oalib

Publish in OALib Journal

ISSN: 2333-9721

APC: Only $99

Submit

Any time

2019 ( 179 )

2018 ( 339 )

2017 ( 337 )

2016 ( 459 )

Custom range...

Search Results: 1 - 10 of 248219 matches for " Duncan C Thomas "
All listed articles are free for downloading (OA Articles)
Page 1 /248219
Display every page Item
A Bayesian Hierarchical Model for Relating Multiple SNPs within Multiple Genes to Disease Risk
Lewei Duan,Duncan C. Thomas
International Journal of Genomics , 2013, DOI: 10.1155/2013/406217
Abstract: A variety of methods have been proposed for studying the association of multiple genes thought to be involved in a common pathway for a particular disease. Here, we present an extension of a Bayesian hierarchical modeling strategy that allows for multiple SNPs within each gene, with external prior information at either the SNP or gene level. The model involves variable selection at the SNP level through latent indicator variables and Bayesian shrinkage at the gene level towards a prior mean vector and covariance matrix that depend on external information. The entire model is fitted using Markov chain Monte Carlo methods. Simulation studies show that the approach is capable of recovering many of the truly causal SNPs and genes, depending upon their frequency and size of their effects. The method is applied to data on 504?SNPs in 38 candidate genes involved in DNA damage response in the WECARE study of second breast cancers in relation to radiotherapy exposure. 1. Introduction The Women’s Environment, Cancer And Radiation Epidemiology (WECARE) study [1] is aimed at a comprehensive examination of genes involved in particular functional pathways. The study is a population-based nested case-control study of 708 contralateral breast cancers (CBC) within a notional cohort of about 65,000 survivors of a first breast cancer, 1401 of whom serve as controls, and the primary exposure of interest is ionizing radiation dose to the contralateral breast from radiotherapy for treatment of the first cancer. Ionizing radiation is known to cause double strand breaks (DSBs) in DNA, which can invoke any of several DNA damage response mechanisms, primarily DSB repair via either homologous recombination or nonhomologous end joining, cell cycle checkpoint regulation, or apoptosis. The original study focused on mutations in the ATM gene, which plays a central role in the recognition of DSBs. The study was then extended to include BRCA1, BRCA2, and CHEK2, which are all involved in homologous recombination repair (HRR), and later still to include a broader set of 38 candidate genes involved in this and other pathways for DSB damage response. We have previously reported on the main effects of ionizing radiation [2, 3], ATM [4–6], BRCA1/2 [7–12], CHEK2 [13], and the interactions of radiation with ATM [14] and BRCA1/2 [15] as well as with other treatments and reproductive factors [16, 17], amongst other risk factors. The aim of this paper is to provide a comprehensive modeling strategy for examining the effects of all genes in a pathway and to apply the approach to candidate genes
Gender difference in symptomatic radiographic knee osteoarthritis in the Knee Clinical Assessment – CAS(K): A prospective study in the general population
Rosie J Lacey, Elaine Thomas, Rachel C Duncan, George Peat
BMC Musculoskeletal Disorders , 2008, DOI: 10.1186/1471-2474-9-82
Abstract: A community-based prospective study. 819 adults aged ≥50 years reporting knee pain in the previous 12 months were recruited by postal questionnaires to a research clinic involving plain radiography (weight-bearing posteroanterior semiflexed, supine skyline and lateral views), clinical interview and physical examination. Any knee ROA, ROA severity, tibiofemoral joint osteoarthritis (TJOA) and patellofemoral joint osteoarthritis (PJOA) were defined using all three radiographic views. Occupational class was derived from current or last job title. Proportions of each gender with symptomatic knee ROA were expressed as percentages, stratified by age; differences between genders were expressed as percentage differences with 95% confidence intervals.745 symptomatic participants were eligible and had complete X-ray data. Males had a higher occurrence (77%) of any knee ROA than females (61%). In 50–64 year olds, the excess in men was mild knee OA (particularly PJOA); in ≥65 year olds, the excess was both mild and moderate/severe knee OA (particularly combined TJOA/PJOA). This male excess persisted when using the posteroanterior view only (64% vs. 52%). The lowest level of participation in the clinic was symptomatic