A semi-parametric Bayesian model for unsupervised differential co-expression analysis

<p>Abstract</p> <p>Background</p> <p>Differential co-expression analysis is an emerging strategy for characterizing disease related dysregulation of gene expression regulatory networks. Given pre-defined sets of biological samples, such analysis aims at identifying genes that are co-expressed in one, but not in the other set of samples.</p> <p>Results</p> <p>We developed a novel probabilistic framework for jointly uncovering contexts (i.e. groups of samples) with specific co-expression patterns, and groups of genes with different co-expression patterns across such contexts. In contrast to current clustering and bi-clustering procedures, the implicit similarity measure in this model used for grouping biological samples is based on the clustering structure of genes within each sample and not on traditional measures of gene expression level similarities. Within this framework, biological samples with widely discordant expression patterns can be placed in the same context as long as the co-clustering structure of genes is concordant within these samples. To the best of our knowledge, this is the first method to date for unsupervised differential co-expression analysis in this generality. When applied to the problem of identifying molecular subtypes of breast cancer, our method identified reproducible patterns of differential co-expression across several independent expression datasets. Sample groupings induced by these patterns were highly informative of the disease outcome. Expression patterns of differentially co-expressed genes provided new insights into the complex nature of the ER<it>α </it>regulatory network.</p> <p>Conclusions</p> <p>We demonstrated that the use of the co-clustering structure as the similarity measure in the unsupervised analysis of sample gene expression profiles provides valuable information about expression regulatory networks.</p

WebGimm: An integrated web-based platform for cluster analysis, functional analysis, and interactive visualization of results

Cluster analysis methods have been extensively researched, but the adoption of new methods is often hindered by technical barriers in their implementation and use. WebGimm is a free cluster analysis web-service, and an open source general purpose clustering web-server infrastructure designed to facilitate easy deployment of integrated cluster analysis servers based on clustering and functional annotation algorithms implemented in R. Integrated functional analyses and interactive browsing of both, clustering structure and functional annotations provides a complete analytical environment for cluster analysis and interpretation of results. The Java Web Start client-based interface is modeled after the familiar cluster/treeview packages making its use intuitive to a wide array of biomedical researchers. For biomedical researchers, WebGimm provides an avenue to access state of the art clustering procedures. For Bioinformatics methods developers, WebGimm offers a convenient avenue to deploy their newly developed clustering methods. WebGimm server, software and manuals can be freely accessed at http://ClusterAnalysis.org/

Genomics Portals: integrative web-platform for mining genomics data

<p>Abstract</p> <p>Background</p> <p>A large amount of experimental data generated by modern high-throughput technologies is available through various public repositories. Our knowledge about molecular interaction networks, functional biological pathways and transcriptional regulatory modules is rapidly expanding, and is being organized in lists of functionally related genes. Jointly, these two sources of information hold a tremendous potential for gaining new insights into functioning of living systems.</p> <p>Results</p> <p>Genomics Portals platform integrates access to an extensive knowledge base and a large database of human, mouse, and rat genomics data with basic analytical visualization tools. It provides the context for analyzing and interpreting new experimental data and the tool for effective mining of a large number of publicly available genomics datasets stored in the back-end databases. The uniqueness of this platform lies in the volume and the diversity of genomics data that can be accessed and analyzed (gene expression, ChIP-chip, ChIP-seq, epigenomics, computationally predicted binding sites, etc), and the integration with an extensive knowledge base that can be used in such analysis.</p> <p>Conclusion</p> <p>The integrated access to primary genomics data, functional knowledge and analytical tools makes Genomics Portals platform a unique tool for interpreting results of new genomics experiments and for mining the vast amount of data stored in the Genomics Portals backend databases. Genomics Portals can be accessed and used freely at <url>http://GenomicsPortals.org</url>.</p

A new method to remove hybridization bias for interspecies comparison of global gene expression profiles uncovers an association between mRNA sequence divergence and differential gene expression in Xenopus

The recent sequencing of a large number of Xenopus tropicalis expressed sequences has allowed development of a high-throughput approach to study Xenopus global RNA gene expression. We examined the global gene expression similarities and differences between the historically significant Xenopus laevis model system and the increasingly used X.tropicalis model system and assessed whether an X.tropicalis microarray platform can be used for X.laevis. These closely related species were also used to investigate a more general question: is there an association between mRNA sequence divergence and differences in gene expression levels? We carried out a comprehensive comparison of global gene expression profiles using microarrays of different tissues and developmental stages of X.laevis and X.tropicalis. We (i) show that the X.tropicalis probes provide an efficacious microarray platform for X.laevis, (ii) describe methods to compare interspecies mRNA profiles that correct differences in hybridization efficiency and (iii) show independently of hybridization bias that as mRNA sequence divergence increases between X.laevis and X.tropicalis differences in mRNA expression levels also increase

Differential expression and prognostic value of long nonâ coding RNA in HPVâ negative head and neck squamous cell carcinoma

