Efron's two-group model is widely used in large scale multiple testing. This model assumes that test statistics are mutually independent, however in realistic settings they are typically dependent, and taking the dependence into account can boost power. The general two-group model takes the dependence between the test statistics into account. Optimal policies in the general two-group model require calculation, for each hypothesis, of the probability that it is a true null given all test statistics, denoted local false discovery rate (locFDR). Unfortunately, calculating locFDRs under realistic dependence structures can be computationally prohibitive. We propose calculating approximate locFDRs based on a properly defined N-neighborhood for each hypothesis. We prove that by thresholding the approximate locFDRs with a fixed threshold, the marginal false discovery rate is controlled for any dependence structure. Furthermore, we prove that this is the optimal procedure in a restricted class of decision rules, where decision for each hypothesis is only guided by its N-neighborhood. We show through extensive simulations that our proposed method achieves substantial power gains compared to alternative practical approaches, while maintaining conceptual simplicity and computational feasibility. We demonstrate the utility of our method on a genome wide association study of height.
Signal identification in large-dimensional settings is a challenging problem in biostatistics. Recently, the method of higher criticism (HC) was shown to be an effective means for determining appropriate decision thresholds. Here, we study HC from a false discovery rate (FDR) perspective. We show that the HC threshold may be viewed as an approximation to a natural class boundary (CB) in two-class discriminant analysis which in turn is expressible as FDR threshold. We demonstrate that in a rare-weak setting in the region of the phase space where signal identification is possible both thresholds…
Scientific hypotheses in a variety of applications have domain-specific structures, such as the tree structure of the International Classification of Diseases (ICD), the directed acyclic graph structure of the Gene Ontology (GO), or the spatial structure in genome-wide association studies. In the context of multiple testing, the resulting relationships among hypotheses can create redundancies among rejections that hinder interpretability. This leads to the practice of filtering rejection sets obtained from multiple testing procedures, which may in turn invalidate their inferential guarantees. …
Controlling the joint local false discovery rate is more powerful than meta-analysis methods in joint analysis of summary statistics from multiple genome-wide association studies
The Hong Kong University of Science and Technology（香港科技大学）
This paper proposes a procedure to obtain monotone estimates of both the local and the tail false discovery rates that arise in large-scale multiple testing. The proposed monotonization is asymptotically optimal for controlling the false discovery rate and also has many attractive finite-sample properties.
We propose a semiparametric mixture model to estimate local false discovery rates in multiple testing problems. The two pilars of the proposed approach are Efron's empirical null principle and log-concave density estimation for the alternative distribution. Compared to existing methods, our method can be easily extended to high dimension. Simulation results show that our method outperforms other existing methods and we illustrate its use via case studies in astronomy and microarray.
Cumulative sum (CUSUM) charts are typically used to detect changes in a stream of observations e.g. shifts in the mean. Usually, after signalling, the chart is restarted by setting it to some value below the signalling threshold. We propose a non-restarting CUSUM chart which is able to detect periods during which the stream is out of control. Further, we advocate an upper boundary to prevent the CUSUM chart rising too high, which helps detecting a change back into control. We present a novel algorithm to control the false discovery rate (FDR) pointwise in time when considering CUSUM charts bas…
Multiple hypothesis testing has been widely applied to problems dealing with high-dimensional data, e.g., selecting significant variables and controlling the selection error rate. The most prevailing measure of error rate used in the multiple hypothesis testing is the false discovery rate (FDR). In recent years, local false discovery rate (fdr) has drawn much attention, due to its advantage of accessing the confidence of individual hypothesis. However, most methods estimate fdr through p-values or statistics with known null distributions, which are sometimes not available or reliable. Adopting…
This paper studies the estimation of high dimensional Gaussian graphical model (GGM). Typically, the existing methods depend on regularization techniques. As a result, it is necessary to choose the regularized parameter. However, the precise relationship between the regularized parameter and the number of false edges in GGM estimation is unclear. Hence, it is impossible to evaluate their performance rigorously. In this paper, we propose an alternative method by a multiple testing procedure. Based on our new test statistics for conditional dependence, we propose a simultaneous testing procedure…
The knockoff-based multiple testing setup of Barber & Candes (2015) for variable selection in multiple regression where sample size is as large as the number of explanatory variables is considered. The method of Benjamini & Hochberg (1995) based on ordinary least squares estimates of the regression coefficients is adjusted to the setup, transforming it to a valid p-value based false discovery rate controlling method not relying on any specific correlation structure of the explanatory variables. Simulations and real data applications show that our proposed method that is agnostic to π0, the pro…
False discovery rates (FDR) are typically estimated from a mixture of a null and an alternative distribution. Here, we study a complementary approach proposed by Rice and Spiegelhalter (2008) that uses as primary quantities the null model and a parametric family for the local false discovery rate. Specifically, we consider the half-normal decay and the beta-uniform mixture models as FDR threshold functions. Using simulations and analysis of real data we compare the performance of the Rice-Spiegelhalter approach with that of competing FDR estimation procedures. If the alternative model is missp…
A method is demonstrated for representing the false discovery rate (FDR) in a set of p-values on a quantile-quantile (Q-Q) plot of the p-values. Recognition of this connection between the FDR and the Q-Q plot facilitates both understanding of the meaning of the FDR, and interpretation of the FDR in a particular data set.
