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Linear models and empirical bayes methods for assessing differential expression in microarray experiments.
- Stat. Appl. Genet. Mol. Biol.
, 2004
"... Abstract The problem of identifying differentially expressed genes in designed microarray experiments is considered. Lonnstedt and Speed (2002) derived an expression for the posterior odds of differential expression in a replicated two-color experiment using a simple hierarchical parametric model. ..."
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Cited by 1321 (24 self)
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Abstract The problem of identifying differentially expressed genes in designed microarray experiments is considered. Lonnstedt and Speed (2002) derived an expression for the posterior odds of differential expression in a replicated two-color experiment using a simple hierarchical parametric model. The purpose of this paper is to develop the hierarchical model of Lonnstedt and Speed (2002) into a practical approach for general microarray experiments with arbitrary numbers of treatments and RNA samples. The model is reset in the context of general linear models with arbitrary coefficients and contrasts of interest. The approach applies equally well to both single channel and two color microarray experiments. Consistent, closed form estimators are derived for the hyperparameters in the model. The estimators proposed have robust behavior even for small numbers of arrays and allow for incomplete data arising from spot filtering or spot quality weights. The posterior odds statistic is reformulated in terms of a moderated t-statistic in which posterior residual standard deviations are used in place of ordinary standard deviations. The empirical Bayes approach is equivalent to shrinkage of the estimated sample variances towards a pooled estimate, resulting in far more stable inference when the number of arrays is small. The use of moderated t-statistics has the advantage over the posterior odds that the number of hyperparameters which need to estimated is reduced; in particular, knowledge of the non-null prior for the fold changes are not required. The moderated t-statistic is shown to follow a t-distribution with augmented degrees of freedom. The moderated t inferential approach extends to accommodate tests of composite null hypotheses through the use of moderated F-statistics. The performance of the methods is demonstrated in a simulation study. Results are presented for two publicly available data sets.
Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation
, 2002
"... There are many sources of systematic variation in cDNA microarray experiments which affect the measured gene expression levels (e.g. differences in labeling efficiency between the two fluorescent dyes). The term normalization refers to the process of removing such variation. A constant adjustment is ..."
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Cited by 718 (9 self)
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There are many sources of systematic variation in cDNA microarray experiments which affect the measured gene expression levels (e.g. differences in labeling efficiency between the two fluorescent dyes). The term normalization refers to the process of removing such variation. A constant adjustment is often used to force the distribution of the intensity log ratios to have a median of zero for each slide. However, such global normalization approaches are not adequate in situations where dye biases can depend on spot overall intensity and/or spatial location within the array. This article proposes normalization methods that are based on robust local regression and account for intensity and spatial dependence in dye biases for different types of cDNA microarray experiments. The selection of appropriate controls for normalization is discussed and a novel set of controls (microarray sample pool, MSP) is introduced to aid in intensity-dependent normalization. Lastly, to allow for comparisons of expression levels across slides, a robust method based on maximum likelihood estimation is proposed to adjust for scale differences among slides.
Empirical Bayes Analysis of a Microarray Experiment
- Journal of the American Statistical Association
, 2001
"... Microarrays are a novel technology that facilitates the simultaneous measurement of thousands of gene expression levels. A typical microarray experiment can produce millions of data points, raising serious problems of data reduction, and simultaneous inference. We consider one such experiment in whi ..."
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Cited by 492 (20 self)
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Microarrays are a novel technology that facilitates the simultaneous measurement of thousands of gene expression levels. A typical microarray experiment can produce millions of data points, raising serious problems of data reduction, and simultaneous inference. We consider one such experiment in which oligonucleotide arrays were employed to assess the genetic effects of ionizing radiation on seven thousand human genes. A simple nonparametric empirical Bayes model is introduced, which is used to guide the ef � cient reduction of the data to a single summary statistic per gene, and also to make simultaneous inferences concerning which genes were affected by the radiation. Although our focus is on one speci � c experiment, the proposed methods can be applied quite generally. The empirical Bayes inferences are closely related to the frequentist false discovery rate (FDR) criterion. 1.
