ArrayWiki: an enabling technology for sharing public microarray data repositories and meta-analyses

© 2008 Stokes et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.DOI: 10.1186/1471-2105-9-S6-S18Background. A survey of microarray databases reveals that most of the repository contents and data models are heterogeneous (i.e., data obtained from different chip manufacturers), and that the repositories provide only basic biological keywords linking to PubMed. As a result, it is difficult to find datasets using research context or analysis parameters information beyond a few keywords. For example, to reduce the "curse-of-dimension" problem in microarray analysis, the number of samples is often increased by merging array data from different datasets. Knowing chip data parameters such as pre-processing steps (e.g., normalization, artefact removal, etc), and knowing any previous biological validation of the dataset is essential due to the heterogeneity of the data. However, most of the microarray repositories do not have meta-data information in the first place, and do not have a a mechanism to add or insert this information. Thus, there is a critical need to create "intelligent" microarray repositories that (1) enable update of meta-data with the raw array data, and (2) provide standardized archiving protocols to minimize bias from the raw data sources. Results. To address the problems discussed, we have developed a community maintained system called ArrayWiki that unites disparate meta-data of microarray meta-experiments from multiple primary sources with four key features. First, ArrayWiki provides a user-friendly knowledge management interface in addition to a programmable interface using standards developed by Wikipedia. Second, ArrayWiki includes automated quality control processes (caCORRECT) and novel visualization methods (BioPNG, Gel Plots), which provide extra information about data quality unavailable in other microarray repositories. Third, it provides a user-curation capability through the familiar Wiki interface. Fourth, ArrayWiki provides users with simple text-based searches across all experiment meta-data, and exposes data to search engine crawlers (Semantic Agents) such as Google to further enhance data discovery. Conclusions. Microarray data and meta information in ArrayWiki are distributed and visualized using a novel and compact data storage format, BioPNG. Also, they are open to the research community for curation, modification, and contribution. By making a small investment of time to learn the syntax and structure common to all sites running MediaWiki software, domain scientists and practioners can all contribute to make better use of microarray technologies in research and medical practices. ArrayWiki is available at http://www.bio-miblab.org/arraywiki

Topics in genomic image processing

The image processing methodologies that have been actively studied and developed now play a very significant role in the flourishing biotechnology research. This work studies, develops and implements several image processing techniques for M-FISH and cDNA microarray images. In particular, we focus on three important areas: M-FISH image compression, microarray image processing and expression-based classification. Two schemes, embedded M-FISH image coding (EMIC) and Microarray BASICA: Background Adjustment, Segmentation, Image Compression and Analysis, have been introduced for M-FISH image compression and microarray image processing, respectively. In the expression-based classification area, we investigate the relationship between optimal number of features and sample size, either analytically or through simulation, for various classifiers

Feature selection and modelling methods for microarray data from acute coronary syndrome

Acute coronary syndrome (ACS) represents a leading cause of mortality and morbidity worldwide. Providing better diagnostic solutions and developing therapeutic strategies customized to the individual patient represent societal and economical urgencies. Progressive improvement in diagnosis and treatment procedures require a thorough understanding of the underlying genetic mechanisms of the disease. Recent advances in microarray technologies together with the decreasing costs of the specialized equipment enabled affordable harvesting of time-course gene expression data. The high-dimensional data generated demands for computational tools able to extract the underlying biological knowledge. This thesis is concerned with developing new methods for analysing time-course gene expression data, focused on identifying differentially expressed genes, deconvolving heterogeneous gene expression measurements and inferring dynamic gene regulatory interactions. The main contributions include: a novel multi-stage feature selection method, a new deconvolution approach for estimating cell-type specific signatures and quantifying the contribution of each cell type to the variance of the gene expression patters, a novel approach to identify the cellular sources of differential gene expression, a new approach to model gene expression dynamics using sums of exponentials and a novel method to estimate stable linear dynamical systems from noisy and unequally spaced time series data. The performance of the proposed methods was demonstrated on a time-course dataset consisting of microarray gene expression levels collected from the blood samples of patients with ACS and associated blood count measurements. The results of the feature selection study are of significant biological relevance. For the first time is was reported high diagnostic performance of the ACS subtypes up to three months after hospital admission. The deconvolution study exposed features of within and between groups variation in expression measurements and identified potential cell type markers and cellular sources of differential gene expression. It was shown that the dynamics of post-admission gene expression data can be accurately modelled using sums of exponentials, suggesting that gene expression levels undergo a transient response to the ACS events before returning to equilibrium. The linear dynamical models capturing the gene regulatory interactions exhibit high predictive performance and can serve as platforms for system-level analysis, numerical simulations and intervention studies

