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Wang X.,University of Alberta | Pyne S.,CR Rao Advanced Institute of Mathematics | Dinu I.,University of Alberta
BMC Bioinformatics | Year: 2014

Background: Gene set analysis (GSA) methods test the association of sets of genes with phenotypes in gene expression microarray studies. While GSA methods on a single binary or categorical phenotype abounds, little attention has been paid to the case of a continuous phenotype, and there is no method to accommodate correlated multiple continuous phenotypes.Result: We propose here an extension of the linear combination test (LCT) to its new version for multiple continuous phenotypes, incorporating correlations among gene expressions of functionally related gene sets, as well as correlations among multiple phenotypes. Further, we extend our new method to its nonlinear version, referred as nonlinear combination test (NLCT), to test potential nonlinear association of gene sets with multiple phenotypes. Simulation study and a real microarray example demonstrate the practical aspects of the proposed methods.Conclusion: The proposed approaches are effective in controlling type I errors and powerful in testing associations between gene-sets and multiple continuous phenotypes. They are both computationally effective. Naively (univariately) analyzing a group of multiple correlated phenotypes could be dangerous. R-codes to perform LCT and NLCT for multiple continuous phenotypes are available at http://www.ualberta.ca/~yyasui/homepage.html. © 2014 Wang et al.; licensee BioMed Central Ltd. Source


Oldfield AndrewJ.,U.S. National Institutes of Health | Yang P.,U.S. National Institutes of Health | Conway AmandaE.,U.S. National Institutes of Health | Cinghu S.,U.S. National Institutes of Health | And 3 more authors.
Molecular Cell | Year: 2014

Cell type-specific master transcription factors (TFs) play vital roles in defining cell identity and function. However, the roles ubiquitous factors play in the specification of cell identity remain underappreciated. Here we show that the ubiquitous CCAAT-binding NF-Y complex is required for the maintenance of embryonic stem cell (ESC) identity and is an essential component of the core pluripotency network. Genome-wide studies in ESCs and neurons reveal that NF-Y regulates not only genes with housekeeping functions through cell type-invariant promoter-proximal binding, but also genes required for cell identity by binding to cell type-specific enhancers with master TFs. Mechanistically, NF-Y's distinct DNA-binding mode promotes master/pioneer TF binding at enhancers by facilitating a permissive chromatin conformation. Our studies unearth a conceptually unique function for histone-fold domain (HFD) protein NF-Y in promoting chromatin accessibility and suggest that other HFD proteins with analogous structural and DNA-binding properties may function in similar ways. © 2014 Elsevier Inc. All rights reserved. Source


Oldfield A.,U.S. National Institutes of Health | Yang P.,U.S. National Institutes of Health | Conway A.,U.S. National Institutes of Health | Cinghu S.,U.S. National Institutes of Health | And 3 more authors.
Molecular Cell | Year: 2014

Cell type-specific master transcription factors (TFs) play vital roles in defining cell identity and function. However, the roles ubiquitous factors play in the specification of cell identity remain underappreciated. Here we show that the ubiquitous CCAAT-binding NF-Y complex is required for the maintenance ofembryonic stem cell (ESC) identity and is an essential component of the core pluripotency network. Genome-wide studies in ESCs and neurons reveal that NF-Y regulates not only genes with housekeeping functions through cell type-invariant promoter-proximal binding, but also genes required for cell identity by binding to cell type-specific enhancers with master TFs. Mechanistically, NF-Y's distinct DNA-binding mode promotes master/pioneer TF binding at enhancers by facilitating a permissive chromatin conformation. Our studies unearth a conceptually unique function for histone-fold domain (HFD) protein NF-Y in promoting chromatin accessibility and suggest that other HFD proteins with analogous structural and DNA-binding properties may function in similar ways. © 2014 Elsevier Inc. Source


Ahfock D.,University of Queensland | Pyne S.,Public Health Foundation of India | Pyne S.,CR Rao Advanced Institute of Mathematics | Lee S.X.,University of Queensland | McLachlan G.J.,University of Queensland
Computational Statistics and Data Analysis | Year: 2016

The statistical matching problem involves the integration of multiple datasets where some variables are not observed jointly. This missing data pattern leaves most statistical models unidentifiable. Statistical inference is still possible when operating under the framework of partially identified models, where the goal is to bound the parameters rather than to estimate them precisely. In many matching problems, developing feasible bounds on the parameters is equivalent to finding the set of positive-definite completions of a partially specified covariance matrix. Existing methods for characterising the set of possible completions do not extend to high-dimensional problems. A Gibbs sampler to draw from the set of possible completions is proposed. The variation in the observed samples gives an estimate of the feasible region of the parameters. The Gibbs sampler extends easily to high-dimensional statistical matching problems. © 2016 The Authors Source


Bennett R.,Harvard University | Ysasi A.,Harvard University | Belle J.,Harvard University | Wagner W.,Johannes Gutenberg University Mainz | And 4 more authors.
Frontiers in Oncology | Year: 2014

Complex tissues such as the lung are composed of structural hierarchies such as alveoli, alveolar ducts and lobules. Some structural units, such as the alveolar duct, appear to participate in tissue repair as well as the development of bronchioalveolar carcinoma. Here, we demonstrate an approach to conduct laser microdissection of the lung alveolar duct for singlecell PCR analysis. Our approach involved three steps. 1) The initial preparation used mechanical sectioning of the lung tissue with sufficient thickness to encompass the structure of interest. In the case of the alveolar duct, the precision-cut lung slices were 200um thick; the slices were processed using near-physiologic conditions to preserve the state of viable cells. 2) The lung slices were examined by transmission light microscopy to target the alveolar duct. The air-filled lung was sufficiently accessible by light microscopy that counterstains or fluorescent labels were unnecessary to identify the alveolar duct. 3) The enzymatic and microfluidic isolation of single cells allowed for the harvest of as few as several thousand cells for PCR analysis. Microfluidics based arrays were used to measure the expression of selected marker genes in individual cells to characterize different cell populations. Preliminary work suggests the unique value of this approach to understanding the intra- and intercellular interactions within the regenerating alveolar duct. © 2014 Bennett, Ysasi, Belle, Wagner, Konerding, Blainey, Pyne and Mentzer. Source

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