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In this article, we study a generalization of the two-groups model in the presence of covariates—a problem that has recently received much attention in the statistical literature due to its applicability in multiple hypotheses testing problems. The model we consider allows for infinite dimensional parameters and offers flexibility in modeling the dependence of the response on the covariates. We discuss the identifiability issues arising in this model and systematically study several estimation strategies. We propose a tuning parameter-free nonparametric maximum likelihood method, implementable via the expectation-maximization algorithm, to estimate the unknown parameters. Further, we derive the rate of convergence of the proposed estimators—in particular we show that the finite sample Hellinger risk for every 'approximate' nonparametric maximum likelihood estimator achieves a near-parametric rate (up to logarithmic multiplicative factors). In addition, we propose and theoretically study two 'marginal' methods that are more scalable and easily implementable. We demonstrate the efficacy of our procedures through extensive simulation studies and relevant data analyses—one arising from neuroscience and the other from astronomy. We also outline the application of our methods to multiple testing. The companion R package NPMLEmix implements all the procedures proposed in this article. [ABSTRACT FROM AUTHOR]

Summary: Analysing data from large‐scale, multiexperiment studies requires scientists to both analyse each experiment and to assess the results as a whole. In this article, we develop double empirical Bayes testing (DEBT), an empirical Bayes method for analysing multiexperiment studies when many covariates are gathered per experiment. DEBT is a two‐stage method: in the first stage, it reports which experiments yielded significant outcomes and in the second stage, it hypothesises which covariates drive the experimental significance. In both of its stages, DEBT builds on the work of Efron, who laid out an elegant empirical Bayes approach to testing. DEBT enhances this framework by learning a series of black box predictive models to boost power and control the false discovery rate. In Stage 1, it uses a deep neural network prior to report which experiments yielded significant outcomes. In Stage 2, it uses an empirical Bayes version of the knockoff filter to select covariates that have significant predictive power of Stage 1 significance. In both simulated and real data, DEBT increases the proportion of discovered significant outcomes and selects more features when signals are weak. In a real study of cancer cell lines, DEBT selects a robust set of biologically plausible genomic drivers of drug sensitivity and resistance in cancer. [ABSTRACT FROM AUTHOR]

We propose a flexible and identifiable version of the 2-groups model, motivated by hierarchical Bayes considerations, that features an empirical null and a semiparametric mixture model for the nonnull cases. We use a computationally efficient predictive recursion (PR) marginal likelihood procedure to estimate the model parameters, even the nonparametric mixing distribution. This leads to a nonparametric empirical Bayes testing procedure, which we call PRtest, based on thresholding the estimated local false discovery rates. Simulations and real data examples demonstrate that, compared to existing approaches, PRtest's careful handling of the nonnull density can give a much better fit in the tails of the mixture distribution which, in turn, can lead to more realistic conclusions. [ABSTRACT FROM PUBLISHER]

A two-groups mixed-effects model for the comparison of (normalized) microarray data from two treatment groups is considered. Most competing parametric methods that have appeared in the literature are obtained as special cases or by minor modification of the proposed model. Approximate maximum likelihood fitting is accomplished via a fast and scalable algorithm, which we call LEMMA (Laplace approximated EM Microarray Analysis). The posterior odds of treatment x gene interactions, derived from the model, involve shrinkage estimates of both the interactions and of the gene specific error variances. Genes are classified as being associated with treatment based on the posterior odds and the local false discovery rate (f.d.r.) with a fixed cutoff. Our model-based approach also allows one to declare the non-null status of a gene by controlling the false discovery rate (FDR). It is shown in a detailed simulation study that the approach outperforms well-known competitors. We also apply the proposed methodology to two previously analyzed microarray examples. Extensions of the proposed method to paired treatments and multiple treatments are also discussed. [ABSTRACT FROM AUTHOR]