A weighted FDR procedure under discrete and heterogeneous null distributions
Xiongzhi Chen, R. W. Doerge, Sanat K. Sarkar
备注：
29 pages; in this version: (1) new weights from arXiv:1812.06551v2 are employed by the wFDR procedure to ensure its conservativeness under independence; (2) non-asymptotic upper bound is provided for the wFDR procedure that uses plug-in weights that are induced by the proportion estimator of arxiv:1410.4274v2; (3) simulation study under dependence uses more a complicated block dependence structure
Multiple testing with false discovery rate (FDR) control has been widely conducted in the ``discrete paradigm" where p-values have discrete and heterogeneous null distributions. However, in this scenario existing FDR procedures often lose some power and may yield unreliable inference, and for this scenario there does not seem to be an FDR procedure that partitions hypotheses into groups, employs data-adaptive weights and is non-asymptotically conservative. We propose a weighted FDR procedure for multiple testing in the discrete paradigm that efficiently adapts to both the heterogeneity and discreteness of p-value distributions. We theoretically justify the non-asymptotic conservativeness of the weighted FDR procedure under independence, and show via simulation studies that, for multiple testing based on p-values of Binomial test or Fisher's exact test, it is more powerful than six other procedures. The weighted FDR procedure is applied to a drug safety study and a differential methylation study based on discrete data, where it makes more discoveries than two existing methods.
False discovery rate (FDR) controlling procedures provide important statistical guarantees for the replicability in signal identification based on multiple hypotheses testing. In many fields of study, FDR controlling procedures are used in high-dimensional (HD) analyses to discover features that are truly associated with the outcome. In some recent applications, data on the same set of candidate features are independently collected in multiple different studies. For example, gene expression data are collected at different facilities and with different cohorts, to identify the genetic biomarker…
We consider multiple testing with false discovery rate (FDR) control when p-values have discrete and heterogeneous null distributions. We propose a new estimator of the proportion of true null hypotheses and demonstrate that it is less upwardly biased than Storey's estimator and two other estimators. The new estimator induces two adaptive procedures, i.e., an adaptive Benjamini-Hochberg (BH) procedure and an adaptive Benjamini-Hochberg-Heyse (BHH) procedure. We prove that the the adaptive BH procedure is conservative non-asymptotically. Through simulation studies, we show that these procedures…
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…
We consider multiple testing means of many dependent Normal random variables that do not necessarily follow a joint Normal distribution. Under weak dependence, we show the uniform consistency of proportion estimators that are constructed as solutions to Lebesgue-Stieltjes equations for the setting of a point, bounded and one-sided null, respectively, and characterize via the index of weak dependence the sparsest proportion these estimators can consistently estimate. On the other hand, under a principal correlation structure and employing a suitable definition of p-value for composite null hypo…
Multiple hypothesis testing often involves composite nulls, i.e., nulls that are associated with two or more distributions. In many cases, it is reasonable to assume that there is a prior distribution on the distributions despite it is unknown. When the number of distributions under true nulls is finite, we show that under the above assumption, the false discover rate (FDR) can be controlled using $p$-values computed under constraints imposed by the empirical distribution of the observations. Comparing to FDR control using $p$-values defined as maximum significance level over all null distribu…
For multiple testing, we introduce Storey-type FDR procedures and the concept of "regular estimator of the proportion of true nulls". We show that the rejection threshold of a Storey-type FDR procedure is a stopping time with respect to the backward filtration generated by the p-values and that a Storey-type FDR estimator at this rejection threshold equals the pre-specified FDR level, when the estimator of the proportion of true nulls is regular. These results hold regardless of the dependence among or the types of distributions of the p-values. They directly imply that a Storey-type FDR proce…
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 traditional approaches to false discovery rate (FDR) control in multiple hypothesis testing are usually based on the null distribution of a test statistic. However, all types of null distributions, including the theoretical, permutation-based and empirical ones, have some inherent drawbacks. For example, the theoretical null might fail because of improper assumptions on the sample distribution. Here, we propose a null distribution-free approach to FDR control for multiple hypothesis testing. This approach, named target-decoy procedure, simply builds on the ordering of tests by some statist…