Bayesian methods for non-gaussian data modeling and applications

Finite mixture models are among the most useful machine learning techniques and are receiving considerable attention in various applications. The use of finite mixture models in image and signal processing has proved to be of considerable interest in terms of both theoretical development and in their usefulness in several applications. In most of the applications, the Gaussian density is used in the mixture modeling of data. Although a Gaussian mixture may provide a reasonable approximation to many real-world distributions, it is certainly not always the best approximation especially in image and signal processing applications where we often deal with non-Gaussian data. In this thesis, we propose two novel approaches that may be used in modeling non-Gaussian data. These approaches use two highly flexible distributions, the generalized Gaussian distribution (GGD) and the general Beta distribution, in order to model the data. We are motivated by the fact that these distributions are able to fit many distributional shapes and then can be considered as a useful class of flexible models to address several problems and applications involving measurements and features having well-known marked deviation from the Gaussian shape. For the mixture estimation and selection problem, researchers have demonstrated that Bayesian approaches are fully optimal. The Bayesian learning allows the incorporation of prior knowledge in a formal coherent way that avoids overfitting problems. For this reason, we adopt different Bayesian approaches in order to learn our models parameters. First, we present a fully Bayesian approach to analyze finite generalized Gaussian mixture models which incorporate several standard mixtures, such as Laplace and Gaussian. This approach evaluates the posterior distribution and Bayes estimators using a Gibbs sampling algorithm, and selects the number of components in the mixture using the integrated likelihood. We also propose a fully Bayesian approach for finite Beta mixtures learning using a Reversible Jump Markov Chain Monte Carlo (RJMCMC) technique which simultaneously allows cluster assignments, parameters estimation, and the selection of the optimal number of clusters. We then validate the proposed methods by applying them to different image processing applications

Inference from binary gene expression data

Microarrays provide a practical method for measuring the mRNA abundances of thousands of genes in a single experiment. Analysing such large dimensional data is a challenge which attracts researchers from many different fields and machine learning is one of them. However, the biological properties of mRNA such as its low stability, measurements being taken from a population of cells rather than from a single cell, etc. should make researchers sceptical about the high numerical precision reported and thus the reproducibility of these measurements. In this study we explore data representation at lower numerical precision, down to binary (retaining only the information whether a gene is expressed or not), thereby improving the quality of inferences drawn from microarray studies. With binary representation, we propose a solution to reduce the effect of algorithmic choice in the pre-processing stages.First we compare the information loss if researchers made the inferences from quantized transcriptome data rather than the continuous values. Classification, clustering, periodicity detection and analysis of developmental time series data are considered here. Our results showed that there is not much information loss with binary data. Then, by focusing on the two most widely used inference tools, classification and clustering, we show that inferences drawn from transcriptome data can actually be improved with a metric suitable for binary data. This is explained with the uncertainties of the probe level data. We also show that binary transcriptome data can be used in cross-platform studies and when used with Tanimoto kernel, this increase the performance of inferences when compared to individual datasets. In the last part of this work we show that binary transcriptome data reduces the effect of algorithm choice for pre-processing raw data. While there are many different algorithms for pre-processing stages there are few guidelines for the users as to which one to choose. In many studies it has been shown that the choice of algorithms has significant impact on the overall results of microarray studies. Here we show in classification, that if transcriptome data is binarized after pre-processed with any combination of algorithms it has the effect of reducing the variability of the results and increasing the performance of the classifier simultaneously

