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      QUADrATiC: scalable gene expression connectivity mapping for repurposing FDA-approved therapeutics

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          Abstract

          Background

          Gene expression connectivity mapping has proven to be a powerful and flexible tool for research. Its application has been shown in a broad range of research topics, most commonly as a means of identifying potential small molecule compounds, which may be further investigated as candidates for repurposing to treat diseases. The public release of voluminous data from the Library of Integrated Cellular Signatures (LINCS) programme further enhanced the utilities and potentials of gene expression connectivity mapping in biomedicine.

          Results

          We describe QUADrATiC ( http://go.qub.ac.uk/QUADrATiC), a user-friendly tool for the exploration of gene expression connectivity on the subset of the LINCS data set corresponding to FDA-approved small molecule compounds. It enables the identification of compounds for repurposing therapeutic potentials. The software is designed to cope with the increased volume of data over existing tools, by taking advantage of multicore computing architectures to provide a scalable solution, which may be installed and operated on a range of computers, from laptops to servers. This scalability is provided by the use of the modern concurrent programming paradigm provided by the Akka framework. The QUADrATiC Graphical User Interface (GUI) has been developed using advanced Javascript frameworks, providing novel visualization capabilities for further analysis of connections. There is also a web services interface, allowing integration with other programs or scripts.

          Conclusions

          QUADrATiC has been shown to provide an improvement over existing connectivity map software, in terms of scope (based on the LINCS data set), applicability (using FDA-approved compounds), usability and speed. It offers potential to biological researchers to analyze transcriptional data and generate potential therapeutics for focussed study in the lab. QUADrATiC represents a step change in the process of investigating gene expression connectivity and provides more biologically-relevant results than previous alternative solutions.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12859-016-1062-1) contains supplementary material, which is available to authorized users.

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          Most cited references39

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          limma powers differential expression analyses for RNA-sequencing and microarray studies

          limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.
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            The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.

            To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project.
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              D³: Data-Driven Documents.

              Data-Driven Documents (D3) is a novel representation-transparent approach to visualization for the web. Rather than hide the underlying scenegraph within a toolkit-specific abstraction, D3 enables direct inspection and manipulation of a native representation: the standard document object model (DOM). With D3, designers selectively bind input data to arbitrary document elements, applying dynamic transforms to both generate and modify content. We show how representational transparency improves expressiveness and better integrates with developer tools than prior approaches, while offering comparable notational efficiency and retaining powerful declarative components. Immediate evaluation of operators further simplifies debugging and allows iterative development. Additionally, we demonstrate how D3 transforms naturally enable animation and interaction with dramatic performance improvements over intermediate representations. © 2010 IEEE
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                Author and article information

                Contributors
                k.mills@qub.ac.uk
                s.zhang@qub.ac.uk
                Journal
                BMC Bioinformatics
                BMC Bioinformatics
                BMC Bioinformatics
                BioMed Central (London )
                1471-2105
                4 May 2016
                4 May 2016
                2016
                : 17
                : 198
                Affiliations
                [ ]Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, BT9 7AE UK
                [ ]Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC Building, Altnagelvin Hospital campus, Glenshane Road, Derry/Londonderry, BT47 6SB UK
                Article
                1062
                10.1186/s12859-016-1062-1
                4855472
                27143038
                248530bf-4ce5-4c77-b8e6-376c306bc8ba
                © O’Reilly et al. 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 January 2016
                : 22 April 2016
                Categories
                Software
                Custom metadata
                © The Author(s) 2016

                Bioinformatics & Computational biology
                connectivity mapping,multicore programming,big data,repurposing,drug discovery,bioinformatics,computational biology

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