females aged 65+. Within each occupational class there were more males with symptomatic knee ROA than females. In those aged 50–64 years, non-articular conditions were equally common in both genders although, in those aged 65+, they occurred more frequently in symptomatic females (41%) than males (31%).The excess of knee ROA among symptomatic males in this study seems unlikely to be attributable to the use of comprehensive X-ray views. Although prior occupational exposures and the presence of non-articular conditions cannot be fully excluded, selective non-participation bias seems the most likely explanation. This has implications for future study design.Gender differences in the occurrence of knee osteoarthritis are well documented. Population studies in developed
Clinical features of symptomatic patellofemoral joint osteoarthritis
George Peat, Rachel C Duncan, Laurence RJ Wood, Elaine Thomas, Sara Muller
Arthritis Research & Therapy , 2012, DOI: 10.1186/ar3779
Abstract: This was a population-based cross-sectional study of 745 adults aged ≥50 years with knee pain. Information on risk factors and clinical signs and symptoms was gathered by a self-complete questionnaire, and standardised clinical interview and examination. Three radiographic views of the knee were obtained (weight-bearing semi-flexed posteroanterior, supine skyline and lateral) and individuals were classified into four subsets (no radiographic OA, isolated PFJOA, isolated tibiofemoral joint OA, combined patellofemoral/tibiofemoral joint OA) according to two different cut-offs: 'any OA' and 'moderate to severe OA'. A series of binary logistic and multinomial regression functions were performed to compare the clinical features of each subset and their ability in combination to discriminate PFJOA from other subsets.Distinctive clinical features of moderate to severe isolated PFJOA included a history of dramatic swelling, valgus deformity, markedly reduced quadriceps strength, and pain on patellofemoral joint compression. Mild isolated PFJOA was barely distinguished from no radiographic OA (AUC 0.71, 95% CI 0.66, 0.76) with only difficulty descending stairs and coarse crepitus marginally informative over age, sex and body mass index. Other cardinal signs of knee OA - the presence of effusion, bony enlargement, reduced flexion range of movement, mediolateral instability and varus deformity - were indicators of tibiofemoral joint OA.Early isolated PFJOA is clinically manifest in symptoms and self-reported functional limitation but has fewer clear clinical signs. More advanced disease is indicated by a small number of simple-to-assess signs and the relative absence of classic signs of knee OA, which are predominantly manifestations of tibiofemoral joint OA. Confident diagnosis of even more advanced PFJOA may be limited in the community setting.Osteoarthritis (OA) is not a single disease [1] and distinct phenotypes are believed to exist even within a single joint complex like
Design considerations in a sib-pair study of linkage for susceptibility loci in cancer
Richard A Kerber, Christopher I Amos, Beow Y Yeap, Dianne M Finkelstein, Duncan C Thomas
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-64
Abstract: We conducted simulation studies to assess the impact of design factors on relative efficiency for a linkage study of colorectal cancer. We considered two test statistics, one comparing the mean IBD probability in affected pairs to its null value of 0.5, and one comparing the mean IBD probabilities between affected and discordant pairs. We varied numbers of parents available, numbers of affected and unaffected siblings, reconstructing the genotype of an unavailable affected sibling by a spouse and offspring, and elimination of sibships where the proband carries a mutation at another locus.Power and efficiency were most affected by the number of affected sibs, the number of sib pairs genotyped, and the risk attributable to linked and unlinked loci. Genotyping unaffected siblings added little power for low penetrance models, but improved validity of tests when there was genetic heterogeneity and for multipoint testing. The efficiency of the concordant-only test was nearly always better than the concordant-discordant test. Replacement of an unavailable affected sibling by a spouse and offspring recovered some linkage information, particularly if several offspring were available. In multipoint analysis, the concordant-only test was showed a small anticonservative bias at 5 cM, while the multipoint concordant-discordant test was generally the most powerful test, and was not biased away from the null at 5 cM.Genotyping parents and unaffected siblings is useful for detecting genotyping errors and if allele frequencies are uncertain. If adequate allele frequency data are available, we suggest a single-point affecteds-only analysis for an initial scan, followed by a multipoint analysis of affected and unaffected members of all available sibships with additional markers around initial hits.The sib pair design has been widely used in human studies for mapping genes that affect both quantitative and dichotomous traits. The objective of sibling studies is to determine whether the
