Differential co-expression framework to quantify goodness of biclusters and compare biclustering algorithms

<p>Abstract</p> <p>Background</p> <p>Biclustering is an important analysis procedure to understand the biological mechanisms from microarray gene expression data. Several algorithms have been proposed to identify biclusters, but very little effort was made to compare the performance of different algorithms on real datasets and combine the resultant biclusters into one unified ranking.</p> <p>Results</p> <p>In this paper we propose differential co-expression framework and a differential co-expression scoring function to objectively quantify quality or goodness of a bicluster of genes based on the observation that genes in a bicluster are co-expressed in the conditions belonged to the bicluster and not co-expressed in the other conditions. Furthermore, we propose a scoring function to stratify biclusters into three types of co-expression. We used the proposed scoring functions to understand the performance and behavior of the four well established biclustering algorithms on six real datasets from different domains by combining their output into one unified ranking.</p> <p>Conclusions</p> <p>Differential co-expression framework is useful to provide quantitative and objective assessment of the goodness of biclusters of co-expressed genes and performance of biclustering algorithms in identifying co-expression biclusters. It also helps to combine the biclusters output by different algorithms into one unified ranking i.e. meta-biclustering.</p

Unsupervised Algorithms for Microarray Sample Stratification

The amount of data made available by microarrays gives researchers the opportunity to delve into the complexity of biological systems. However, the noisy and extremely high-dimensional nature of this kind of data poses significant challenges. Microarrays allow for the parallel measurement of thousands of molecular objects spanning different layers of interactions. In order to be able to discover hidden patterns, the most disparate analytical techniques have been proposed. Here, we describe the basic methodologies to approach the analysis of microarray datasets that focus on the task of (sub)group discovery.Peer reviewe

Unique networks: a method to identity disease-specific regulatory networks from microarray data

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The survival of any organismis determined by the mechanisms triggered in response to the inputs received. Underlying mechanisms are described by graphical networks that can be inferred from different types of data such as microarrays. Deriving robust and reliable networks can be complicated due to the microarray structure of the data characterized by a discrepancy between the number of genes and samples of several orders of magnitude, bias and noise. Researchers overcome this problem by integrating independent data together and deriving the common mechanisms through consensus network analysis. Different conditions generate different inputs to the organism which reacts triggering different mechanisms with similarities and differences. A lot of effort has been spent into identifying the commonalities under different conditions. Highlighting similarities may overshadow the differences which often identify the main characteristics of the triggered mechanisms. In this thesis we introduce the concept of study-specific mechanism. We develop a pipeline to semiautomatically identify study-specific networks called unique-networks through a combination of consensus approach, graphical similarities and network analysis. The main pipeline called UNIP (Unique Networks Identification Pipeline) takes a set of independent studies, builds gene regulatory networks for each of them, calculates an adaptation of the sensitivity measure based on the networks graphical similarities, applies clustering to group the studies who generate the most similar networks into study-clusters and derives the consensus networks. Once each study-cluster is associated with a consensus-network, we identify the links that appear only in the consensus network under consideration but not in the others (unique-connections). Considering the genes involved in the unique-connections we build Bayesian networks to derive the unique-networks. Finally, we exploit the inference tool to calculate each gene prediction-accuracy across all studies to further refine the unique-networks. Biological validation through different software and the literature are explored to validate our method. UNIP is first applied to a set of synthetic data perturbed with different levels of noise to study the performance and verify its reliability. Then, wheat under stress conditions and different types of cancer are explored. Finally, we develop a user-friendly interface to combine the set of studies by using AND and NOT logic operators. Based on the findings, UNIP is a robust and reliable method to analyse large sets of transcriptomic data. It easily detects the main complex relationships between transcriptional expression of genes specific for different conditions and also highlights structures and nodes that could be potential targets for further research

Understanding co-expressed gene sets by identifying regulators and modeling genomic elements

