297 GWAS for complex models accounting for populations structure with GBLUP and ssGBLUP

Genomic Best Linear Unbiased Prediction (GBLUP) is the method of choice for incorporating genomic information into the genetic evaluation of livestock species. Furthermore, single step GBLUP (ssGBLUP) is adopted by many breeders’ associations and private entities managing large scale breeding programs. While prediction of breeding values remains the primary use of genomic markers in animal breeding, a secondary interest focuses on performing genome-wide association studies (GWAS). The goal of GWAS is to uncover genomic regions that harbor variants that explain a large proportion of the phenotypic variance, and thus become candidates for discovering and studying causative variants. Several methods have been proposed and successfully applied for embedding GWAS into genomic prediction models. Most methods commonly avoid formal hypothesis testing and resort to estimation of SNP effects, relying on visual inspection of graphical outputs to determine candidate regions. However, with the advent of high throughput phenomics and transcriptomics, a more formal testing approach with automatic discovery thresholds is more appealing. In this work we present the methodological details of a method for performing formal hypothesis testing for GWAS in GBLUP models. First, we present the method and its equivalencies and differences with other GWAS methods. Moreover, we demonstrate through simulation analyses that the proposed method controls type I error rate at the nominal level. Second, we demonstrate two possible computational implementations based on mixed model equations for ssGBLUP and based on the generalized least square equations (GLS). We show that ssGBLUP can deal with datasets with extremely large number of animals and markers and with multiple traits. GLS implementations are well suited for dealing with smaller number of animals with tens of thousands of phenotypes. Third, we show several useful extensions, such as: testing multiple markers at once, testing pleiotropic effects and testing association of social genetic effects.

Indices of Rank Histogram Flatness and Their Sampling Properties

Quantitative evaluation of the flatness of the verification rank histogram can be approached through formal hypothesis testing. Traditionally, the familiar χ2 test has been used for this purpose. Recently, two alternatives—the reliability index (RI) and an entropy statistic (Ω)—have been suggested in the literature. This paper presents approximations to the sampling distributions of these latter two rank histogram flatness metrics, and compares the statistical power of tests based on the three statistics, in a controlled setting. The χ2 test is generally most powerful (i.e., most sensitive to violations of the null hypothesis of rank uniformity), although for overdispersed ensembles and small sample sizes, the test based on the entropy statistic Ω is more powerful. The RI-based test is preferred only for unbiased forecasts with small ensembles and very small sample sizes.

Quality of reporting of pilot and feasibility cluster randomised trials: a systematic review

ObjectivesTo systematically review the quality of reporting of pilot and feasibility of cluster randomised trials (CRTs). In particular, to assess (1) the number of pilot CRTs conducted between 1 January 2011 and 31 December 2014, (2) whether objectives and methods are appropriate and (3) reporting quality.MethodsWe searched PubMed (2011–2014) for CRTs with ‘pilot’ or ‘feasibility’ in the title or abstract; that were assessing some element of feasibility and showing evidence the study was in preparation for a main effectiveness/efficacy trial. Quality assessment criteria were based on the Consolidated Standards of Reporting Trials (CONSORT) extensions for pilot trials and CRTs.ResultsEighteen pilot CRTs were identified. Forty-four per cent did not have feasibility as their primary objective, and many (50%) performed formal hypothesis testing for effectiveness/efficacy despite being underpowered. Most (83%) included ‘pilot’ or ‘feasibility’ in the title, and discussed implications for progression from the pilot to the future definitive trial (89%), but fewer reported reasons for the randomised pilot trial (39%), sample size rationale (44%) or progression criteria (17%). Most defined the cluster (100%), and number of clusters randomised (94%), but few reported how the cluster design affected sample size (17%), whether consent was sought from clusters (11%), or who enrolled clusters (17%).ConclusionsThat only 18 pilot CRTs were identified necessitates increased awareness of the importance of conducting and publishing pilot CRTs and improved reporting. Pilot CRTs should primarily be assessing feasibility, avoiding formal hypothesis testing for effectiveness/efficacy and reporting reasons for the pilot, sample size rationale and progression criteria, as well as enrolment of clusters, and how the cluster design affects design aspects. We recommend adherence to the CONSORT extensions for pilot trials and CRTs.

The prevalence and magnitude of job insecurity

This study investigates the prevalence and magnitude of job insecurity experienced by employees in an organisation undergoing major transformation, while taking cognisance of intercorrelations among its sub-dimensions. The research adopted a formal, hypothesis-testing approach whereby quantitative data was collected using a cross-sectional survey method from a sample of 1620 employees. The findings indicate that threats to salient job features/total job and feelings of powerlessness trigger the potential for job insecurity. This study identifies conditions that increase the potential for job insecurity. Recommendations are presented for reducing the prevalence and magnitude of job insecurity.

Employee susceptibility to experiencing job insecurity

Employees attach value to their job features/total job and when they perceive threats to these and experience feelings of powerlessness, their level of job insecurity increases. Since job insecurity is a subjective phenomenon, the study aims to assess who is more susceptible to experiencing job insecurity by assessing biographical correlates. The research adopts a formal, hypothesis-testing approach where quantitative data were collected using a cross-sectional, survey method from a sample of 1620 employees. The results, generated using the ANOVA model, indicate that biographical influences do exist in terms of job insecurity. The implication is that change managers need to take cognisance of these influences and develop suitable strategies for each group to reduce the prevalence of job insecurity. Recommendations are made in this regard.

Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy

We evaluated the efficacy and safety of romiplostim, a thrombopoietin mimetic, in patients with low- or intermediate-risk myelodysplastic syndromes (MDS) receiving azacitidine therapy. Forty patients with low- or intermediate-risk MDS were stratified by baseline platelet counts (< 50 vs ≥ 50 × 109/L) and randomized to romiplostim 500 μg or 750 μg or placebo subcutaneously once weekly during 4 cycles of azacitidine. The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined by grade 3 or 4 thrombocytopenia starting on day 15 of the first cycle or platelet transfusion at any time during the 4-cycle treatment period. No formal hypothesis testing was planned. The incidence of clinically significant thrombocytopenic events in patients receiving romiplostim 500 μg, romiplostim 750 μg, or placebo was 62%, 71%, and 85%, respectively. The incidence of platelet transfusions was 46%, 36%, and 69%, respectively. These differences were not statistically significant with the small numbers in each group. Romiplostim 750 μg significantly raised median platelet counts during cycle 3 on day 1 (P = .0373) and at the nadir (P = .0035) compared with placebo. Grade 3 rash and arthralgia each were reported in 1 romiplostim-treated patient (4%). This study suggests romiplostim may provide clinical benefits in MDS patients during azacitidine therapy. This study was registered at www.clinicaltrials.gov as #NCT00321711.