Estimating the proportion of true null hypotheses, with application to DNA microarray data

Summary.  We consider the problem of estimating the proportion of true null hypotheses, π ₀, in a multiple-hypothesis set-up. The tests are based on observed p -values. We first review published estimators based on the estimator that was suggested by Schweder and Spjøtvoll. Then we derive new estimators based on nonparametric maximum likelihood estimation of the p -value density, restricting to decreasing and convex decreasing densities. The estimators of π ₀ are all derived under the assumption of independent test statistics. Their performance under dependence is investigated in a simulation study. We find that the estimators are relatively robust with respect to the assumption of independence and work well also for test statistics with moderate dependence.     

Two new estimators for the proportion of true null hypotheses in multiple test

In multiple hypothesis test, an important problem is estimating the proportion of true null hypotheses. Existing methods are mainly based on the p-values of the single tests. In this paper, we propose two new estimations for this proportion. One is a natural extension of the commonly used methods based on p-values and the other is based on a mixed distribution. Simulations show that the first method is comparable with existing methods and performs better under some cases. And the method based on a mixed distribution can get accurate estimators even if the variance of data is large or the difference between the null hypothesis and alternative hypothesis is very small.     

Adaptive procedure for generalized familywise error rate control

This article considers multiple hypotheses testing with the generalized familywise error rate k-FWER control, which is the probability of at least k false rejections. We first assume the p-values corresponding to the true null hypotheses are independent, and propose adaptive generalized Bonferroni procedure with k-FWER control based on the estimation of the number of true null hypotheses. Then, we assume the p-values are dependent, satisfying block dependence, and propose adaptive procedure with k-FWER control. Extensive simulations compare the performance of the adaptive procedures with different estimators.     

Controlling the familywise error rate with plug-in estimator for the proportion of true null hypotheses

Summary.  Estimation of the number or proportion of true null hypotheses in multiple-testing problems has become an interesting area of research. The first important work in this field was performed by Schweder and Spjøtvoll. Among others, they proposed to use plug-in estimates for the proportion of true null hypotheses in multiple-test procedures to improve the power. We investigate the problem of controlling the familywise error rate FWER when such estimators are used as plug-in estimators in single-step or step-down multiple-test procedures. First we investigate the case of independent p -values under the null hypotheses and show that a suitable choice of plug-in estimates leads to control of FWER in single-step procedures. We also investigate the power and study the asymptotic behaviour of the number of false rejections. Although step-down procedures are more difficult to handle we briefly consider a possible solution to this problem. Anyhow, plug-in step-down procedures are not recommended here. For dependent p -values we derive a condition for asymptotic control of FWER and provide some simulations with respect to FWER and power for various models and hypotheses.     

Bonferroni-type Plug-in Procedure Controlling Generalized Familywise Error Rate

Consider the multiple hypotheses testing problem controlling the generalized familywise error rate k-FWER, the probability of at least k false rejections. We propose a plug-in procedure based on the estimation of the number of true null hypotheses. Under the independence assumption of the p-values corresponding to the true null hypotheses, we first introduce the least favorable configuration (LFC) of k-FWER for Bonferroni-type plug-in procedure, then we construct a plug-in k-FWER-controlled procedure based on LFC. For dependent p-values, we establish the asymptotic k-FWER control under some mild conditions. Simulation studies suggest great improvement over generalized Bonferroni test and generalized Holm test.     

Estimating the Proportion of True Null Hypotheses in Nonparametric Exponential Mixture Model with Appication to the Leukemia Gene Expression Data

We revisit the problem of estimating the proportion π of true null hypotheses where a large scale of parallel hypothesis tests are performed independently. While the proportion is a quantity of interest in its own right in applications, the problem has arisen in assessing or controlling an overall false discovery rate. On the basis of a Bayes interpretation of the problem, the marginal distribution of the p-value is modeled in a mixture of the uniform distribution (null) and a non-uniform distribution (alternative), so that the parameter π of interest is characterized as the mixing proportion of the uniform component on the mixture. In this article, a nonparametric exponential mixture model is proposed to fit the p-values. As an alternative approach to the convex decreasing mixture model, the exponential mixture model has the advantages of identifiability, flexibility, and regularity. A computation algorithm is developed. The new approach is applied to a leukemia gene expression data set where multiple significance tests over 3,051 genes are performed. The new estimate for π with the leukemia gene expression data appears to be about 10% lower than the other three estimates that are known to be conservative. Simulation results also show that the new estimate is usually lower and has smaller bias than the other three estimates.     

