A combined long-range phasing and long haplotype imputation method to impute phase for SNP genotypes

<p>Abstract</p> <p>Background</p> <p>Knowing the phase of marker genotype data can be useful in genome-wide association studies, because it makes it possible to use analysis frameworks that account for identity by descent or parent of origin of alleles and it can lead to a large increase in data quantities via genotype or sequence imputation. Long-range phasing and haplotype library imputation constitute a fast and accurate method to impute phase for SNP data.</p> <p>Methods</p> <p>A long-range phasing and haplotype library imputation algorithm was developed. It combines information from surrogate parents and long haplotypes to resolve phase in a manner that is not dependent on the family structure of a dataset or on the presence of pedigree information.</p> <p>Results</p> <p>The algorithm performed well in both simulated and real livestock and human datasets in terms of both phasing accuracy and computation efficiency. The percentage of alleles that could be phased in both simulated and real datasets of varying size generally exceeded 98% while the percentage of alleles incorrectly phased in simulated data was generally less than 0.5%. The accuracy of phasing was affected by dataset size, with lower accuracy for dataset sizes less than 1000, but was not affected by effective population size, family data structure, presence or absence of pedigree information, and SNP density. The method was computationally fast. In comparison to a commonly used statistical method (fastPHASE), the current method made about 8% less phasing mistakes and ran about 26 times faster for a small dataset. For larger datasets, the differences in computational time are expected to be even greater. A computer program implementing these methods has been made available.</p> <p>Conclusions</p> <p>The algorithm and software developed in this study make feasible the routine phasing of high-density SNP chips in large datasets.</p

A tale of two societies : The doing of qualitative comparative research in Hong Kong and Britain

This article explores the challenges and opportunities for methodological innovation arising from an exploratory, cross-national, qualitative study of women’s lives in Hong Kong and Britain. We begin by briefly outlining the aims of our study and its original research design, based on life history interviews with young adult women and their mothers in each location.We then turn to a discussion of how this was modified as we recruited participants and conducted the interviews, including the use of vignettes. We aim to be transparent about some of the problems of implementing a symmetrical approach to generating qualitative data in very different socio-cultural settings compounded by the practical difficulties of geographical distance between team members. We argue for a flexible approach that takes account of local cultural sensibilities rather than trying to follow rigidly identical procedures, recognising also that, in any qualitative research team, there will be differences in approach that affect the data produced. We highlight some of the insights yielded by the problems we encountered and, in particular, an accidental innovation that occurred through an ad hoc decision to conduct focus groups with the young women, which we call ‘cross-cultural data feedback’. This innovation involved our participants in contributing to cross cultural comparison and also brought taken-for-granted assumptions in each setting into sharp relief, as well as sensitising us to issues that proved important in analysing our data. This leads us to raise issues of interpreting and analysing data from differing socio-cultural locations and translating between cultures. We conclude with some recommendations including the potential for the future development of our method of cross-cultural data feedback

Microarray-based gene set analysis: a comparison of current methods

BACKGROUND: The analysis of gene sets has become a popular topic in recent times, with researchers attempting to improve the interpretability and reproducibility of their microarray analyses through the inclusion of supplementary biological information. While a number of options for gene set analysis exist, no consensus has yet been reached regarding which methodology performs best, and under what conditions. The goal of this work was to examine the performance characteristics of a collection of existing gene set analysis methods, on both simulated and real microarray data sets. Of particular interest was the potential utility gained through the incorporation of inter-gene correlation into the analysis process. RESULTS: Each of six gene set analysis methods was applied to both simulated and publicly available microarray data sets. Overall, the various methodologies were all found to be better at detecting gene sets that moved from non-active (i.e., genes not expressed) to active states (or vice versa), rather than those that simply changed their level of activity. Methods which incorporate correlation structures were found to provide increased ability to detect altered gene sets in some settings. CONCLUSION: Based on the results obtained through the analysis of simulated data, it is clear that the performance of gene set analysis methods is strongly influenced by the features of the data set in question, and that methods which incorporate correlation structures into the analysis process tend to achieve better performance, relative to methods which rely on univariate test statistics

The impact of atrial fibrillation on prognosis in aortic stenosis

Background: Atrial fibrillation (AF) and aortic stenosis (AS) are both highly prevalent and often coexist. Various studies have focused on the prognostic value of AF in patients with AS, but rarely considered left ventricular (LV) diastolic function as a prognostic factor. Objective: To evaluate the prognostic impact of AF in patients with AS while correcting for LV diastolic function. Methods: Patients with first diagnosis of significant AS were selected and stratified according to history of AF. The endpoint was all-cause mortality. Results: In total, 2849 patients with significant AS (mean age 72 +/- 12 years, 54.8% men) were evaluated, and 686 (24.1%) had a history of AF. During a median follow-up of 60 (30-97) months, 1182 (41.5%) patients died. Ten-year mortality rate in patients with AF was 46.8% compared to 36.8% in patients with sinus rhythm (SR) (log-rank P P P = 0.026), AF was independently associated with mortality. However, when correcting for indexed left atrial volume, E/e' or both, AF was no longer independently associated with all-cause mortality. Conclusion: Patients with significant AS and AF have a reduced survival as compared to patients with SR. Nonetheless, when correcting for markers of LV diastolic function, AF was not independently associated with outcomes in patients with significant AS.</p