Benjamini and Hochberg (1995) proposed the false discovery rate (FDR) as an alternative to the family-wise error rate in multiple testing problems, and proposed a procedure to control the FDR. For discrete data this procedure may be highly conservative. We investigate alternative, more powerful, procedures that exploit the discreteness of the tests and have FDR levels closer in magnitude to the desired nominal level. Moreover, we develop a novel step-down procedure that dominates the step-down procedure of Benjamini and Liu (1999) for discrete data. We consider an application to pharmacovigila…
Multiple hypothesis testing is a fundamental problem in high dimensional inference, with wide applications in many scientific fields. In genome-wide association studies, tens of thousands of tests are performed simultaneously to find if any genes are associated with some traits and those tests are correlated. When test statistics are correlated, false discovery control becomes very challenging under arbitrary dependence. In the current paper, we propose a new methodology based on principal factor approximation, which successfully substracts the common dependence and weakens significantly the c…
The use of weights provides an effective strategy to incorporate prior domain knowledge in large-scale inference. This paper studies weighted multiple testing in a decision-theoretic framework. We develop oracle and data-driven procedures that aim to maximize the expected number of true positives subject to a constraint on the weighted false discovery rate. The asymptotic validity and optimality of the proposed methods are established. The results demonstrate that incorporating informative domain knowledge enhances the interpretability of results and precision of inference. Simulation studies …
Models specified by low-rank matrices are ubiquitous in contemporary applications. In many of these problem domains, the row/column space structure of a low-rank matrix carries information about some underlying phenomenon, and it is of interest in inferential settings to evaluate the extent to which the row/column spaces of an estimated low-rank matrix signify discoveries about the phenomenon. However, in contrast to variable selection, we lack a formal framework to assess true/false discoveries in low-rank estimation; in particular, the key source of difficulty is that the standard notion of …
Closed testing procedures are classically used for familywise error rate (FWER) control, but they can also be used to obtain simultaneous confidence bounds for the false discovery proportion (FDP) in all subsets of the hypotheses. In this paper we investigate the special case of closed testing with Simes local tests. We construct a novel fast and exact shortcut which we use to investigate the power of this method when the number of hypotheses goes to infinity. We show that, if a minimal amount of signal is present, the average power to detect false hypotheses at any desired FDP level does not …
We propose a ranking and selection procedure to prioritize relevant predictors and control false discovery proportion (FDP) of variable selection. Our procedure utilizes a new ranking method built upon the de-sparsified Lasso estimator. We show that the new ranking method achieves the optimal order of minimum non-zero effects in ranking relevant predictors ahead of irrelevant ones. Adopting the new ranking method, we develop a variable selection procedure to asymptotically control FDP at a user-specified level. We show that our procedure can consistently estimate the FDP of variable selection …
Large-scale multiple testing is a fundamental problem in high dimensional statistical inference. It is increasingly common that various types of auxiliary information, reflecting the structural relationship among the hypotheses, are available. Exploiting such auxiliary information can boost statistical power. To this end, we propose a framework based on a two-group mixture model with varying probabilities of being null for different hypotheses a priori, where a shape-constrained relationship is imposed between the auxiliary information and the prior probabilities of being null. An optimal reje…
The popularity of penalized regression in high-dimensional data analysis has led to a demand for new inferential tools for these models. False discovery rate control is widely used in high-dimensional hypothesis testing, but has only recently been considered in the context of penalized regression. Almost all of this work, however, has focused on lasso-penalized linear regression. In this paper, we derive a general method for controlling the marginal false discovery rate that can be applied to any penalized likelihood-based model, such as logistic regression and Cox regression. Our approach is …