Expected Power for the False Discovery Rate with Independence

The Benjamini–Hochberg procedure is widely used in multiple comparisons. Previous power results for this procedure have been based on simulations. This article produces theoretical expressions for expected power. To derive them, we make assumptions about the number of hypotheses being tested, which null hypotheses are true, which are false, and the distributions of the test statistics under each null and alternative. We use these assumptions to derive bounds for multiple dimensional rejection regions. With these bounds and a permanent based representation of the joint density function of the largest p-values, we use the law of total probability to derive the distribution of the total number of rejections. We derive the joint distribution of the total number of rejections and the number of rejections when the null hypothesis is true. We give an analytic expression for the expected power for a false discovery rate procedure that assumes the hypotheses are independent.     

On tests of symmetry,marginal homogeneity and quasi-symmetry in two-way contingency tables based on minimum φ-divergence estimator with constraints

The restricted minimum φ-divergence estimator, [Pardo, J.A., Pardo, L. and Zografos, K., 2002, Minimum φ-divergence estimators with constraints in multinomial populations. Journal of Statistical Planning and Inference, 104, 221–237], is employed to obtain estimates of the cell frequencies of an I×I contingency table under hypotheses of symmetry, marginal homogeneity or quasi-symmetry. The associated φ-divergence statistics are distributed asymptotically as chi-squared distributions under the null hypothesis. The new estimators and test statistics contain, as particular cases, the classical estimators and test statistics previously presented in the literature for the cited problems. A simulation study is presented, for the symmetry problem, to choose the best function φ₂ for estimation and the best function φ₁ for testing.     

Comparisons of estimators of the number of true null hypotheses and adaptive FDR procedures in multiplicity testing

Many exploratory studies such as microarray experiments require the simultaneous comparison of hundreds or thousands of genes. It is common to see that most genes in many microarray experiments are not expected to be differentially expressed. Under such a setting, a procedure that is designed to control the false discovery rate (FDR) is aimed at identifying as many potential differentially expressed genes as possible. The usual FDR controlling procedure is constructed based on the number of hypotheses. However, it can become very conservative when some of the alternative hypotheses are expected to be true. The power of a controlling procedure can be improved if the number of true null hypotheses (m ₀) instead of the number of hypotheses is incorporated in the procedure [Y. Benjamini and Y. Hochberg, On the adaptive control of the false discovery rate in multiple testing with independent statistics, J. Edu. Behav. Statist. 25(2000), pp. 60–83]. Nevertheless, m ₀ is unknown, and has to be estimated. The objective of this article is to evaluate some existing estimators of m ₀ and discuss the feasibility of these estimators in incorporating into FDR controlling procedures under various experimental settings. The results of simulations can help the investigator to choose an appropriate procedure to meet the requirement of the study.     

A note on estimating the false discovery rate under mixture model

In this note, we focus on estimating the false discovery rate (FDR) of a multiple testing method with a common, non-random rejection threshold under a mixture model. We develop a new class of estimates of the FDR and prove that it is less conservatively biased than what is traditionally used. Numerical evidence is presented to show that the mean squared error (MSE) is also often smaller for the present class of estimates, especially in small-scale multiple testings. A similar class of estimates of the positive false discovery rate (pFDR) less conservatively biased than what is usually used is then proposed. When modified using our estimate of the pFDR and applied to a gene-expression data, Storey's q-value method identifies a few more significant genes than his original q-value method at certain thresholds. The BH like method developed by thresholding our estimate of the FDR is shown to control the FDR in situations where the p  -values have the same dependence structure as required by the BH method and, for lack of information about the proportion _π0${\pi }_0$ of true null hypotheses, it is reasonable to assume that _π0${\pi }_0$ is uniformly distributed over (0,1).     