Use of pathway information in molecular epidemiology
Duncan C Thomas, David V Conti, James Baurley, Frederik Nijhout, Michael Reed, Cornelia M Ulrich
Human Genomics , 2009, DOI: 10.1186/1479-7364-4-1-21
Abstract: Molecular epidemiology has advanced from testing associations of disease with single polymorphisms, to exhaustive examination of all polymorphisms in a candidate gene using haplotype tagging single nucleotide polymorphisms (SNPs), to studying increasing numbers of candidate genes simultaneously. Often, gene-environment and gene-gene interactions are considered at the same time. As the number of main effects and interactions proliferate, there is a growing need for a more systematic approach to model development [1].In recognition of this need, the American Association for Cancer Research held a special conference [2] in May 2007, bringing together experts in epidemiology, genetics, statistics, computational biology, systems biology, toxicology, bioinformatics and other fields to discuss various multidisciplinary approaches to this problem.A broad range of exploratory methods have been developed recently for identifying interactions, such as neural nets, classification and regression trees, multi-factor dimension reduction, random forests, hierarchical clustering, etc. [3-7] Our focus here, however, is instead on hypothesis-driven methods based on prior understanding about the structure of biological pathways postulated to be relevant to a particular disease. Our primary purpose is to contrast mechanistic and empirical methods and explore ways of combining the two.Folate metabolism provides a rich example to illustrate these challenges. Folate has been implicated in colorectal cancer, [8] coronary heart disease [9] and neural tube defects, [10,11] among other conditions. Several steps in the metabolism of folate could be involved in these various diseases (Figure 1) and could have quite different effects. The pathway is complex, involving 19 enzymes or carrier proteins, with various feedback loops and two main cycles, the folate and the methionine cycles. The former is involved in pyrimidine synthesis through the action of thymidylate synthase (TS), potentially leadi
Are we PREPared? Quality of information available to patients in the UK about PREP on the internet
S Duncan,C Duncan
Journal of the International AIDS Society , 2012, DOI: 10.7448/ias.15.6.18167
Abstract: Professional bodies in the UK (BASHH/BHIVA) do not currently recommended pre-exposure prophylaxis (PREP) to prevent HIV aquisition for men who have sex with men (MSM) [1]. Conversely, although Federal Drug Administration approval is awaited, the Centers for Disease Control (CDC) have issued clinicians in the USA with interim guidance to facilitate PREP prescriptions [2]. Increasingly patients search the internet for information on HIV treatment, but disparate international policy can lead to confusing patient messages. This study was conducted to systematically assess the quality of internet information available to patients in the UK about PREP. More than 90% of internet searches in the UK are performed using ‘Google.co.uk’ and ‘Bing’ [3]. Using pre-specified criteria, we reviewed the first 100 hits retrieved from each search engine when the following searches were performed: [“HIV pre-exposure prophylaxis”]; [“HIV PREP”]; [“HIV PREP guidelines”]; [“HIV PREP guidelines UK”]; [“truvada prophylaxis HIV”]. Of 172 unique websites identified, 124 websites were active at the time of the review (July 2012). 33 websites were links to academic journals including commentaries and clinical trials, not intended to specifically provide patient information; 5 were internet portals directing users to alternative sites and 10 websites contained no information about PREP. Of the remaining 76 websites, 28 were written by medical professionals and 48 were written by journalists, where 7/48 (15%) were individual blogs. 