Controlling False Discoveries in Multidimensional Directional Decisions, with Applications to Gene Expression Data on Ordered Categories

Microarray gene expression studies over ordered categories are routinely conducted to gain insights into biological functions of genes and the underlying biological processes. Some common experiments are time-course/dose-response experiments where a tissue or cell line is exposed to different doses and/or durations of time to a chemical. A goal of such studies is to identify gene expression patterns/profiles Over the ordered categories. This problem can be formulated as a multiple testing problem where for each gene the null hypothesis of no difference between the successive mean gene expressions is tested and further directional decisions are made if it is rejected. Sloth of the existing multiple testing procedures are devised ha controlling the usual false discovery rate (FDR) rather than the mixed directional FUR (mdFDR), the expected proportion of Type I and directional errors among all rejections. Benjamini and Yekutieli (2005, Journal of the American Statistical Association 100, 71-93) proved that an augmentation of the usual Benjamini Hochberg (1:111) procedure can control the rndFDR. while testing simple null hypotheses against; two-sided alternatives in terms of one-dimensional parameters. Ill this article. we consider the problem of controlling the mdFDR, involving multidimensional parameters. To deal with this problem. we develop a procedure extending that of Benjamini and Yekutieli based on the Bonferroni test for each gene. A proof is given for its mdFDR)R. control when the underlying test statistics are independent across the genes. The results of a simulation Study evaluating its performance under independence as well as under dependence of the underlying test statistics across the genes relative to other relevant procedures are reported. Finally, the proposed methodology is applied to a tune-course microarray data obtained by Lobenhofer et al. (2002, Molecular Endocrinology 16. 1215-1229). We identified several important cell-cycle genus, such as DNA replication/repair gene MCM4 and replication factor subunit C2, which were not identified by the previous analyses of the same data by Lobenholer et al. (2002) and Peddada et al. (2003, Bioinformatics 19, 834-841). Although some of our findings overlap with previous findings; we identify several other genes that; complement the results of Lobenhofer et al. (2002).