Methods For Robust Quantification Of Rna Alternative Splicing In Heterogeneous Rna-Seq Datasets

RNA alternative splicing is primarily responsible for transcriptome diversity and is relevant to human development and disease. However, current approaches to splicing quantication make simplifying assumptions which are violated when RNA sequencing data are heterogeneous. Influences from genetic and environmental background contribute to variability within a group of samples purported to represent the same biological condition. This work describes three methods which account for data heterogeneity when detecting differential RNA splicing between sample groups. First, a robust model is implemented for outlier detection within a group of purported replicates. Next, large RNA-seq datasets with high within-group variability are addressed with a statistical approach which retains power to detect changing splice junctions without sacricing specicity. Finally, applying these tools to call sQTLs in GTEx tissues has identified splicing variations associated with risk loci for cardiovascular disease and anomalous skeletal development. Each of these methods correctly handles the properties of heterogeneous RNA-seq data to improve precision and reduce false discovery rate

Corporate financing decisions: UK survey evidence

Despite theoretical developments in recent years, our understanding of corporate capital structure remains incomplete. Prior empirical research has been dominated by archival regression studies which are limited in their ability to fully reflect the diversity found in practice. The present paper reports on a comprehensive survey of corporate financing decision-making in UK listed companies. A key finding is that firms are heterogeneous in their capital structure policies. About half of the firms seek to maintain a target debt level, consistent with trade-off theory, but 60 per cent claim to follow a financing hierarchy, consistent with pecking order theory. These two theories are not viewed by respondents as either mutually exclusive or exhaustive. Many of the theoretical determinants of debt levels are widely accepted by respondents, in particular the importance of interest tax shield, financial distress, agency costs and also, at least implicitly, information asymmetry. Results also indicate that cross-country institutional differences have a significant impact on financial decisions

Ecological landscape elements: long-term monitoring in Great Britain, the Countryside Survey 1978-2007 and beyond

The Countryside Survey (CS) of Great Britain (GB) provides a unique and statistically robust series of datasets, consisting of an extensive set of repeated ecological measurements at a national scale, covering a time span of 29 years. CS was first undertaken in 1978 to provide a baseline for ecological and land use change monitoring in the rural environment of GB, following a stratified random design, based on 1 km squares. Originally, eight random 1 km squares were drawn from each of 32 environmental classes, thus comprising 256 sample squares in the 1978 survey. The number of these sites increased to 382 in 1984, 506 in 1990, 569 in 1998 and 591 in 2007. Detailed information regarding vegetation types and land use was mapped in all five surveys, allowing reporting by defined standard habitat classifications. Additionally, point and linear landscape features (such as trees and hedgerows) are available from all surveys after 1978. From these stratified, randomly located sample squares, information can be converted into national estimates, with associated error terms. Other data, relating to soils, freshwater and vegetation, were also sampled on analogous dates. However, the present paper describes only the surveys of landscape features and habitats. The resulting datasets provide a unique, comprehensive, quantitative ecological coverage of extent and change in these features in GB. Basic results are presented and their implications discussed. However, much opportunity for further analyses remains. Data from each of the survey years are available via the following DOIs: Landscape area data 1978: https://doi.org/10.5285/86c017ba-dc62-46f0-ad13-c862bf31740e, 1984: https://doi.org/10.5285/b656bb43-448d-4b2c-aade-7993aa243ea3, 1990: https://doi.org/10.5285/94f664e5-10f2-4655-bfe6-44d745f5dca7, 1998: https://doi.org/10.5285/1e050028-5c55-42f4-a0ea-c895d827b824, and 2007: https://doi.org/10.5285/bf189c57-61eb-4339-a7b3-d2e81fdde28d; Landscape linear feature data 1984: https://doi.org/10.5285/a3f5665c-94b2-4c46-909e-a98be97857e5, 1990: https://doi.org/10.5285/311daad4-bc8c-485a-bc8a-e0d054889219, 1998: https://doi.org/10.5285/8aaf6f8c-c245-46bb-8a2a-f0db012b2643 and 2007: https://doi.org/10.5285/e1d31245-4c0a-4dee-b36c-b23f1a697f88, Landscape point feature data 1984: https://doi.org/10.5285/124b872e-036e-4dd3-8316-476b5f42c16e, 1990: https://doi.org/10.5285/1481bc63-80d7-4d18-bcba-8804aa0a9e1b, 1998: https://doi.org/10.5285/ed10944f-40c8-4913-b3f5-13c8e844e153 and 2007: https://doi.org/10.5285/55dc5fd7-d3f7-4440-b8a7-7187f8b0550b

Glastir Monitoring & Evaluation Programme. First year annual report

The Welsh Government has commissioned a comprehensive new ecosystem monitoring and evaluation programme to monitor the effects of Glastir, its new land management scheme, and to monitor progress towards a range of international biodiversity and environmental targets. A random sample of 1 km squares stratified by landcover types will be used both to monitor change at a national level in the wider countryside and to provide a backdrop against which intervention measures are assessed using a second sample of 1 km squares located in areas eligible for enhanced payments for advanced interventions. Modelling in the first year has forecast change based on current understanding, whilst a rolling national monitoring programme based on an ecosystem approach will provide an evidence-base for on-going, adaptive development of the scheme by Welsh Government. To our knowledge, this will constitute the largest and most in-depth ecosystem monitoring and evaluation programme of any member state of the European Union

Early ultrasound surveillance of newly-created haemodialysis arteriovenous fistula