In many practical applications of multiple hypothesis testing using the False Discovery Rate (FDR), the given hypotheses can be naturally partitioned into groups, and one may not only want to control the number of false discoveries (wrongly rejected null hypotheses), but also the number of falsely discovered groups of hypotheses (we say a group is falsely discovered if at least one hypothesis within that group is rejected, when in reality the group contains only nulls). In this paper, we introduce the p-filter, a procedure which unifies and generalizes the standard FDR procedure by Benjamini a…
False discovery rate (FDR) procedures provide misleading inference when testing multiple null hypotheses with heterogeneous multinomial data. For example, in the motivating study the goal is to identify species of bacteria near the roots of wheat plants (rhizobacteria) that are associated with productivity, but standard procedures discover the most abundant species even when the association is weak or negligible, and fail to discover strong associations when species are not abundant. Consequently, a list of abundant species is produced by the multiple testing procedure even though the goal was…
We investigate asymptotically optimal multiple testing procedures for streams of sequential data in the context of prior information on the number of false null hypotheses ("signals"). We show that the "gap" and "gap-intersection" procedures, recently proposed and shown by Song and Fellouris (2017, Electron. J. Statist.) to be asymptotically optimal for controlling type 1 and 2 familywise error rates (FWEs), are also asymptotically optimal for controlling FDR/FNR when their critical values are appropriately adjusted. Generalizing this result, we show that these procedures, again with appropria…
The introduction of the false discovery rate (FDR) by Benjamini and Hochberg has spurred a great interest in developing methodologies to control the FDR in various settings. The majority of existing approaches, however, address the FDR control for the case where an appropriate univariate test statistic is available. Modern hypothesis testing and data integration applications, on the other hand, routinely involve multivariate test statistics. The goal, in such settings, is to combine the evidence for each hypothesis and achieve greater power, while controlling the number of false discoveries. T…
False discovery rates (FDR) are an essential component of statistical inference, representing the propensity for an observed result to be mistaken. FDR estimates should accompany observed results to help the user contextualize the relevance and potential impact of findings. This paper introduces a new user-friendly R package for computing FDRs and adjusting p-values for FDR control. These tools respect the critical difference between the adjusted p-value and the estimated FDR for a particular finding, which are sometimes numerically identical but are often confused in practice. Newly augmented…
University of Southern California（南加州大学）；Stanford University（斯坦福大学）
Multiple hypothesis testing is a core problem in statistical inference and arises in almost every scientific field. Given a set of null hypotheses $\mathcal{H}(n) = (H_1,\dotsc, H_n)$, Benjamini and Hochberg introduced the false discovery rate (FDR), which is the expected proportion of false positives among rejected null hypotheses, and proposed a testing procedure that controls FDR below a pre-assigned significance level. Nowadays FDR is the criterion of choice for large scale multiple hypothesis testing. In this paper we consider the problem of controlling FDR in an "online manner". Concrete…
In many applications of multiple hypothesis testing where more than one false rejection can be tolerated, procedures controlling error rates measuring at least $k$ false rejections, instead of at least one, for some fixed $k\ge 1$ can potentially increase the ability of a procedure to detect false null hypotheses. The $k$-FWER, a generalized version of the usual familywise error rate (FWER), is such an error rate that has recently been introduced in the literature and procedures controlling it have been proposed. A further generalization of a result on the $k$-FWER is provided in this article.…
Two recently introduced model based bias corrected estimators for proportion of true null hypotheses ($π_0$) under multiple hypotheses testing scenario have been restructured for exponentially distributed random observations available for each of the common hypotheses. Based on stochastic ordering, a new motivation behind formulation of some related estimators for $π_0$ is given. The reduction of bias for the model based estimators are theoretically justified and algorithms for computing the estimators are also presented. The estimators are also used to formulate a popular adaptive multiple te…
University of Waterloo（滑铁卢大学）；Carnegie Mellon University（卡内基梅隆大学）
In bandit multiple hypothesis testing, each arm corresponds to a different null hypothesis that we wish to test, and the goal is to design adaptive algorithms that correctly identify large set of interesting arms (true discoveries), while only mistakenly identifying a few uninteresting ones (false discoveries). One common metric in non-bandit multiple testing is the false discovery rate (FDR). We propose a unified, modular framework for bandit FDR control that emphasizes the decoupling of exploration and summarization of evidence. We utilize the powerful martingale-based concept of "e-processe…
