Control of the mean number of false discoveries, Bonferroni and stability of multiple testing

The Bonferroni multiple testing procedure is commonly perceived as being overly conservative in large-scale simultaneous testing situations such as those that arise in microarray data analysis. The objective of the present study is to show that this popular belief is due to overly stringent requirements that are typically imposed on the procedure rather than to its conservative nature. To get over its notorious conservatism, we advocate using the Bonferroni selection rule as a procedure that controls the per family error rate (PFER). The present paper reports the first study of stability properties of the Bonferroni and Benjamini--Hochberg procedures. The Bonferroni procedure shows a superior stability in terms of the variance of both the number of true discoveries and the total number of discoveries, a property that is especially important in the presence of correlations between individual $p$-values. Its stability and the ability to provide strong control of the PFER make the Bonferroni procedure an attractive choice in microarray studies.Comment: Published at http://dx.doi.org/10.1214/07-AOAS102 in the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Extraction of Transcript Diversity from Scientific Literature

Transcript diversity generated by alternative splicing and associated mechanisms contributes heavily to the functional complexity of biological systems. The numerous examples of the mechanisms and functional implications of these events are scattered throughout the scientific literature. Thus, it is crucial to have a tool that can automatically extract the relevant facts and collect them in a knowledge base that can aid the interpretation of data from high-throughput methods. We have developed and applied a composite text-mining method for extracting information on transcript diversity from the entire MEDLINE database in order to create a database of genes with alternative transcripts. It contains information on tissue specificity, number of isoforms, causative mechanisms, functional implications, and experimental methods used for detection. We have mined this resource to identify 959 instances of tissue-specific splicing. Our results in combination with those from EST-based methods suggest that alternative splicing is the preferred mechanism for generating transcript diversity in the nervous system. We provide new annotations for 1,860 genes with the potential for generating transcript diversity. We assign the MeSH term “alternative splicing” to 1,536 additional abstracts in the MEDLINE database and suggest new MeSH terms for other events. We have successfully extracted information about transcript diversity and semiautomatically generated a database, LSAT, that can provide a quantitative understanding of the mechanisms behind tissue-specific gene expression. LSAT (Literature Support for Alternative Transcripts) is publicly available at http://www.bork.embl.de/LSAT/

MIDAW: a web tool for statistical analysis of microarray data

MIDAW (microarray data analysis web tool) is a web interface integrating a series of statistical algorithms that can be used for processing and interpretation of microarray data. MIDAW consists of two main sections: data normalization and data analysis. In the normalization phase the simultaneous processing of several experiments with background correction, global and local mean and variance normalization are carried out. The data analysis section allows graphical display of expression data for descriptive purposes, estimation of missing values, reduction of data dimension, discriminant analysis and identification of marker genes. The statistical results are organized in dynamic web pages and tables, where the transcript/gene probes contained in a specific microarray platform can be linked (according to user choice) to external databases (GenBank, Entrez Gene, UniGene). Tutorial files help the user throughout the statistical analysis to ensure that the forms are filled out correctly. MIDAW has been developed using Perl and PHP and it uses R/Bioconductor languages and routines. MIDAW is GPL licensed and freely accessible at . Perl and PHP source codes are available from the authors upon request

A STAT3 Gene Expression Signature in Gliomas is Associated with a Poor Prognosis

Gliomas frequently display constitutive activation of the transcription factor STAT3, a protein that is known to be able to mediate neoplastic transformation. STAT3 regulates genes that play a central role in cellular survival, proliferation, self-renewal, and invasion, and a cohort of STAT3 target genes have been found that are commonly coexpressed in human cancers. Thus, these genes likely subserve the transforming ability of constitutively activated STAT3. To determine whether the coordinated expression of STAT3 target genes is present in a subset of human gliomas, and whether this changes the biology of these tumors in patients, gene expression analysis was performed in four distinct human glioma data sets for which patient survival information was available. Coordinate expression of STAT3 targets was significantly associated with poor patient outcome in each data set. Specifically, patients with tumors displaying high expression of STAT3 targets had a shorter median survival time compared to patients whose tumors had low expression of STAT3 targets. These data suggest that constitutively activated STAT3 in gliomas can alter the biology of these tumors, and that development of targeted STAT3 inhibitors would likely be of particular benefit in treatment of this disease

Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy.

The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long-term pressure overload. Acp1(-/-) mice develop normally and ageing mice do not show pathology in major tissues under basal conditions. However, Acp1(-/-) mice are strikingly resistant to pressure overload hypertrophy and heart failure. Lmptp expression is high in the embryonic mouse heart, decreased in the postnatal stage, and increased in the adult mouse failing heart. We also show that LMPTP expression increases in end-stage heart failure in humans. Consistent with their protected phenotype, Acp1(-/-) mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of fibrotic genes. Transcriptional profiling and analysis of molecular signalling show that the resistance of Acp1(-/-) mice to pathological cardiac stress correlates with marginal re-expression of fetal cardiac genes, increased insulin receptor beta phosphorylation, as well as PKA and ephrin receptor expression, and inactivation of the CaMKIIδ pathway. Our data show that ablation of Lmptp inhibits pathological cardiac remodelling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of human heart failure