Diverse correlation structures in gene expression data and their utility in improving statistical inference

It is well known that correlations in microarray data represent a serious nuisance deteriorating the performance of gene selection procedures. This paper is intended to demonstrate that the correlation structure of microarray data provides a rich source of useful information. We discuss distinct correlation substructures revealed in microarray gene expression data by an appropriate ordering of genes. These substructures include stochastic proportionality of expression signals in a large percentage of all gene pairs, negative correlations hidden in ordered gene triples, and a long sequence of weakly dependent random variables associated with ordered pairs of genes. The reported striking regularities are of general biological interest and they also have far-reaching implications for theory and practice of statistical methods of microarray data analysis. We illustrate the latter point with a method for testing differential expression of nonoverlapping gene pairs. While designed for testing a different null hypothesis, this method provides an order of magnitude more accurate control of type 1 error rate compared to conventional methods of individual gene expression profiling. In addition, this method is robust to the technical noise. Quantitative inference of the correlation structure has the potential to extend the analysis of microarray data far beyond currently practiced methods.Comment: Published in at http://dx.doi.org/10.1214/07-AOAS120 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Strong approximations of level exceedences related to multiple hypothesis testing

Particularly in genomics, but also in other fields, it has become commonplace to undertake highly multiple Student's $t$-tests based on relatively small sample sizes. The literature on this topic is continually expanding, but the main approaches used to control the family-wise error rate and false discovery rate are still based on the assumption that the tests are independent. The independence condition is known to be false at the level of the joint distributions of the test statistics, but that does not necessarily mean, for the small significance levels involved in highly multiple hypothesis testing, that the assumption leads to major errors. In this paper, we give conditions under which the assumption of independence is valid. Specifically, we derive a strong approximation that closely links the level exceedences of a dependent ``studentized process'' to those of a process of independent random variables. Via this connection, it can be seen that in high-dimensional, low sample-size cases, provided the sample size diverges faster than the logarithm of the number of tests, the assumption of independent $t$-tests is often justified.Comment: Published in at http://dx.doi.org/10.3150/09-BEJ220 the Bernoulli (http://isi.cbs.nl/bernoulli/) by the International Statistical Institute/Bernoulli Society (http://isi.cbs.nl/BS/bshome.htm

Covariate-assisted ranking and screening for large-scale two-sample inference

Two-sample multiple testing has a wide range of applications. The conventionalpractice first reduces the original observations to a vector of p-values and then chooses a cutoffto adjust for multiplicity. However, this data reduction step could cause significant loss ofinformation and thus lead to suboptimal testing procedures.We introduce a new framework fortwo-sample multiple testing by incorporating a carefully constructed auxiliary variable in inferenceto improve the power. A data-driven multiple-testing procedure is developed by employinga covariate-assisted ranking and screening (CARS) approach that optimally combines the informationfrom both the primary and the auxiliary variables. The proposed CARS procedureis shown to be asymptotically valid and optimal for false discovery rate control. The procedureis implemented in the R package CARS. Numerical results confirm the effectiveness of CARSin false discovery rate control and show that it achieves substantial power gain over existingmethods. CARS is also illustrated through an application to the analysis of a satellite imagingdata set for supernova detection

The Reproducibility of Lists of Differentially Expressed Genes in Microarray Studies

Reproducibility is a fundamental requirement in scientific experiments and clinical contexts. Recent publications raise concerns about the reliability of microarray technology because of the apparent lack of agreement between lists of differentially expressed genes (DEGs). In this study we demonstrate that (1) such discordance may stem from ranking and selecting DEGs solely by statistical significance (P) derived from widely used simple t-tests; (2) when fold change (FC) is used as the ranking criterion, the lists become much more reproducible, especially when fewer genes are selected; and (3) the instability of short DEG lists based on P cutoffs is an expected mathematical consequence of the high variability of the t-values. We recommend the use of FC ranking plus a non-stringent P cutoff as a baseline practice in order to generate more reproducible DEG lists. The FC criterion enhances reproducibility while the P criterion balances sensitivity and specificity

Model misspecification in peaks over threshold analysis

Classical peaks over threshold analysis is widely used for statistical modeling of sample extremes, and can be supplemented by a model for the sizes of clusters of exceedances. Under mild conditions a compound Poisson process model allows the estimation of the marginal distribution of threshold exceedances and of the mean cluster size, but requires the choice of a threshold and of a run parameter, $K$, that determines how exceedances are declustered. We extend a class of estimators of the reciprocal mean cluster size, known as the extremal index, establish consistency and asymptotic normality, and use the compound Poisson process to derive misspecification tests of model validity and of the choice of run parameter and threshold. Simulated examples and real data on temperatures and rainfall illustrate the ideas, both for estimating the extremal index in nonstandard situations and for assessing the validity of extremal models.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS292 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org