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Open Access Highly Accessed Methodology article

Arrow plot: a new graphical tool for selecting up and down regulated genes and genes differentially expressed on sample subgroups

Carina Silva-Fortes1*, Maria Antónia Amaral Turkman2 and Lisete Sousa2

Author Affiliations

1 Natural and Exact Sciences Department, Higher School of Health Technology of Lisbon of Polytechnic Institute of Lisbon and Center of Statistics and Applications of University of Lisbon, Lisbon, Portugal

2 Department of Statistics and Operational Research, Faculty of Sciences of University of Lisbon, and Center of Statistics and Applications of University of Lisbon, Lisbon, Portugal

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BMC Bioinformatics 2012, 13:147  doi:10.1186/1471-2105-13-147

Published: 26 June 2012

Abstract

Background

A common task in analyzing microarray data is to determine which genes are differentially expressed across two (or more) kind of tissue samples or samples submitted under experimental conditions. Several statistical methods have been proposed to accomplish this goal, generally based on measures of distance between classes. It is well known that biological samples are heterogeneous because of factors such as molecular subtypes or genetic background that are often unknown to the experimenter. For instance, in experiments which involve molecular classification of tumors it is important to identify significant subtypes of cancer. Bimodal or multimodal distributions often reflect the presence of subsamples mixtures. Consequently, there can be genes differentially expressed on sample subgroups which are missed if usual statistical approaches are used. In this paper we propose a new graphical tool which not only identifies genes with up and down regulations, but also genes with differential expression in different subclasses, that are usually missed if current statistical methods are used. This tool is based on two measures of distance between samples, namely the overlapping coefficient (OVL) between two densities and the area under the receiver operating characteristic (ROC) curve. The methodology proposed here was implemented in the open-source R software.

Results

This method was applied to a publicly available dataset, as well as to a simulated dataset. We compared our results with the ones obtained using some of the standard methods for detecting differentially expressed genes, namely Welch t-statistic, fold change (FC), rank products (RP), average difference (AD), weighted average difference (WAD), moderated t-statistic (modT), intensity-based moderated t-statistic (ibmT), significance analysis of microarrays (samT) and area under the ROC curve (AUC). On both datasets all differentially expressed genes with bimodal or multimodal distributions were not selected by all standard selection procedures. We also compared our results with (i) area between ROC curve and rising area (ABCR) and (ii) the test for not proper ROC curves (TNRC). We found our methodology more comprehensive, because it detects both bimodal and multimodal distributions and different variances can be considered on both samples. Another advantage of our method is that we can analyze graphically the behavior of different kinds of differentially expressed genes.

Conclusion

Our results indicate that the arrow plot represents a new flexible and useful tool for the analysis of gene expression profiles from microarrays.