Efforts to develop more efficient multiple hypothesis testing procedures for false discovery rate (FDR) control have focused on incorporating an estimate of the proportion of true null hypotheses (such procedures are called adaptive) or exploiting heterogeneity across tests via some optimal weighting scheme. This paper combines these approaches using a weighted adaptive multiple decision function (WAMDF) framework. Optimal weights for a flexible random effects model are derived and a WAMDF that controls the FDR for arbitrary weighting schemes when test statistics are independent under the null…
False discovery rate (FDR) has been widely used as an error measure in large scale multiple testing problems, but most research in the area has been focused on procedures for controlling the FDR based on independent test statistics or the properties of such procedures for test statistics with certain types of stochastic dependence. Based on an approach proposed in Tang and Zhang (2005), we further develop in this paper empirical Bayes methods for controlling the FDR with dependent data. We implement our methodology in a time series model and report the results of a simulation study to demonstr…
Simultaneously finding multiple influential variables and controlling the false discovery rate (FDR) for linear regression models is a fundamental problem. We here propose the Gaussian Mirror (GM) method, which creates for each predictor variable a pair of mirror variables by adding and subtracting a randomly generated Gaussian perturbation, and proceeds with a certain regression method, such as the ordinary least-square or the Lasso (the mirror variables can also be created after selection). The mirror variables naturally lead to test statistics effective for controlling the FDR. Under a mild…
This paper continues the line of research initiated in Liu et. al. (2016) on developing a novel framework for multiple testing of hypotheses grouped in a one-way classified form using hypothesis-specific local false discovery rates (Lfdr's). It is built on an extension of the standard two-class mixture model from single to multiple groups, defining hypothesis-specific Lfdr as a function of the conditional Lfdr for the hypothesis given that it is within an important group and the Lfdr for the group itself and involving a new parameter that measures grouping effect. This definition captures the …
Large-scale multiple testing with correlated and heavy-tailed data arises in a wide range of research areas from genomics, medical imaging to finance. Conventional methods for estimating the false discovery proportion (FDP) often ignore the effect of heavy-tailedness and the dependence structure among test statistics, and thus may lead to inefficient or even inconsistent estimation. Also, the commonly imposed joint normality assumption is arguably too stringent for many applications. To address these challenges, in this paper we propose a Factor-Adjusted Robust Multiple Testing (FarmTest) proc…
It is frequently of interest to jointly analyze multiple sequences of multiple tests in order to identify simultaneous signals, defined as features tested in multiple studies whose test statistics are non-null in each. In many problems, however, the null distributions of the test statistics may be complicated or even unknown, and there do not currently exist any procedures that can be employed in these cases. This paper proposes a new nonparametric procedure that can identify simultaneous signals across multiple studies even without knowing the null distributions of the test statistics. The me…
False discovery rate (FDR) control in structured hypotheses testing is an important topic in simultaneous inference. Most existing methods that aim to utilize group structure among hypotheses either employ the groupwise mixture model or weight all p-values or hypotheses. Thus, their powers can be improved when the groupwise mixture model is inappropriate or when most groups contain only true null hypotheses. Motivated by this, we propose a grouped, selectively weighted FDR procedure, which we refer to as "sGBH". Specifically, without employing the groupwise mixture model, sGBH identifies group…
Since Benjamini and Hochberg introduced false discovery rate (FDR) in their seminal paper, this has become a very popular approach to the multiple comparisons problem. An increasingly popular topic within functional data analysis is local inference, i.e., the continuous statistical testing of a null hypothesis along the domain. The principal issue in this topic is the infinite amount of tested hypotheses, which can be seen as an extreme case of the multiple comparisons problem. In this paper we define and discuss the notion of false discovery rate in a very general functional data setting. Mor…