In multiple testing problems, where a large number of hypotheses are tested simultaneously, false discovery rate (FDR) control can be achieved with the well-known Benjamini-Hochberg procedure, which adapts to the amount of signal present in the data. Many modifications of this procedure have been proposed to improve power in scenarios where the hypotheses are organized into groups or into a hierarchy, as well as other structured settings. Here we introduce SABHA, the "structure-adaptive Benjamini-Hochberg algorithm", as a generalization of these adaptive testing methods. SABHA incorporates pri…
Results on the false discovery rate (FDR) and the false nondiscovery rate (FNR) are developed for single-step multiple testing procedures. In addition to verifying desirable properties of FDR and FNR as measures of error rates, these results extend previously known results, providing further insights, particularly under dependence, into the notions of FDR and FNR and related measures. First, considering fixed configurations of true and false null hypotheses, inequalities are obtained to explain how an FDR- or FNR-controlling single-step procedure, such as a Bonferroni or uSidák procedure, can …
In many existing methods in multiple comparison, one starts with either Fisher's p-values or the local fdr scores. The former one, with a usual definition as the tail probability exceeding the observed test statistic under the null distribution, fails to use the information from the alternative hypothesis and the targeted region of signals could be completely wrong especially when the likelihood ratio function is not monotone. The local fdr based approaches, usually relying on the density functions, are optimal oracally. However, the targeted region of the signals of the data-driven version is…
In recent mutation studies, analyses based on protein domain positions are gaining popularity over gene-centric approaches since the latter have limitations in considering the functional context that the position of the mutation provides. This presents a large-scale simultaneous inference problem, with hundreds of hypothesis tests to consider at the same time. This paper aims to select significant mutation counts while controlling a given level of Type I error via False Discovery Rate (FDR) procedures. One main assumption is that there exists a cut-off value such that smaller counts than this …
In the multiple testing context, a challenging problem is the estimation of the proportion $π_0$ of true-null hypotheses. A large number of estimators of this quantity rely on identifiability assumptions that either appear to be violated on real data, or may be at least relaxed. Under independence, we propose an estimator $\hatπ_0$ based on density estimation using both histograms and cross-validation. Due to the strong connection between the false discovery rate (FDR) and $π_0$, many multiple testing procedures (MTP) designed to control the FDR may be improved by introducing an estimator of $…
We provide the first differentially private algorithms for controlling the false discovery rate (FDR) in multiple hypothesis testing, with essentially no loss in power under certain conditions. Our general approach is to adapt a well-known variant of the Benjamini-Hochberg procedure (BHq), making each step differentially private. This destroys the classical proof of FDR control. To prove FDR control of our method, (a) we develop a new proof of the original (non-private) BHq algorithm and its robust variants -- a proof requiring only the assumption that the true null test statistics are indepen…
Multiple testing problems are a staple of modern statistical analysis. The fundamental objective of multiple testing procedures is to reject as many false null hypotheses as possible (that is, maximize some notion of power), subject to controlling an overall measure of false discovery, like family-wise error rate (FWER) or false discovery rate (FDR). In this paper we formulate multiple testing of simple hypotheses as an infinite-dimensional optimization problem, seeking the most powerful rejection policy which guarantees strong control of the selected measure. In that sense, our approach is a …
The False Discovery Rate (FDR) paradigm aims to attain certain control on Type I errors with relatively high power for multiple hypothesis testing. The Benjamini--Hochberg (BH) procedure is a well-known FDR controlling procedure. Under a random effects model, we show that, in general, unlike the FDR, the positive FDR (pFDR) of the BH procedure cannot be controlled at an arbitrarily low level due to the limited evidence provided by the observations to separate false and true nulls. This results in a criticality phenomenon, which is characterized by a transition of the procedure's power from bei…
Multiple hypotheses testing is a core problem in statistical inference and arises in almost every scientific field. Given a sequence of null hypotheses $\mathcal{H}(n) = (H_1,..., H_n)$, Benjamini and Hochberg \cite{benjamini1995controlling} introduced the false discovery rate (FDR) criterion, which is the expected proportion of false positives among rejected null hypotheses, and proposed a testing procedure that controls FDR below a pre-assigned significance level. They also proposed a different criterion, called mFDR, which does not control a property of the realized set of tests; rather it …
