Efron et al. (2001) proposed empirical Bayes formulation of the frequentist Benjamini and Hochbergs False Discovery Rate method (Benjamini and Hochberg,1995). This article attempts to unify the `two cultures' using concepts of comparison density and distribution function. We have also shown how almost all of the existing local fdr methods can be viewed as proposing various model specification for comparison density - unifies the vast literature of false discovery methods under one concept and notation.
We consider the problem of large-scale inference on the row or column variables of data in the form of a matrix. Often this data is transposable, meaning that both the row variables and column variables are of potential interest. An example of this scenario is detecting significant genes in microarrays when the samples or arrays may be dependent due to underlying relationships. We study the effect of both row and column correlations on commonly used test-statistics, null distributions, and multiple testing procedures, by explicitly modeling the covariances with the matrix-variate normal distribution. Using this model, we give both theoretical and simulation results revealing the problems associated with using standard statistical methodology on transposable data. We solve these problems by estimating the row and column covariances simultaneously, with transposable regularized covariance models, and de-correlating or sphering the data as a pre-processing step. Under reasonable assumptions, our method gives test statistics that follow the scaled theoretical null distribution and are approximately independent. Simulations based on various models with structured and observed covariances from real microarray data reveal that our method offers substantial improvements in two areas: 1) increased statistical power and 2) correct estimation of false discovery rates.
We revisit the problem of feature selection in linear discriminant analysis (LDA), that is, when features are correlated. First, we introduce a pooled centroids formulation of the multiclass LDA predictor function, in which the relative weights of Mahalanobis-transformed predictors are given by correlation-adjusted $t$-scores (cat scores). Second, for feature selection we propose thresholding cat scores by controlling false nondiscovery rates (FNDR). Third, training of the classifier is based on James--Stein shrinkage estimates of correlations and variances, where regularization parameters are chosen analytically without resampling. Overall, this results in an effective and computationally inexpensive framework for high-dimensional prediction with natural feature selection. The proposed shrinkage discriminant procedures are implemented in the R package ``sda'' available from the R repository CRAN.
With recent advances in high throughput technology, researchers often find themselves running a large number of hypothesis tests (thousands+) and esti- mating a large number of effect-sizes. Generally there is particular interest in those effects estimated to be most extreme. Unfortunately naive estimates of these effect-sizes (even after potentially accounting for multiplicity in a testing procedure) can be severely biased. In this manuscript we explore this bias from a frequentist perspective: we give a formal definition, and show that an oracle estimator using this bias dominates the naive maximum likelihood estimate. We give a resampling estimator to approximate this oracle, and show that it works well on simulated data. We also connect this to ideas in empirical Bayes.
As datasets grow richer, an important challenge is to leverage the full features in the data to maximize the number of useful discoveries while controlling for false positives. We address this problem in the context of multiple hypotheses testing, where for each hypothesis, we observe a p-value along with a set of features specific to that hypothesis. For example, in genetic association studies, each hypothesis tests the correlation between a variant and the trait. We have a rich set of features for each variant (e.g. its location, conservation, epigenetics etc.) which could inform how likely the variant is to have a true association. However popular testing approaches, such as Benjamini-Hochberg's procedure (BH) and independent hypothesis weighting (IHW), either ignore these features or assume that the features are categorical. We propose a new algorithm, NeuralFDR, which automatically learns a discovery threshold as a function of all the hypothesis features. We parametrize the discovery threshold as a neural network, which enables flexible handling of multi-dimensional discrete and continuous features as well as efficient end-to-end optimization. We prove that NeuralFDR has strong false discovery rate (FDR) guarantees, and show that it makes substantially more discoveries in synthetic and real datasets. Moreover, we demonstrate that the learned discovery threshold is directly interpretable.