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

The IRYSS-COPD appropriateness study: objectives, methodology, and description of the prospective cohort

<p>Abstract</p> <p>Background</p> <p>Patients with chronic obstructive pulmonary disease (COPD) often experience exacerbations of the disease that require hospitalization. Current guidelines offer little guidance for identifying patients whose clinical situation is appropriate for admission to the hospital, and properly developed and validated severity scores for COPD exacerbations are lacking. To address these important gaps in clinical care, we created the IRYSS-COPD Appropriateness Study.</p> <p>Methods/Design</p> <p>The RAND/UCLA Appropriateness Methodology was used to identify appropriate and inappropriate scenarios for hospital admission for patients experiencing COPD exacerbations. These scenarios were then applied to a prospective cohort of patients attending the emergency departments (ED) of 16 participating hospitals. Information was recorded during the time the patient was evaluated in the ED, at the time a decision was made to admit the patient to the hospital or discharge home, and during follow-up after admission or discharge home. While complete data were generally available at the time of ED admission, data were often missing at the time of decision making. Predefined assumptions were used to impute much of the missing data.</p> <p>Discussion</p> <p>The IRYSS-COPD Appropriateness Study will validate the appropriateness criteria developed by the RAND/UCLA Appropriateness Methodology and thus better delineate the requirements for admission or discharge of patients experiencing exacerbations of COPD. The study will also provide a better understanding of the determinants of outcomes of COPD exacerbations, and evaluate the equity and variability in access and outcomes in these patients.</p

Microstructural evolution in solution heat treatment of gas- atomised Al alloy (7075) powder for cold spray

Cold gas dynamic spray is being explored as a repair technique for high-value metallic components, given its potential to produce pore and oxide-free deposits of between several micrometers and several millimeters thick with good levels of adhesion and mechanical strength. However, feedstock powders for cold spray experience rapid solidification if manufactured by gas atomization and hence can exhibit non-equilibrium microstructures and localized segregation of alloying elements. Here, we used sealed quartz tube solution heat treatment of a precipitation hardenable 7075 aluminum alloy feedstock to yield a consistent and homogeneous powder phase composition and microstructure prior to cold spraying, aiming for a more controllable heat treatment response of the cold spray deposits. It was shown that the dendritic microstructure and solute segregation in the gas-atomized powders were altered, such that the heat-treated powder exhibits a homogeneous distribution of solute atoms. Micro-indentation testing revealed that the heat-treated powder exhibited a mean hardness decrease of nearly 25% compared to the as received powder. Deformation of the powder particles was enhanced by heat treatment, resulting in an improved coating with higher thickness (* 300 lm compared to * 40 um for untreated feedstock). Improved particle–substrate bonding was evidenced by formation of jets at the particle boundaries

Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly

<p>Abstract</p> <p>Background</p> <p>Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in <it>CDK5RAP2 </it>gene at MCPH3 locus have been least involved in causing MCPH phenotype.</p> <p>Methods</p> <p>All coding exons and exon/intron splice junctions of <it>CDK5RAP2 </it>gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.</p> <p>Results</p> <p>A previously described nonsense mutation [243 T>A (S81X)] in exon 4 of <it>CDK5RAP2 </it>gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).</p> <p>Conclusion</p> <p>Recurrent observation of Y82X mutation in <it>CDK5RAP2 </it>gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.</p

Bioinformatics Analysis of Macrophages Exposed to Porphyromonas gingivalis: Implications in Acute vs. Chronic Infections

BACKGROUND. Periodontitis is the most common human infection affecting tooth-supporting structures. It was shown to play a role in aggravating atherosclerosis. To deepen our understanding of the pathogenesis of this disease, we exposed human macrophages to an oral bacteria, Porphyromonas gingivalis (P. gingivalis), either as live bacteria or its LPS or fimbria. Microarray data from treated macrophages or control cells were analyzed to define molecular signatures. Changes in genes identified in relevant pathways were validated by RT-PCR. METHODOLOGY/PRINCIPAL FINDINGS. We focused our analysis on three important groups of genes. Group PG (genes differentially expressed by live bacteria only); Group LFG (genes differentially expressed in response to exposure to LPS and/or FimA); Group CG (core gene set jointly activated by all 3 stimulants). A total of 842 macrophage genes were differentially expressed in at least one of the three conditions compared to naïve cells. Using pathway analysis, we found that group CG activates the initial phagocytosis process and induces genes relevant to immune response, whereas group PG can de-activate the phagocytosis process associated with phagosome-lysosome fusion. LFG mostly affected RIG-I-like receptor signaling pathway. CONCLUSION/SIGNIFICANCE. In light of the fact that acute infections involve live bacteria while chronic infections involve a combination of live bacteria and their byproducts, group PG could represent acute P. gingivalis infection while group LFG could represent chronic P. gingivalis infection. Group CG may be associated with core immune pathways, triggered irrespective of the specific stimulants and indispensable to mount an appropriate immune response. Implications in acute vs. chronic infection are discussed.National Institutes of Health (R01 DE014079, DE15989, HL7680