Genomic researchers commonly study complex phenotypes by identifying experimentally derived sets of functionally related genes with similar transcriptional profiles. These gene sets are then frequently subjected to statistical tests of association relating them to previously characterized gene sets from literature and public databases. However, few tools exist examining the non-coding, regulatory sequence of gene sets for evidence of a shared regulatory signature that may signal the involvement of important DNA-binding proteins called transcription factors (TFs). Here, we proposed and developed new computational methods for identifying major regulatory features of co-expressed gene sets that incorporate TF-DNA binding specificities (“motifs”) with other important features such as sequence conservation and chromatin structure. We additionally demonstrated a novel approach for discovering regulatory signatures that are shared across gene sets from multiple experimental conditions or tissues. Given the co-expressed genes of a particular cell type, we also attempted to annotate their specific regulatory sequences (“enhancers”) by constructing models of enhancer activity that incorporate the expression and binding specificities of the relevant transcription factors. We first developed and tested these models in well-characterized cell types, and then evaluated the extent to which these models were applicable using only minimal experimental evidence to poorly characterized systems without known transcriptional regulators and functional enhancers. Finally, we developed a network-based algorithm for examining novel gene sets that integrates many diverse types of biological evidences and relationships to better discover functionally related genes. This novel approach processed a comprehensive, heterogeneous network of biological knowledge and ranked genes and molecular properties represented in the network for their relevance to the given set of co-expressed genes

Gene regulatory network modelling with evolutionary algorithms -an integrative approach

Building models for gene regulation has been an important aim of Systems Biology over the past years, driven by the large amount of gene expression data that has become available. Models represent regulatory interactions between genes and transcription factors and can provide better understanding of biological processes, and means of simulating both natural and perturbed systems (e.g. those associated with disease). Gene regulatory network (GRN) quantitative modelling is still limited, however, due to data issues such as noise and restricted length of time series, typically used for GRN reverse engineering. These issues create an under-determination problem, with many models possibly fitting the data. However, large amounts of other types of biological data and knowledge are available, such as cross-platform measurements, knockout experiments, annotations, binding site affinities for transcription factors and so on. It has been postulated that integration of these can improve model quality obtained, by facilitating further filtering of possible models. However, integration is not straightforward, as the different types of data can provide contradictory information, and are intrinsically noisy, hence large scale integration has not been fully explored, to date. Here, we present an integrative parallel framework for GRN modelling, which employs evolutionary computation and different types of data to enhance model inference. Integration is performed at different levels. (i) An analysis of cross-platform integration of time series microarray data, discussing the effects on the resulting models and exploring crossplatform normalisation techniques, is presented. This shows that time-course data integration is possible, and results in models more robust to noise and parameter perturbation, as well as reduced noise over-fitting. (ii) Other types of measurements and knowledge, such as knock-out experiments, annotated transcription factors, binding site affinities and promoter sequences are integrated within the evolutionary framework to obtain more plausible GRN models. This is performed by customising initialisation, mutation and evaluation of candidate model solutions. The different data types are investigated and both qualitative and quantitative improvements are obtained. Results suggest that caution is needed in order to obtain improved models from combined data, and the case study presented here provides an example of how this can be achieved. Furthermore, (iii), RNA-seq data is studied in comparison to microarray experiments, to identify overlapping features and possibilities of integration within the framework. The extension of the framework to this data type is straightforward and qualitative improvements are obtained when combining predicted interactions from single-channel and RNA-seq datasets

Archives of Data Science, Series A. Vol. 1,1: Special Issue: Selected Papers of the 3rd German-Polish Symposium on Data Analysis and Applications

The first volume of Archives of Data Science, Series A is a special issue of a selection of contributions which have been originally presented at the {\em 3rd Bilateral German-Polish Symposium on Data Analysis and Its Applications} (GPSDAA 2013). All selected papers fit into the emerging field of data science consisting of the mathematical sciences (computer science, mathematics, operations research, and statistics) and an application domain (e.g. marketing, biology, economics, engineering)

Integrative Analysis Methods for Biological Problems Using Data Reduction Approaches

The "big data" revolution of the past decade has allowed researchers to procure or access biological data at an unprecedented scale, on the front of both volume (low-cost high-throughput technologies) and variety (multi-platform genomic profiling). This has fueled the development of new integrative methods, which combine and consolidate across multiple sources of data in order to gain generalizability, robustness, and a more comprehensive systems perspective. The key challenges faced by this new class of methods primarily relate to heterogeneity, whether it is across cohorts from independent studies or across the different levels of genomic regulation. While the different perspectives among data sources is invaluable in providing different snapshots of the global system, such diversity also brings forth many analytic difficulties as each source introduces a distinctive element of noise. In recent years, many styles of data integration have appeared to tackle this problem ranging from Bayesian frameworks to graphical models, a wide assortment as diverse as the biology they intend to explain. My focus in this work is dimensionality reduction-based methods of integration, which offer the advantages of efficiency in high-dimensions (an asset among genomic datasets) and simplicity in allowing for elegant mathematical extensions. In the course of these chapters I will describe the biological motivations, the methodological directions, and the applications of three canonical reductionist approaches for relating information across multiple data groups.PHDStatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/138564/1/yangzi_1.pd