On Efficient Estimators of the Proportion of True Null Hypotheses in a Multiple Testing Setup

We consider the problem of estimating the proportion θ of true null hypotheses in a multiple testing context. The setup is classically modelled through a semiparametric mixture with two components: a uniform distribution on interval [0,1] with prior probability θ and a non‐parametric density f . We discuss asymptotic efficiency results and establish that two different cases occur whether f vanishes on a non‐empty interval or not. In the first case, we exhibit estimators converging at a parametric rate, compute the optimal asymptotic variance and conjecture that no estimator is asymptotically efficient (i.e. attains the optimal asymptotic variance). In the second case, we prove that the quadratic risk of any estimator does not converge at a parametric rate. We illustrate those results on simulated data.     

On the estimation of the proportion of positives in a sequence of screening experiments

A metaanalytic estimator of the proportion of positives in a sequence of screening experiments is proposed. The distribution-free estimator is based on the empirical distribution of P-values from individual experiments, which is uniform under the global null hypotheses of no positives in the sequence of experiments performed. Under certain regularity conditions, the proportion of positives corresponds to the derivative of this distribution under the alternative hypothesis of the existence of some positives. The statistical properties of the estimator are established, including its bias, variance, and rate of convergence to normality. Optimal estimators with minimum mean squared error are also developed under specific alternative hypotheses. The application of the proposed methods is illustrated using data from a sequence of screening experiments with chemicals to determine their carcinogenic potential.     

Generalized Holm’s procedure for multiple hypotheses testing problems

A generalized Holm’s procedure is proposed which can reject several null hypotheses at each step sequentially and also strongly controls the family-wise error rate regardless of the dependence of individual test statistics. The new procedure is more powerful than Holm’s procedure if the number of rejections m and m > 0 is prespecified before the test.     

The Likelihood Ratio Test for the Presence of Immunes in a Censored Sample

Models for populations with immune or cured individuals but with others subject to failure are important in many areas, such as medical statistics and criminology. One method of analysis of data from such populations involves estimating an immune proportion 1 ? p and the parameter(s) of a failure distribution for those individuals subject to failure. We use the exponential distribution with parameter λ for the latter and a mixture of this distribution with a mass 1 ? p at infinity to model the complete data. This paper develops the asymptotic theory of a test for whether an immune proportion is indeed present in the population, i.e., for H ₀:p = 1. This involves testing at the boundary of the parameter space for p. We use a likelihood ratio test for H ₀. and prove that minus twice the logarithm of the likelihood ratio has as an asymptotic distribution, not the chi-square distribution, but a 50–50 mixture of a chi-square distribution with 1 degree of freedom, and a point mass at 0. The result is proved under an independent censoring assumption with very mild restrictions.     

Bayesian inference for the proportion of true null hypotheses using minimum Hellinger distance

It is important that the proportion of true null hypotheses be estimated accurately in a multiple hypothesis context. Current estimation methods, however, are not suitable for high-dimensional data such as microarray data. First, they do not consider the (strong) dependence between hypotheses (or genes), thereby resulting in inaccurate estimation. Second, the unknown distribution of false null hypotheses cannot be estimated properly by these methods. Third, the estimation is affected strongly by outliers. In this paper, we find out the optimal procedure for estimating the proportion of true null hypotheses under a (strong) dependence based on the Dirichlet process prior. In addition, by using the minimum Hellinger distance, the estimation should be robust to any model misspecification as well as to any outliers while maintaining efficiency. The results are confirmed by a simulation study, and the newly developed methodology is illustrated by a real microarray data.     

Role of weights in improving the efficiency of Kim and Warde's mixed randomized response model

ABSTARCT

In this paper we have suggested a class of unbiased estimators of π_S, the proportion of respondents possessing a sensitive attribute A using mixed randomized response model. The variance of the proposed class of estimators has been obtained. In addition to Kim and Warde's (2005) estimator, several other acceptable estimators of π_S have been identified from the proposed class for suitable weights. It has been shown that the newly identified estimators are more efficient than the Kim and Warde's (2005) estimator. Numerical illustrations and graphs are also given in support of the present study.     

