107 research outputs found
Linkage analysis of GAW14 simulated data: comparison of multimarker, multipoint, and conditional approaches
The purposes of this study were 1) to examine the performance of a new multimarker regression approach for model-free linkage analysis in comparison to a conventional multipoint approach, and 2) to determine the whether a conditioning strategy would improve the performance of the conventional multipoint method when applied to data from two interacting loci. Linkage analysis of the Kofendrerd Personality Disorder phenotype to chromosomes 1 and 3 was performed in three populations for all 100 replicates of the Genetic Analysis Workshop 14 simulated data. Three approaches were used: a conventional multipoint analysis using the Zlr statistic as calculated in the program ALLEGRO; a conditioning approach in which the per-family contribution on one chromosome was weighted according to evidence for linkage on the other chromosome; and a novel multimarker regression approach. The multipoint and multimarker approaches were generally successful in localizing known susceptibility loci on chromosomes 1 and 3, and were found to give broadly similar results. No advantage was found with the per-family conditioning approach. The effect on power and type I error of different choices of weighting scheme (to account for different numbers of affected siblings) in the multimarker approach was examined
Genome-wide Association of Lipid-lowering Response to Statins in Combined Study Populations
Background: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy. Methods and Principal Findings: Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8×10). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0×10). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol. Conclusions and Significance: Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance.Trial Registration PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT0045182
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Genome-Wide Association of Lipid-Lowering Response to Statins in Combined Study Populations
Background: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy.Methods and Principal Findings: Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8×10−8). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0×10−6). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol.Conclusions and Significance: Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance.Trial Registration: PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT00451828</p
Deeper knowledge of shallow waters: reviewing the invertebrate fauna of southern African temporary wetlands
Temporary lentic wetlands are becoming
increasingly recognised for their collective role in
contributing to biodiversity at the landscape scale. In
southern Africa, a region with a high density of such
wetlands, information characterising the fauna of
these systems is disparate and often obscurely published.
Here we provide a collation and synthesis of
published research on the aquatic invertebrate fauna
inhabiting temporary lentic wetlands of the region. We
expose the poor taxonomic knowledge of most groups,
which makes it difficult to comment on patterns of
richness and endemism. Only a few groups (e.g. large
branchiopods, ostracods, copepods and cladocerans)
appear to reach higher richness and/or endemicity in
temporary wetlands compared to their permanent
wetland counterparts. IUCN Red List information is
lacking for most taxa, thus making it difficult to
comment on the conservation status of much of the
invertebrate fauna. However, except for a few specialist
groups, many of the taxa inhabiting these
environments appear to be habitat generalists that
opportunistically exploit these waterbodies and this is hypothesised as one of the reasons why endemism
appears to be low for most taxa. Given that taxonomy
underpins ecology, the urgent need for more foundational
taxonomic work on these systems becomes
glaringly apparent
Bayesian inference of accurate population sizes and FRET efficiencies from single diffusing biomolecules.
It is of significant biophysical interest to obtain accurate intramolecular distance information and population sizes from single-molecule Förster resonance energy transfer (smFRET) data obtained from biomolecules in solution. Experimental methods of increasing cost and complexity are being developed to improve the accuracy and precision of data collection. However, the analysis of smFRET data sets currently relies on simplistic, and often arbitrary methods, for the selection and denoising of fluorescent bursts. Although these methods are satisfactory for the analysis of simple, low-noise systems with intermediate FRET efficiencies, they display systematic inaccuracies when applied to more complex systems. We have developed an inference method for the analysis of smFRET data from solution studies based on rigorous model-based Bayesian techniques. We implement a Monte Carlo Markov chain (MCMC) based algorithm that simultaneously estimates population sizes and intramolecular distance information directly from a raw smFRET data set, with no intermediate event selection and denoising steps. Here, we present both our parametric model of the smFRET process and the algorithm developed for data analysis. We test the algorithm using a combination of simulated data sets and data from dual-labeled DNA molecules. We demonstrate that our model-based method systematically outperforms threshold-based techniques in accurately inferring both population sizes and intramolecular distances.This is the final published version. It's also available from ACS in Analytical Chemistry: http://pubs.acs.org/doi/pdf/10.1021/ac501188r
Polymorphisms of the HNF1A Gene Encoding Hepatocyte Nuclear Factor-1α are Associated with C-Reactive Protein
Data from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study and the Cardiovascular Health Study (CHS) provide independent and confirmatory evidence for association between common polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1α and plasma C-reactive protein (CRP) concentration. Analyses with the use of imputation-based methods to combine genotype data from both studies and to test untyped SNPs from the HapMap database identified several SNPs within a 5 kb region of HNF1A intron 1 with the strongest evidence of association with CRP phenotype
Measurement of the cosmic ray spectrum above eV using inclined events detected with the Pierre Auger Observatory
A measurement of the cosmic-ray spectrum for energies exceeding
eV is presented, which is based on the analysis of showers
with zenith angles greater than detected with the Pierre Auger
Observatory between 1 January 2004 and 31 December 2013. The measured spectrum
confirms a flux suppression at the highest energies. Above
eV, the "ankle", the flux can be described by a power law with
index followed by
a smooth suppression region. For the energy () at which the
spectral flux has fallen to one-half of its extrapolated value in the absence
of suppression, we find
eV.Comment: Replaced with published version. Added journal reference and DO
An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital
Pneumocystis jirovecii pneumonia (PCP) is associated with high mortality in immunocompromised patients without human immunodeficiency virus infection. However, chemoprophylaxis is highly effective. In patients with solid tumours or haematologic malignancy, several risk factors for developing PCP have been identified, predominantly corticosteroid therapy. The aims of this study were to identify the potentially preventable cases of PCP in patients receiving corticosteroid therapy at a tertiary care cancer centre and to estimate the frequency of utilisation of chemoprophylaxis in these patients. Two retrospective reviews were performed. Over a 10-year period, 14 cases of PCP were identified: no cases were attributable to failed chemoprophylaxis, drug allergy or intolerance. During a 6-month period, 73 patients received high-dose corticosteroid therapy (⩾25 mg prednisolone or ⩾4 mg dexamethasone daily) for ⩾4 weeks. Of these, 22 (30%) had haematologic malignancy, and 51 (70%) had solid tumours. Fewer patients with solid tumours received prophylaxis compared to patients with haematologic malignancy (3.9 vs 63.6%, P<0.0001). Guidelines for PCP chemoprophylaxis in patients with haematologic malignancy or solid tumours who receive corticosteroid therapy are proposed. Successful primary prevention of PCP in this population will require a multifaceted approach targeting the suboptimal prescribing patterns for chemoprophylaxis
Activation of the Innate Immune Response against DENV in Normal Non-Transformed Human Fibroblasts
In this work, we demonstrate that that both human whole skin and freshly isolated skin fibroblasts are productively infected with Dengue virus (DENV). In addition, primary skin fibroblast cultures were established and subsequently infected with DENV-2; we showed in these cells the presence of the viral antigen NS3, and we found productive viral infection by a conventional plaque assay. Of note, the infectivity rate was almost the same in all the primary cultures analyzed from different donors. The skin fibroblasts infected with DENV-2 underwent signaling through both TLR3 and RIG-1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 IRF7, when compared with mock-infected fibroblasts. Our data suggest that fibroblasts might even participate producing mediators involved in innate immunity that activate and contribute to the orchestration of the local innate responses. This work is the first evaluating primary skin fibroblast cultures obtained from different humans, assessing both their susceptibility to DENV infection as well as their ability to produce molecules crucial for innate immunity
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