IntroductionWe assess if ultrasound surveillance of newly-created arteriovenous fistulas (AVFs) can predict nonmaturation sufficiently reliably to justify randomized controlled trial (RCT) evaluation of ultrasound-directed salvage intervention.MethodsConsenting adults underwent blinded fortnightly ultrasound scanning of their AVF after creation, with scan characteristics that predicted AVF nonmaturation identified by logistic regression modeling.ResultsOf 333 AVFs created, 65.8% matured by 10 weeks. Serial scanning revealed that maturation occurred rapidly, whereas consistently lower fistula flow rates and venous diameters were observed in those that did not mature. Wrist and elbow AVF nonmaturation could be optimally modeled from week 4 ultrasound parameters alone, but with only moderate positive predictive values (PPVs) (wrist, 60.6% [95% confidence interval, CI: 43.9–77.3]; elbow, 66.7% [48.9–84.4]). Moreover, 40 (70.2%) of the 57 AVFs that thrombosed by week 10 had already failed by the week 4 scan, thus limiting the potential of salvage procedures initiated by that scan’s findings to alter overall maturation rates. Modeling of the early ultrasound characteristics could also predict primary patency failure at 6 months; however, that model performed poorly at predicting assisted primary failure (those AVFs that failed despite a salvage attempt), partly because patency of at-risk AVFs was maintained by successful salvage performed without recourse to the early scan data.ConclusionEarly ultrasound surveillance may predict fistula maturation, but is likely, at best, to result in only very modest improvements in fistula patency. Power calculations suggest that an impractically large number of participants (>1700) would be required for formal RCT evaluation

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Determinants of Collaborative Leadership: Civic Engagement, Gender or Organizational Norms?

This analysis attempts to unravel competing explanations of collaborative leadership styles of state legislative committee chairs. Specifically, the paper considers the influence of community or volunteer experience, gender, and institutional variables. The data show that women chairs are more likely than their male peers to cite as valuable the leadership skills and experiences that they gain through community and volunteer experience. Compared to their male colleagues, women committee chairs on average also report a greater reliance on collaborative strategies in the management of their committees. Prior community or volunteer experience has little or no direct effect on collaborative styles. In contrast, institutional factors have a much stronger and countervailing influence. Legislative professionalization produces a strong negative effect on collaborative style. Results suggest that conformity to institutional norms may be a more compelling influence than prior community experience. The analysis also points to the gendered nature of organizational leadership with men's and women's styles showing different associations to style depending on the number and power of women in a legislature.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Urine tests for Down's syndrome screening

Background Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age. Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. Objectives To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome. Search methods We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles. Selection criteria Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. Data collection and analysis We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses. Main results We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies). In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR). Authors' conclusions Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available

From Sea to Sea: Canada's Three Oceans of Biodiversity

Evaluating and understanding biodiversity in marine ecosystems are both necessary and challenging for conservation. This paper compiles and summarizes current knowledge of the diversity of marine taxa in Canada's three oceans while recognizing that this compilation is incomplete and will change in the future. That Canada has the longest coastline in the world and incorporates distinctly different biogeographic provinces and ecoregions (e.g., temperate through ice-covered areas) constrains this analysis. The taxonomic groups presented here include microbes, phytoplankton, macroalgae, zooplankton, benthic infauna, fishes, and marine mammals. The minimum number of species or taxa compiled here is 15,988 for the three Canadian oceans. However, this number clearly underestimates in several ways the total number of taxa present. First, there are significant gaps in the published literature. Second, the diversity of many habitats has not been compiled for all taxonomic groups (e.g., intertidal rocky shores, deep sea), and data compilations are based on short-term, directed research programs or longer-term monitoring activities with limited spatial resolution. Third, the biodiversity of large organisms is well known, but this is not true of smaller organisms. Finally, the greatest constraint on this summary is the willingness and capacity of those who collected the data to make it available to those interested in biodiversity meta-analyses. Confirmation of identities and intercomparison of studies are also constrained by the disturbing rate of decline in the number of taxonomists and systematists specializing on marine taxa in Canada. This decline is mostly the result of retirements of current specialists and to a lack of training and employment opportunities for new ones. Considering the difficulties encountered in compiling an overview of biogeographic data and the diversity of species or taxa in Canada's three oceans, this synthesis is intended to serve as a biodiversity baseline for a new program on marine biodiversity, the Canadian Healthy Ocean Network. A major effort needs to be undertaken to establish a complete baseline of Canadian marine biodiversity of all taxonomic groups, especially if we are to understand and conserve this part of Canada's natural heritage

Psychometric properties of the Mandarin version of the Childhood Autism Spectrum Test (CAST):an exploratory study

Limited studies have investigated the latent autistic traits in the mainland Chinese population for autism spectrum conditions (ASC). This study explored the psychometric properties of a Mandarin Chinese version of the CAST in a sample consisting of 737 children in mainstream schools and 50 autistic cases. A combination of categorical data factor analysis and item response theory suggested a good-fit model of a two-factor solution for 28 items on the Mandarin CAST including social and communication, and inflexible/stereotyped language and behaviours (Goodness-of-fit indices: RMSEA = 0.029, CFI = 0.957, TLI = 0.950, SRMR = 0.064). The correlation between the two factors was moderate (GFC = 0.425). This study provided evidence for the CAST as a multidimensional measure for ASC screening in a Chinese population and also showed that the symptom manifestation of ASC in Chinese children shares similarity with western populations. © 2014 Springer Science+Business Media