Statistical methods for identifying differentially expressed genes in replicated cDNA microarray experiments
- STATISTICA SINICA
, 2002
"... DNA microarrays are a new and promising biotechnology whichallows the monitoring of expression levels in cells for thousands of genes simultaneously. The present paper describes statistical methods for the identification of differentially expressed genes in replicated cDNA microarray experiments. A ..."
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Cited by 438 (12 self)
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DNA microarrays are a new and promising biotechnology whichallows the monitoring of expression levels in cells for thousands of genes simultaneously. The present paper describes statistical methods for the identification of differentially expressed genes in replicated cDNA microarray experiments. Although it is not the main focus of the paper, new methods for the important pre-processing steps of image analysis and normalization are proposed. Given suitably normalized data, the biological question of differential expression is restated as a problem in multiple hypothesis testing: the simultaneous test for each gene of the null hypothesis of no association between the expression levels and responses or covariates of interest. Di erentially expressed genes are identified based on adjusted p-values for a multiple testing procedure which strongly controls the family-wise Type I error rate and takes into account the dependence structure between the gene expression levels. No specific parametric form is assumed for the distribution of the test statistics and a permutation procedure is used to estimate adjusted p-values. Several data displays are suggested for the visual identification of differentially expressed genes and of important features of these genes. The above methods are applied to microarray data from a study of gene expression in the livers of mice with very low HDL cholesterol levels. The genes identified using data from multiple slides are compared to those identified by recently published single-slide methods.
Analysis of variance for gene expression microarray data
- Journal of Computational Biology
, 2000
"... Spotted cDNA microarrays are emerging as a powerful and cost-effective tool for largescale analysis of gene expression. Microarrays can be used to measure the relative quantities of speci � c mRNAs in two or more tissue samples for thousands of genes simultaneously. While the power of this technolog ..."
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Cited by 362 (5 self)
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Spotted cDNA microarrays are emerging as a powerful and cost-effective tool for largescale analysis of gene expression. Microarrays can be used to measure the relative quantities of speci � c mRNAs in two or more tissue samples for thousands of genes simultaneously. While the power of this technology has been recognized, many open questions remain about appropriate analysis of microarray data. One question is how to make valid estimates of the relative expression for genes that are not biased by ancillary sources of variation. Recognizing that there is inherent “noise ” in microarray data, how does one estimate the error variation associated with an estimated change in expression, i.e., how does one construct the error bars? We demonstrate that ANOVA methods can be used to normalize microarray data and provide estimates of changes in gene expression that are corrected for potential confounding effects. This approach establishes a framework for the general analysis and interpretation of microarray data. Key words: Gene expression microarray, differential expression, analysis of variance, bootstrap.
A review of feature selection techniques in bioinformatics
- BIOINFORMATICS
, 2007
"... Feature selection techniques have become an apparent need in many bioinformatics applications. In addition to the large pool of techniques that have already been developed in the machine learning and data mining fields, specific applications in bioinformatics have led to a wealth of newly proposed t ..."
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Cited by 358 (10 self)
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Feature selection techniques have become an apparent need in many bioinformatics applications. In addition to the large pool of techniques that have already been developed in the machine learning and data mining fields, specific applications in bioinformatics have led to a wealth of newly proposed techniques. In this paper, we make the interested reader aware of the possibilities of feature selection, providing a basic taxonomy of feature selection techniques, and discussing their use, variety and potential in a number of both common as well as upcoming bioinformatics applications.
Use of within-array replicate spots for assessing differential expression in microarray experiments
- Bioinformatics
, 2005
"... Motivation. Spotted arrays are often printed with probes in duplicate or triplicate, but current methods for assessing differential expression are not able to make full use of the resulting information. Usual practice is to average the duplicate or triplicate results for each probe before assessing ..."