BackgroundLong nonâ coding RNA (lncRNA) has emerged as a new avenue of interest due to its various biological functions in cancer. Abnormal expression of lncRNA has been reported in other malignancies but has been understudied in head and neck squamous cell carcinoma (HNSCC).MethodsThe lncRNA expression was interrogated via quantitative realâ time polymerase chain reaction (qRTâ PCR) array for 19 human papillomavirus (HPV)â negative HNSCC tumorâ normal pairs. The Cancer Genome Atlas (TCGA) was used to validate these results. The association between differentially expressed lncRNA and survival outcomes was analyzed.ResultsDifferential expression was validated for 5 lncRNA (SPRY4â IT1, HEIH, LUCAT1, LINC00152, and HAND2â AS1). There was also an inverse association between MEG3 expression (not significantly differentially expressed in TCGA tumors but highly variable expression) and 3â year recurrenceâ free survival (RFS).ConclusionWe identified and validated differential expression of 5 lncRNA in HPVâ negative HNSCC. Low MEG3 expression was associated with favorable 3â year RFS, although the significance of this finding remains unclear.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144638/1/hed25136_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144638/2/hed25136.pd

Detection of associations with rare and common SNPs for quantitative traits: a nonparametric Bayes-based approach

We propose a nonparametric Bayes-based clustering algorithm to detect associations with rare and common single-nucleotide polymorphisms (SNPs) for quantitative traits. Unlike current methods, our approach identifies associations with rare genetic variants at the variant level, not the gene level. In this method, we use a Dirichlet process prior for the distribution of SNP-specific regression coefficients, conduct hierarchical clustering with a distance measure derived from posterior pairwise probabilities of two SNPs having the same regression coefficient, and explore data-driven approaches to select the number of clusters. SNPs falling inside the largest cluster have relatively low or close to zero estimates of regression coefficients and are considered not associated with the trait. SNPs falling outside the largest cluster have relatively high estimates of regression coefficients and are considered potential risk variants. Using the data from the Genetic Analysis Workshop 17, we successfully detected associations with both rare and common SNPs for a quantitative trait. We conclude that our method provides a novel and broadly applicable strategy for obtaining association results with a reasonably low proportion of false discovery and that it can be routinely used in resequencing studies

NeatMap - non-clustering heat map alternatives in R

<p>Abstract</p> <p>Background</p> <p>The clustered heat map is the most popular means of visualizing genomic data. It compactly displays a large amount of data in an intuitive format that facilitates the detection of hidden structures and relations in the data. However, it is hampered by its use of cluster analysis which does not always respect the intrinsic relations in the data, often requiring non-standardized reordering of rows/columns to be performed post-clustering. This sometimes leads to uninformative and/or misleading conclusions. Often it is more informative to use dimension-reduction algorithms (such as Principal Component Analysis and Multi-Dimensional Scaling) which respect the topology inherent in the data. Yet, despite their proven utility in the analysis of biological data, they are not as widely used. This is at least partially due to the lack of user-friendly visualization methods with the visceral impact of the heat map.</p> <p>Results</p> <p>NeatMap is an R package designed to meet this need. NeatMap offers a variety of novel plots (in 2 and 3 dimensions) to be used in conjunction with these dimension-reduction techniques. Like the heat map, but unlike traditional displays of such results, it allows the entire dataset to be displayed while visualizing relations between elements. It also allows superimposition of cluster analysis results for mutual validation. NeatMap is shown to be more informative than the traditional heat map with the help of two well-known microarray datasets.</p> <p>Conclusions</p> <p>NeatMap thus preserves many of the strengths of the clustered heat map while addressing some of its deficiencies. It is hoped that NeatMap will spur the adoption of non-clustering dimension-reduction algorithms.</p

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Coordinated targeting of S6K1/2 and AXL disrupts pyrimidine biosynthesis in PTEN-deficient glioblastoma

Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis. Genetic inactivation studies to map the signaling network indicated that both S6K1 and S6K2 transmit growth signals in PTEN-deficient GBM. Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM

Expression profiles of switch-like genes accurately classify tissue and infectious disease phenotypes in model-based classification

<p>Abstract</p> <p>Background</p> <p>Large-scale compilation of gene expression microarray datasets across diverse biological phenotypes provided a means of gathering a priori knowledge in the form of identification and annotation of bimodal genes in the human and mouse genomes. These switch-like genes consist of 15% of known human genes, and are enriched with genes coding for extracellular and membrane proteins. It is of interest to determine the prediction potential of bimodal genes for class discovery in large-scale datasets.</p> <p>Results</p> <p>Use of a model-based clustering algorithm accurately classified more than 400 microarray samples into 19 different tissue types on the basis of bimodal gene expression. Bimodal expression patterns were also highly effective in differentiating between infectious diseases in model-based clustering of microarray data. Supervised classification with feature selection restricted to switch-like genes also recognized tissue specific and infectious disease specific signatures in independent test datasets reserved for validation. Determination of "on" and "off" states of switch-like genes in various tissues and diseases allowed for the identification of activated/deactivated pathways. Activated switch-like genes in neural, skeletal muscle and cardiac muscle tissue tend to have tissue-specific roles. A majority of activated genes in infectious disease are involved in processes related to the immune response.</p> <p>Conclusion</p> <p>Switch-like bimodal gene sets capture genome-wide signatures from microarray data in health and infectious disease. A subset of bimodal genes coding for extracellular and membrane proteins are associated with tissue specificity, indicating a potential role for them as biomarkers provided that expression is altered in the onset of disease. Furthermore, we provide evidence that bimodal genes are involved in temporally and spatially active mechanisms including tissue-specific functions and response of the immune system to invading pathogens.</p