Rejoinder: Microarrays, Empirical Bayes and the Two-Groups Model

Rejoinder to ``Microarrays, Empirical Bayes and the Two-Groups Model'' [arXiv:0808.0572]Comment: Published in at http://dx.doi.org/10.1214/08-STS236REJ the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Size, power and false discovery rates

Modern scientific technology has provided a new class of large-scale simultaneous inference problems, with thousands of hypothesis tests to consider at the same time. Microarrays epitomize this type of technology, but similar situations arise in proteomics, spectroscopy, imaging, and social science surveys. This paper uses false discovery rate methods to carry out both size and power calculations on large-scale problems. A simple empirical Bayes approach allows the false discovery rate (fdr) analysis to proceed with a minimum of frequentist or Bayesian modeling assumptions. Closed-form accuracy formulas are derived for estimated false discovery rates, and used to compare different methodologies: local or tail-area fdr's, theoretical, permutation, or empirical null hypothesis estimates. Two microarray data sets as well as simulations are used to evaluate the methodology, the power diagnostics showing why nonnull cases might easily fail to appear on a list of ``significant'' discoveries.Comment: Published in at http://dx.doi.org/10.1214/009053606000001460 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Microarrays, Empirical Bayes and the Two-Groups Model

The classic frequentist theory of hypothesis testing developed by Neyman, Pearson and Fisher has a claim to being the twentieth century's most influential piece of applied mathematics. Something new is happening in the twenty-first century: high-throughput devices, such as microarrays, routinely require simultaneous hypothesis tests for thousands of individual cases, not at all what the classical theory had in mind. In these situations empirical Bayes information begins to force itself upon frequentists and Bayesians alike. The two-groups model is a simple Bayesian construction that facilitates empirical Bayes analysis. This article concerns the interplay of Bayesian and frequentist ideas in the two-groups setting, with particular attention focused on Benjamini and Hochberg's False Discovery Rate method. Topics include the choice and meaning of the null hypothesis in large-scale testing situations, power considerations, the limitations of permutation methods, significance testing for groups of cases (such as pathways in microarray studies), correlation effects, multiple confidence intervals and Bayesian competitors to the two-groups model.Comment: This paper commented in: [arXiv:0808.0582], [arXiv:0808.0593], [arXiv:0808.0597], [arXiv:0808.0599]. Rejoinder in [arXiv:0808.0603]. Published in at http://dx.doi.org/10.1214/07-STS236 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Are a set of microarrays independent of each other?

Having observed an $m\times n$ matrix $X$ whose rows are possibly correlated, we wish to test the hypothesis that the columns are independent of each other. Our motivation comes from microarray studies, where the rows of $X$ record expression levels for $m$ different genes, often highly correlated, while the columns represent $n$ individual microarrays, presumably obtained independently. The presumption of independence underlies all the familiar permutation, cross-validation and bootstrap methods for microarray analysis, so it is important to know when independence fails. We develop nonparametric and normal-theory testing methods. The row and column correlations of $X$ interact with each other in a way that complicates test procedures, essentially by reducing the accuracy of the relevant estimators.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS236 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Rejoinder: The Future of Indirect Evidence

Rejoinder to "The Future of Indirect Evidence" [arXiv:1012.1161]Comment: Published in at http://dx.doi.org/10.1214/10-STS308REJ the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Multivariate limited translation hierarchical Bayes estimators

Based on the notion of predictive influence functions, the paper develops multivariate limited translation hierarchical Bayes estimators of the normal mean vector which serve as a compromise between the hierarchical Bayes and maximum likelihood estimators. The paper demonstrates the superiority of the limited translation estimators over the usual hierarchical Bayes estimators in terms of the frequentist risks when the true parameter to be estimated departs widely from the grand average of all the parameters

Correcting the Minimization Bias in Searches for Small Signals

We discuss a method for correcting the bias in the limits for small signals if those limits were found based on cuts that were chosen by minimizing a criterion such as sensitivity. Such a bias is commonly present when a "minimization" and an "evaluation" are done at the same time. We propose to use a variant of the bootstrap to adjust the limits. A Monte Carlo study shows that these new limits have correct coverage.Comment: 14 pages, 5 figue

Pathwise Least Angle Regression and a Significance Test for the Elastic Net

Least angle regression (LARS) by Efron et al. (2004) is a novel method for constructing the piece-wise linear path of Lasso solutions. For several years, it remained also as the de facto method for computing the Lasso solution before more sophisticated optimization algorithms preceded it. LARS method has recently again increased its popularity due to its ability to find the values of the penalty parameters, called knots, at which a new parameter enters the active set of non-zero coefficients. Significance test for the Lasso by Lockhart et al. (2014), for example, requires solving the knots via the LARS algorithm. Elastic net (EN), on the other hand, is a highly popular extension of Lasso that uses a linear combination of Lasso and ridge regression penalties. In this paper, we propose a new novel algorithm, called pathwise (PW-)LARS-EN, that is able to compute the EN knots over a grid of EN tuning parameter {\alpha} values. The developed PW-LARS-EN algorithm decreases the EN tuning parameter and exploits the previously found knot values and the original LARS algorithm. A covariance test statistic for the Lasso is then generalized to the EN for testing the significance of the predictors. Our simulation studies validate the fact that the test statistic has an asymptotic Exp(1) distribution.Comment: 5 pages, 25th European Signal Processing Conference (EUSIPCO 2017