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Cited by 239 (8 self)
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Motivation. Spotted arrays are often printed with probes in duplicate or triplicate, but current methods for assessing differential expression are not able to make full use of the resulting information. Usual practice is to average the duplicate or triplicate results for each probe before assessing differential expression. This loses valuable information about gene-wise variability. Results. A method is proposed for extracting more information from within-array replicate spots in microarray experiments by estimating the strength of the correlation between them. The method involves fitting separate linear models to the expression data for each gene but with a common value for the between-replicate correlation. The method greatly improves the precision with which the genewise variances are estimated and thereby improves inference methods designed to identify differentially expressed genes. The method may be combined with empirical Bayes methods for moderating the genewise variances between genes. The method is validated using data from a microarray experiment involving calibration and ratio control spots in conjunction with spiked-in RNA. Comparing results for calibration and ratio control spots shows that the common correlation method results in substantially better discrimination of differentially expressed genes from those which are not. The spike-in experiment also confirms that the results may be further improved by empirical Bayes smoothing of the variances when the sample size is small. Availability. The methodology is implemented in the limma software package for R, available from the CRAN repository
Assessing Gene Significance from cDNA Microarray Expression Data via Mixed Models
, 2001
"... The determination of a list of differentially expressed genes is a basic objective in many cDNA microarray experiments. We present a statistical approach that allows direct control over the percentage of false positives in such a list and, under certain reasonable assumptions, improves on existing m ..."
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Cited by 218 (6 self)
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The determination of a list of differentially expressed genes is a basic objective in many cDNA microarray experiments. We present a statistical approach that allows direct control over the percentage of false positives in such a list and, under certain reasonable assumptions, improves on existing methods with respect to the percentage of false negatives. The method accommodates a wide variety of experimental designs and can simultaneously assess significant differences between multiple types of biological samples. Two interconnected mixed linear models are central to the method and provide a flexible means to properly account for variability both across and within genes. The mixed model also provides a convenient framework for evaluating the statistical power of any particular experimental design and thus enables a researcher to a priori select an appropriate number of replicates. We also suggest some basic graphics for visualizing lists of significant genes. Analyses of published experiments studying human cancer and yeast cells illustrate the results.
A Model Based Background Adjustment for Oligonucleotide Expression Arrays.
- Journal of the American Statistical Association
, 2004
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Cluster Analysis for Gene Expression Data: A Survey
- IEEE Transactions on Knowledge and Data Engineering
, 2004
"... Abstract—DNA microarray technology has now made it possible to simultaneously monitor the expression levels of thousands of genes during important biological processes and across collections of related samples. Elucidating the patterns hidden in gene expression data offers a tremendous opportunity f ..."
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Cited by 149 (5 self)
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Abstract—DNA microarray technology has now made it possible to simultaneously monitor the expression levels of thousands of genes during important biological processes and across collections of related samples. Elucidating the patterns hidden in gene expression data offers a tremendous opportunity for an enhanced understanding of functional genomics. However, the large number of genes and the complexity of biological networks greatly increases the challenges of comprehending and interpreting the resulting mass of data, which often consists of millions of measurements. A first step toward addressing this challenge is the use of clustering techniques, which is essential in the data mining process to reveal natural structures and identify interesting patterns in the underlying data. Cluster analysis seeks to partition a given data set into groups based on specified features so that the data points within a group are more similar to each other than the points in different groups. A very rich literature on cluster analysis has developed over the past three decades. Many conventional clustering algorithms have been adapted or directly applied to gene expression data, and also new algorithms have recently been proposed specifically aiming at gene expression data. These clustering algorithms have been proven useful for identifying biologically relevant groups of genes and samples. In this paper, we first briefly introduce the concepts of microarray technology and discuss the basic elements of clustering on gene expression data. In particular, we divide cluster analysis for gene expression data into three categories. Then, we present specific challenges pertinent to each clustering category and introduce several representative approaches. We also discuss the problem of cluster validation in three aspects and review various methods to assess the quality and reliability of clustering results. Finally, we conclude this paper and suggest the promising trends in this field. Index Terms—Microarray technology, gene expression data, clustering.