Microarray Data Mining and Gene Regulatory Network Analysis

The novel molecular biological technology, microarray, makes it feasible to obtain quantitative measurements of expression of thousands of genes present in a biological sample simultaneously. Genome-wide expression data generated from this technology are promising to uncover the implicit, previously unknown biological knowledge. In this study, several problems about microarray data mining techniques were investigated, including feature(gene) selection, classifier genes identification, generation of reference genetic interaction network for non-model organisms and gene regulatory network reconstruction using time-series gene expression data. The limitations of most of the existing computational models employed to infer gene regulatory network lie in that they either suffer from low accuracy or computational complexity. To overcome such limitations, the following strategies were proposed to integrate bioinformatics data mining techniques with existing GRN inference algorithms, which enables the discovery of novel biological knowledge. An integrated statistical and machine learning (ISML) pipeline was developed for feature selection and classifier genes identification to solve the challenges of the curse of dimensionality problem as well as the huge search space. Using the selected classifier genes as seeds, a scale-up technique is applied to search through major databases of genetic interaction networks, metabolic pathways, etc. By curating relevant genes and blasting genomic sequences of non-model organisms against well-studied genetic model organisms, a reference gene regulatory network for less-studied organisms was built and used both as prior knowledge and model validation for GRN reconstructions. Networks of gene interactions were inferred using a Dynamic Bayesian Network (DBN) approach and were analyzed for elucidating the dynamics caused by perturbations. Our proposed pipelines were applied to investigate molecular mechanisms for chemical-induced reversible neurotoxicity

Use of Large, Immunosignature Databases to Pose New Questions About Infection and Health Status

abstract: Immunosignature is a technology that retrieves information from the immune system. The technology is based on microarrays with peptides chosen from random sequence space. My thesis focuses on improving the Immunosignature platform and using Immunosignatures to improve diagnosis for diseases. I first contributed to the optimization of the immunosignature platform by introducing scoring metrics to select optimal parameters, considering performance as well as practicality. Next, I primarily worked on identifying a signature shared across various pathogens that can distinguish them from the healthy population. I further retrieved consensus epitopes from the disease common signature and proposed that most pathogens could share the signature by studying the enrichment of the common signature in the pathogen proteomes. Following this, I worked on studying cancer samples from different stages and correlated the immune response with whether the epitope presented by tumor is similar to the pathogen proteome. An effective immune response is defined as an antibody titer increasing followed by decrease, suggesting elimination of the epitope. I found that an effective immune response usually correlates with epitopes that are more similar to pathogens. This suggests that the immune system might occupy a limited space and can be effective against only certain epitopes that have similarity with pathogens. I then participated in the attempt to solve the antibiotic resistance problem by developing a classification algorithm that can distinguish bacterial versus viral infection. This algorithm outperforms other currently available classification methods. Finally, I worked on the concept of deriving a single number to represent all the data on the immunosignature platform. This is in resemblance to the concept of temperature, which is an approximate measurement of whether an individual is healthy. The measure of Immune Entropy was found to work best as a single measurement to describe the immune system information derived from the immunosignature. Entropy is relatively invariant in healthy population, but shows significant differences when comparing healthy donors with patients either infected with a pathogen or have cancer.Dissertation/ThesisDoctoral Dissertation Molecular and Cellular Biology 201

Integrate qualitative biological knowledge for gene regulatory network reconstruction with dynamic Bayesian networks

Reconstructing gene regulatory networks, especially the dynamic gene networks that reveal the temporal program of gene expression from microarray expression data, is essential in systems biology. To overcome the challenges posed by the noisy and under-sampled microarray data, developing data fusion methods to integrate legacy biological knowledge for gene network reconstruction is a promising direction. However, large amount of qualitative biological knowledge accumulated by previous research, albeit very valuable, has received less attention for reconstructing dynamic gene networks due to its incompatibility with the quantitative computational models.;In this dissertation, I introduce a novel method to fuse qualitative gene interaction information with quantitative microarray data under the Dynamic Bayesian Networks framework. This method extends the previous data integration methods by its capabilities of both utilizing qualitative biological knowledge by using Bayesian Networks without the involvement of human experts, and taking time-series data to produce dynamic gene networks. The experimental study shows that when compared with standard Dynamic Bayesian Networks method which only uses microarray data, our method excels by both accuracy and consistency