In the multiple testing problem with independent tests, the classical linear step-up procedure controls the false discovery rate (FDR) at level $π_0α$, where $π_0$ is the proportion of true null hypotheses and $α$ is the target FDR level. Adaptive procedures can improve power by incorporating estimates of $π_0$, which typically rely on a tuning parameter. Fixed adaptive procedures set their tuning parameters before seeing the data and can be shown to control the FDR in finite samples. We develop theoretical results for dynamic adaptive procedures whose tuning parameters are determined by the d…
Synthetic-Powered Multiple Testing with FDR Control
Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, USA（统计与数据科学系，沃顿商学院，宾夕法尼亚大学）；Department of Electrical and Computer Engineering, Technion IIT, Israel（电气工程与计算机科学系，技术学院（IIT），以色列）；Department of Computer Science, Technion IIT, Israel（计算机科学系，技术学院（IIT），以色列）
The multiple testing procedure plays an important role in detecting the presence of spatial signals for large-scale imaging data. Typically, the spatial signals are sparse but clustered. This paper provides empirical evidence that for a range of commonly used control levels, the conventional $\operatorname {FDR}$ procedure can lack the ability to detect statistical significance, even if the $p$-values under the true null hypotheses are independent and uniformly distributed; more generally, ignoring the neighboring information of spatially structured data will tend to diminish the detection eff…
In the context of multiple hypotheses testing, the proportion $π_0$ of true null hypotheses in the pool of hypotheses to test often plays a crucial role, although it is generally unknown a priori. A testing procedure using an implicit or explicit estimate of this quantity in order to improve its efficency is called adaptive. In this paper, we focus on the issue of False Discovery Rate (FDR) control and we present new adaptive multiple testing procedures with control of the FDR. First, in the context of assuming independent $p$-values, we present two new procedures and give a unified review of …
An important limitation of standard multiple testing procedures is that the null distribution should be known. Here, we consider a null distribution-free approach for multiple testing in the following semi-supervised setting: the user does not know the null distribution, but has at hand a sample drawn from this null distribution. In practical situations, this null training sample (NTS) can come from previous experiments, from a part of the data under test, from specific simulations, or from a sampling process. In this work, we present theoretical results that handle such a framework, with a fo…
In this article, we propose a generalized weighted version of the well-known Benjamini-Hochberg (BH) procedure. The rigorous weighting scheme used by our method enables it to encode structural information from simultaneous multi-way classification as well as hierarchical partitioning of hypotheses into groups, with provisions to accommodate overlapping groups. The method is proven to control the False Discovery Rate (FDR) when the p-values involved are Positively Regression Dependent on the Subset (PRDS) of null p-values. A data-adaptive version of the method is proposed. Simulations show that…
Replicability is a fundamental quality of scientific discoveries: we are interested in those signals that are detectable in different laboratories, study populations, across time etc. Unlike meta-analysis which accounts for experimental variability but does not guarantee replicability, testing a partial conjunction (PC) null aims specifically to identify the signals that are discovered in multiple studies. In many contemporary applications, e.g., comparing multiple high-throughput genetic experiments, a large number $M$ of PC nulls need to be tested simultaneously, calling for a multiple compa…
The generalized linear models (GLM) have been widely used in practice to model non-Gaussian response variables. When the number of explanatory features is relatively large, scientific researchers are of interest to perform controlled feature selection in order to simplify the downstream analysis. This paper introduces a new framework for feature selection in GLMs that can achieve false discovery rate (FDR) control in two asymptotic regimes. The key step is to construct a mirror statistic to measure the importance of each feature, which is based upon two (asymptotically) independent estimates o…
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…
Negative control is a common technique in scientific investigations and broadly refers to the situation where a null effect (''negative result'') is expected. Motivated by a real proteomic dataset, we will present three promising and closely connected methods of using negative controls to assist simultaneous hypothesis testing. The first method uses negative controls to construct a permutation p-value for every hypothesis under investigation, and we give several sufficient conditions for such p-values to be valid and positive regression dependent on the set (PRDS) of true nulls. The second met…
Controlling the false discovery rate in high-dimensional linear models using model-X knockoffs and $p$-values
Southwestern University of Finance and Economics（西南财经大学）；Academy of Mathematics and Systems Science, Chinese Academy of Sciences（中国科学院数学与系统科学研究院）；Temple University（天普大学）；Tongji University（同济大学）