64/76 (84%) contained a definition of PREP; 63/76 (83%) discussed the rationale and 58/76 (76%) reported efficacy data. Advantages and disadvantages of PREP were presented in 56/76 (74%) and 41/76 (54%) of websites respectively. Only 21/76 (28%) of sites referenced existing national guidelines (CDC/BASHH). A minority of sites described the current clinical practice in the UK (7/76, 9%) with an even smaller number presenting the contrast in clinical stance between the CDC and BASHH/BHIVA (3/76, 4%). The use of PREP is evolving, and the internet is an important patient resource. However, current clinical practice in the UK is seldom described in accessible websites. Avoiding ad hoc and unsupervised use of PREP is crucial to prevent future drug resistance and risky sexual behaviour. More should be done to engage at-risk groups and ensure patients in the UK have access to comprehensive information including the current UK PREP professional guidance.
Health, nutrition and prosperity: a microeconomic perspective
Thomas,Duncan; Frankenberg,Elizabeth;
Bulletin of the World Health Organization , 2002, DOI: 10.1590/S0042-96862002000200005
Abstract: a positive correlation between health and economic prosperity has been widely documented, but the extent to which this reflects a causal effect of health on economic outcomes is very controversial. two classes of evidence are examined. first, carefully designed random assignment studies in the laboratory and field provide compelling evidence that nutritional deficiency - particularly iron deficiency - reduces work capacity and, in some cases, work output. confidence in these results is bolstered by a good understanding of the underlying biological mechanisms. some random assignment studies indicate an improved yield from health services in the labour market. second, observational studies suggest that general markers of nutritional status, such as height and body mass index (bmi), are significant predictors of economic success although their interpretation is confounded by the fact that they reflect influences from early childhood and family background. energy intake and possibly the quality of the diet have also been found to be predictive of economic success in observational studies. however, the identification of causal pathways in these studies is difficult and involves statistical assumptions about unobserved heterogeneity that are difficult to test. illustrations using survey data demonstrate the practical importance of this concern. furthermore, failure to take into account the dynamic interplay between changes in health and economic status has led to limited progress being reported in the literature. a broadening of random assignment studies to measure the effects of an intervention on economic prosperity, investment in population-based longitudinal socioeconomic surveys, and application of emerging technologies for a better measure of health in these surveys will yield very high returns in improving our understanding of how health influences economic prosperity.
Health, nutrition and prosperity: a microeconomic perspective
Thomas Duncan,Frankenberg Elizabeth
Bulletin of the World Health Organization , 2002,
Abstract: A positive correlation between health and economic prosperity has been widely documented, but the extent to which this reflects a causal effect of health on economic outcomes is very controversial. Two classes of evidence are examined. First, carefully designed random assignment studies in the laboratory and field provide compelling evidence that nutritional deficiency - particularly iron deficiency - reduces work capacity and, in some cases, work output. Confidence in these results is bolstered by a good understanding of the underlying biological mechanisms. Some random assignment studies indicate an improved yield from health services in the labour market. Second, observational studies suggest that general markers of nutritional status, such as height and body mass index (BMI), are significant predictors of economic success although their interpretation is confounded by the fact that they reflect influences from early childhood and family background. Energy intake and possibly the quality of the diet have also been found to be predictive of economic success in observational studies. However, the identification of causal pathways in these studies is difficult and involves statistical assumptions about unobserved heterogeneity that are difficult to test. Illustrations using survey data demonstrate the practical importance of this concern. Furthermore, failure to take into account the dynamic interplay between changes in health and economic status has led to limited progress being reported in the literature. A broadening of random assignment studies to measure the effects of an intervention on economic prosperity, investment in population-based longitudinal socioeconomic surveys, and application of emerging technologies for a better measure of health in these surveys will yield very high returns in improving our understanding of how health influences economic prosperity.