Estimating the number of true null hypotheses in multiple hypothesis testing

The overall Type I error computed based on the traditional means may be inflated if many hypotheses are compared simultaneously. The family-wise error rate (FWER) and false discovery rate (FDR) are some of commonly used error rates to measure Type I error under the multiple hypothesis setting. Many controlling FWER and FDR procedures have been proposed and have the ability to control the desired FWER/FDR under certain scenarios. Nevertheless, these controlling procedures become too conservative when only some hypotheses are from the null. Benjamini and Hochberg (J. Educ. Behav. Stat. 25:60–83, 2000) proposed an adaptive FDR-controlling procedure that adapts the information of the number of true null hypotheses (m ₀) to overcome this problem. Since m ₀ is unknown, estimators of m ₀ are needed. Benjamini and Hochberg (J. Educ. Behav. Stat. 25:60–83, 2000) suggested a graphical approach to construct an estimator of m ₀, which is shown to overestimate m ₀ (see Hwang in J. Stat. Comput. Simul. 81:207–220, 2011). Following a similar construction, this paper proposes new estimators of m ₀. Monte Carlo simulations are used to evaluate accuracy and precision of new estimators and the feasibility of these new adaptive procedures is evaluated under various simulation settings.     

Estimating the parameter of selected uniform population under the squared log error loss function

Let π₁, …, π_k be k (? 2) independent populations, where π_i denotes the uniform distribution over the interval (0, θ_i) and θ_i > 0 (i = 1, …, k) is an unknown scale parameter. The population associated with the largest scale parameter is called the best population. For selecting the best population, We use a selection rule based on the natural estimators of θ_i, i = 1, …, k, for the case of unequal sample sizes. Consider the problem of estimating the scale parameter θ_L of the selected uniform population when sample sizes are unequal and the loss is measured by the squared log error (SLE) loss function. We derive the uniformly minimum risk unbiased (UMRU) estimator of θ_L under the SLE loss function and two natural estimators of θ_L are also studied. For k = 2, we derive a sufficient condition for inadmissibility of an estimator of θ_L. Using these condition, we conclude that the UMRU estimator and natural estimator are inadmissible. Finally, the risk functions of various competing estimators of θ_L are compared through simulation.     

Editorial Collaborators

Abstract

The present note explores sources of misplaced criticisms of P-values, such as conflicting definitions of “significance levels” and “P-values” in authoritative sources, and the consequent misinterpretation of P-values as error probabilities. It then discusses several properties of P-values that have been presented as fatal flaws: That P-values exhibit extreme variation across samples (and thus are “unreliable”), confound effect size with sample size, are sensitive to sample size, and depend on investigator sampling intentions. These properties are often criticized from a likelihood or Bayesian framework, yet they are exactly the properties P-values should exhibit when they are constructed and interpreted correctly within their originating framework. Other common criticisms are that P-values force users to focus on irrelevant hypotheses and overstate evidence against those hypotheses. These problems are not however properties of P-values but are faults of researchers who focus on null hypotheses and overstate evidence based on misperceptions that p?=?0.05 represents enough evidence to reject hypotheses. Those problems are easily seen without use of Bayesian concepts by translating the observed P-value p into the Shannon information (S-value or surprisal) –log₂(p).     

A combined p-value test for multiple hypothesis testing

Tests that combine p-values, such as Fisher's product test, are popular to test the global null hypothesis H₀ that each of n component null hypotheses, H₁,…,H_n, is true versus the alternative that at least one of H₁,…,H_n is false, since they are more powerful than classical multiple tests such as the Bonferroni test and the Simes tests. Recent modifications of Fisher's product test, popular in the analysis of large scale genetic studies include the truncated product method (TPM) of Zaykin et al. (2002), the rank truncated product (RTP) test of Dudbridge and Koeleman (2003) and more recently, a permutation based test—the adaptive rank truncated product (ARTP) method of Yu et al. (2009). The TPM and RTP methods require users' specification of a truncation point. The ARTP method improves the performance of the RTP method by optimizing selection of the truncation point over a set of pre-specified candidate points. In this paper we extend the ARTP by proposing to use all the possible truncation points {1,…,n} as the candidate truncation points. Furthermore, we derive the theoretical probability distribution of the test statistic under the global null hypothesis H₀. Simulations are conducted to compare the performance of the proposed test with the Bonferroni test, the Simes test, the RTP test, and Fisher's product test. The simulation results show that the proposed test has higher power than the Bonferroni test and the Simes test, as well as the RTP method. It is also significantly more powerful than Fisher's product test when the number of truly false hypotheses is small relative to the total number of hypotheses, and has comparable power to Fisher's product test otherwise.