Motivation: DNA microarray experiments generating thousands of gene expression measurements, are being used to gather information from tissue and cell samples regarding gene expression differences that will be useful in diagnosing disease. We have developed a new method to analyse this kind of data using support vector machines (SVMs). This analysis consists of both classification of the tissue samples, and an exploration of the data for mis-labeled or questionable tissue results. Results: We demonstrate the method in detail on samples consisting of ovarian cancer tissues, normal ovarian tissues, and other normal tissues. The dataset consists of expression experiment results for 97 802 cDNAs for each tissue. As a result of computational analysis, a tissue sample is discovered and confirmed to be wrongly labeled. Upon correction of this mistake and the removal of an outlier, perfect classification of tissues is achieved, but not with high confidence. We identify and analyse a subset of genes from the ovarian dataset whose expression is highly differentiated between the types of tissues. To show robustness of the SVM method, two previously published datasets from other types of tissues or cells are analysed. The results are comparable to those previously obtained. We show that other machine learning methods also perform comparably to the SVM on many of those datasets. Availability: The SVM software is available at http:// www. cs.columbia.edu/#bgrundy/svm. Contact: booch@cse.ucsc.edu

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.

Motivation: Increasingly, biological processes are being studied through time series of RNA expression data collected for large numbers of genes. Because common processes may unfold at varying rates in different experiments or individuals, methods are needed that will allow corresponding expression states in different time series to be mapped to one another. Results: We present implementations of time warping algorithms applicable to RNA and protein expression data and demonstrate their application to published yeast RNA expression time series. Programs executing two warping algorithms are described, a simple warping algorithm and an interpolative algorithm, along with programs that generate graphics that visually present alignment information. We show time warping to be superior to simple clustering at mapping corresponding time states. We document the impact of statistical measurement noise and sample size on the quality of time alignments, and present issues related to statistical assessment of alignment quality through alignment scores. We also discuss directions for algorithm improvement including development of multiple time series alignments and possible applications to causality searches and non-temporal processes (`concentration warping'). Availability: Academic implementations of alignment programs genewarp and genewarpi and the graphics generation programs grphwarp and grphwarpi are available as Win32 system DOS box executables on our web site along with documentation on their use. The publicly available data on which they were demonstrated may be found at http://genome-www.stanford.edu/cellcycle/. Postscript files generated by grphwarp and grphwarpi may be directly printed or viewed using GhostView software available at http://www.cs.wisc.edu/#ghost/. Con...

The past decade has seen a tremendous growth in the amount of experimental and computational biomedical data, specifically in the areas of Genomics and Proteomics. This growth is accompanied by an accelerated increase in the number of biomedical publications discussing the findings. In the last few years there is a lot of interest within the scientific community in literature-mining tools to help sort through this abundance of literature, and find the nuggets of information most relevant and useful for specific analysis tasks. This paper

Microarray expression analysis has become one of the most widely used functional genomics tools. Efficient application of this technique requires the development of robust and reproducible protocols. We have optimized all aspects of the process, including PCR amplification of target cDNA clones, microarray printing, probe labeling, and hybridization, and we have developed strategies for data normalization and analysis. † Address correspondence to:

Classification of patient samples is a crucial aspect of cancer diagnosis and treatment. We present a method for classifying samples by computational analysis of gene expression data. We consider the classification problem in two parts: class discovery and class prediction. Class discovery refers to the process of dividing samples into reproducible classes that have similar behavior or properties, while class prediction places new samples into already known classes. We describe a method for performing class prediction and illustrate its strength by correctly classifying bone marrow and blood samples from acute leukemia patients. We also describe how to use our predictor to validate newly discovered classes, and we demonstrate how this technique could have discovered the key distinctions among leukemias if they were not already known. This proof-of-concept experiment paves the way for a wealth of future work on the molecular classification and understanding of disease. Whitehead/MIT C...

NASC operates an Affymetrix `GeneChip ' (microarray) service for the Arabidopsis thaliana community. All data produced by the service are publicly available through our microarray database `NASCArrays ' published at

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.

The complexity of biological systems provides for a great diversity of relationships between genes. The current analysis of whole-genome expression data focuses on relationships based on global correlation over a whole time-course, identifying clusters of genes whose expression levels simultaneously rise and fall. There are, of course, other potential relationships between genes, which are missed by such global clustering. These include activation, where one expects a time-delay between related expression pro®les, and inhibition, where one expects an inverted relationship. Here, we propose a new method, which we call local clustering, for identifying these time-delayed and inverted relationships. It is related to conventional gene-expression clustering in a fashion analogous to the way local sequence alignment (the Smith-Waterman algorithm) is derived from global alignment (Needleman-Wunsch). An integral part of our method is the use of random score distributions to assess the statistical signi®cance of each cluster. We applied our method to the yeast cellcycle

With the advent of DNA hybridization microarrays comes the remarkable ability, in principle, to simultaneously monitor the expression levels of large numbers of genes. The quantitative comparison of 2 or more microarrays can reveal, for example, the distinct patterns of gene expression that dene dierent cellular phenotypes or the genes induced in the cellular response to insult or changing environmental conditions. Normalization of the measured intensities is a prerequisite of such comparisons, and indeed of any statistical analysis, yet little attention has been paid to its systematic study. The most straightforward normalization techniques in use rest on the implicit assumption of linear response between true expression level and output intensity. We nd that these assumptions are not generally met and that these simple methods can be improved. We have developed a robust semi-parametric normalization technique based upon the assumption that the large majority of genes will not have...