We consider statistical hypothesis testing simultaneously over a fairly general, possibly uncountably infinite, set of null hypotheses, under the assumption that a suitable single test (and corresponding $p$-value) is known for each individual hypothesis. We extend to this setting the notion of false discovery rate (FDR) as a measure of type I error. Our main result studies specific procedures based on the observation of the $p$-value process. Control of the FDR at a nominal level is ensured either under arbitrary dependence of $p$-values, or under the assumption that the finite dimensional di…
The analysis of environmental mixtures is of growing importance in environmental epidemiology, and one of the key goals in such analyses is to identify exposures and their interactions that are associated with adverse health outcomes. Typical approaches utilize flexible regression models combined with variable selection to identify important exposures and estimate a potentially nonlinear relationship with the outcome of interest. Despite this surge in interest, no approaches to date can identify exposures and interactions while controlling any form of error rates with respect to exposure selec…
Large-scale multiple testing with highly correlated test statistics arises frequently in many scientific research. Incorporating correlation information in estimating false discovery proportion has attracted increasing attention in recent years. When the covariance matrix of test statistics is known, Fan, Han & Gu (2012) provided a consistent estimate of False Discovery Proportion (FDP) under arbitrary dependence structure. However, the covariance matrix is often unknown in many applications and such dependence information has to be estimated before estimating FDP (Efron, 2010). The estimation…
This paper explores the intrinsic connections between the Bayesian false discovery rate (FDR) control procedures and their counterpart of frequentist procedures. We attempt to offer a unified view of FDR control within and beyond the setting of testing exchangeable hypotheses. Under the standard two-groups model and the Oracle condition, we show that the Bayesian and the frequentist methods can achieve asymptotically equivalent FDR control at arbitrary levels. Built on this result, we further illustrate that rigorous post-fitting model diagnosis is necessary and effective to ensure robust FDR …
For multiple testing based on p-values with càdlàg distribution functions, we propose an FDR procedure "BH+" with proven conservativeness. BH+ is at least as powerful as the BH procedure when they are applied to super-uniform p-values. Further, when applied to mid p-values, BH+ is more powerful than it is applied to conventional p-values. An easily verifiable necessary and sufficient condition for this is provided. BH+ is perhaps the first conservative FDR procedure applicable to mid p-values. BH+ is applied to multiple testing based on discrete p-values in a methylation study, an HIV study an…
Statistical dependence between hypotheses poses a significant challenge to the stability of large scale multiple hypotheses testing. Ignoring it often results in an unacceptably large spread in the false positive proportion even though the average value is acceptable [21, 39, 40, 49]. However, the statistical dependence structure of data is often unknown. Using a generic signalprocessing model, Bayesian multiple testing, and simulations, we demonstrate that the variance of the false positive proportion can be substantially reduced even under unknown short range dependence. We do this by modeli…
Selecting relevant features associated with a given response variable is an important issue in many scientific fields. Quantifying quality and uncertainty of a selection result via false discovery rate (FDR) control has been of recent interest. This paper introduces a way of using data-splitting strategies to asymptotically control the FDR while maintaining a high power. For each feature, the method constructs a test statistic by estimating two independent regression coefficients via data splitting. FDR control is achieved by taking advantage of the statistic's property that, for any null feat…
We discuss several approaches to defining power in studies designed around the Benjamini-Hochberg (BH) false discovery rate (FDR) procedure. We focus primarily on the \textit{average power} and the $λ$-\textit{power}, which are the expected true positive fraction and the probability that the true positive fraction exceeds $λ$, respectively. We prove results concerning strong consistency and asymptotic normality for the positive call fraction (PCF), the true positive fraction (TPF) and false discovery fraction (FDF). Convergence of their corresponding expected values, including a convergence re…