Methodological Issues in Multistage Genome-Wide Association Studies
Duncan C. Thomas,Graham Casey,David V. Conti,Robert W. Haile,Juan Pablo Lewinger,Daniel O. Stram
Quantitative Biology , 2010, DOI: 10.1214/09-STS288
Abstract: Because of the high cost of commercial genotyping chip technologies, many investigations have used a two-stage design for genome-wide association studies, using part of the sample for an initial discovery of ``promising'' SNPs at a less stringent significance level and the remainder in a joint analysis of just these SNPs using custom genotyping. Typical cost savings of about 50% are possible with this design to obtain comparable levels of overall type I error and power by using about half the sample for stage I and carrying about 0.1% of SNPs forward to the second stage, the optimal design depending primarily upon the ratio of costs per genotype for stages I and II. However, with the rapidly declining costs of the commercial panels, the generally low observed ORs of current studies, and many studies aiming to test multiple hypotheses and multiple endpoints, many investigators are abandoning the two-stage design in favor of simply genotyping all available subjects using a standard high-density panel. Concern is sometimes raised about the absence of a ``replication'' panel in this approach, as required by some high-profile journals, but it must be appreciated that the two-stage design is not a discovery/replication design but simply a more efficient design for discovery using a joint analysis of the data from both stages. Once a subset of highly-significant associations has been discovered, a truly independent ``exact replication'' study is needed in a similar population of the same promising SNPs using similar methods.
Genomic analysis of human lung fibroblasts exposed to vanadium pentoxide to identify candidate genes for occupational bronchitis
Jennifer L Ingram, Aurita Antao-Menezes, Elizabeth A Turpin, Duncan G Wallace, James B Mangum, Linda J Pluta, Russell S Thomas, James C Bonner
Respiratory Research , 2007, DOI: 10.1186/1465-9921-8-34
Abstract: Normal human lung fibroblasts were exposed to V2O5 in a time course experiment. Gene expression was measured at various time points over a 24 hr period using the Affymetrix Human Genome U133A 2.0 Array. Selected genes that were significantly changed in the microarray experiment were validated by RT-PCR.V2O5 altered more than 1,400 genes, of which ~300 were induced while >1,100 genes were suppressed. Gene ontology categories (GO) categories unique to induced genes included inflammatory response and immune response, while GO catogories unique to suppressed genes included ubiquitin cycle and cell cycle. A dozen genes were validated by RT-PCR, including growth factors (HBEGF, VEGF, CTGF), chemokines (IL8, CXCL9, CXCL10), oxidative stress response genes (SOD2, PIPOX, OXR1), and DNA-binding proteins (GAS1, STAT1).Our study identified a variety of genes that could play pivotal roles in inflammation, fibrosis and repair during V2O5-induced bronchitis. The induction of genes that mediate inflammation and immune responses, as well as suppression of genes involved in growth arrest appear to be important to the lung fibrotic reaction to V2O5.Occupational exposure to vanadium pentoxide (V2O5) has been associated with an increased incidence of chronic obstructive airway disease and a reduction in lung function [1]. V2O5 is the most common commercial form of vanadium and is the primary form found in industrial exposure situations [2]. Occupational exposure to V2O5 occurs during the cleaning of oil-fired boilers and furnaces, during handling of catalysts in chemical plants, and during the refining, processing, and burning of vanadium-rich fossil fuels [3].We previously reported that V2O5 causes airway disease in rats that is similar to the pathology of asthma and bronchitis in humans [4]. These pathologic changes include mucous cell hyperplasia, increased airway smooth muscle mass, and peribronchiolar fibrosis. Lung fibroblasts are thought to play a major role in V2O5-induced airwa
Page 1 /248219
Display every page Item


Home
Copyright © 2008-2017 Open Access Library. All rights reserved.