-Macaulay over $\integ /2\integ $, but it is Cohen-Macaulay over fields of characteristic $p>m$ (independent of $l$). This yields corresponding characteristic-dependent results for the ring of invariants $k[x_1,..., x_{lm}]^{S_l\wr S_m}$. We also prove that this quotient complex and the links of many of its faces are collapsible, and we give a partitioning for this quotient complex.
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