A method for combining p-values in meta-analysis by gamma distributions

Combining p-values from statistical tests across different studies is the most commonly used approach in meta-analysis for evolutionary biology. The most commonly used p-value combination methods mainly incorporate the z-transform tests (e.g., the un-weighted z-test and the weighted z-test) and the gamma-transform tests (e.g., the CZ method [Z. Chen, W. Yang, Q. Liu, J.Y. Yang, J. Li, and M.Q. Yang, A new statistical approach to combining p-values using gamma distribution and its application to genomewide association study, Bioinformatics 15 (2014), p. S3]). However, among these existing p-value combination methods, no method is uniformly most powerful in all situations [Chen et al. 2014]. In this paper, we propose a meta-analysis method based on the gamma distribution, MAGD, by pooling the p-values from independent studies. The newly proposed test, MAGD, allows for flexible accommodating of the different levels of heterogeneity of effect sizes across individual studies. The MAGD simultaneously retains all the characters of the z-transform tests and the gamma-transform tests. We also propose an easy-to-implement resampling approach for estimating the empirical p-values of MAGD for the finite sample size. Simulation studies and two data applications show that the proposed method MAGD is essentially as powerful as the z-transform tests (the gamma-transform tests) under the circumstance with the homogeneous (heterogeneous) effect sizes across studies.     

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.     

Content Audit for p-value Principles in Introductory Statistics

ABSTRACT

Longstanding concerns with the role and interpretation of p-values in statistical practice prompted the American Statistical Association (ASA) to make a statement on p-values. The ASA statement spurred a flurry of responses and discussions by statisticians, with many wondering about the steps necessary to expand the adoption of these principles. Introductory statistics classrooms are key locations to introduce and emphasize the nuance related to p-values; in part because they engrain appropriate analysis choices at the earliest stages of statistics education, and also because they reach the broadest group of students. We propose a framework for statistics departments to conduct a content audit for p-value principles in their introductory curriculum. We then discuss the process and results from applying this course audit framework within our own statistics department. We also recommend meeting with client departments as a complement to the course audit. Discussions about analyses and practices common to particular fields can help to evaluate if our service courses are meeting the needs of client departments and to identify what is needed in our introductory courses to combat the misunderstanding and future misuse of p-values.     

Inferences on a linear combination of K multivariate normal mean vectors

In this paper, the hypothesis testing and confidence region construction for a linear combination of mean vectors for K independent multivariate normal populations are considered. A new generalized pivotal quantity and a new generalized test variable are derived based on the concepts of generalized p-values and generalized confidence regions. When only two populations are considered, our results are equivalent to those proposed by Gamage et al. [Generalized p-values and confidence regions for the multivariate Behrens–Fisher problem and MANOVA, J. Multivariate Aanal. 88 (2004), pp. 117–189] in the bivariate case, which is also known as the bivariate Behrens–Fisher problem. However, in some higher dimension cases, these two results are quite different. The generalized confidence region is illustrated with two numerical examples and the merits of the proposed method are numerically compared with those of the existing methods with respect to their expected areas, coverage probabilities under different scenarios.     

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.     

Accurate unconditional p-values for a two-arm study with binary endpoints

Unconditional exact tests are increasingly used in practice for categorical data to increase the power of a study and to make the data analysis approach being consistent with the study design. In a two-arm study with a binary endpoint, p-value based on the exact unconditional Barnard test is computed by maximizing the tail probability over a nuisance parameter with a range from 0 to 1. The traditional grid search method is able to find an approximate maximum with a partition of the parameter space, but it is not accurate and this approach becomes computationally intensive for a study beyond two groups. We propose using a polynomial method to rewrite the tail probability as a polynomial. The solutions from the derivative of the polynomial contain the solution for the global maximum of the tail probability. We use an example from a double-blind randomized Phase II cancer clinical trial to illustrate the application of the proposed polynomial method to achieve an accurate p-value. We also compare the performance of the proposed method and the traditional grid search method under various conditions. We would recommend using this new polynomial method in computing accurate exact unconditional p-values.     

Empirical null distribution-based modeling of multi-class differential gene expression detection

In this paper, we study the multi-class differential gene expression detection for microarray data. We propose a likelihood-based approach to estimating an empirical null distribution to incorporate gene interactions and provide a more accurate false-positive control than the commonly used permutation or theoretical null distribution-based approach. We propose to rank important genes by p-values or local false discovery rate based on the estimated empirical null distribution. Through simulations and application to lung transplant microarray data, we illustrate the competitive performance of the proposed method.     

Abandon Statistical Significance

ABSTRACT

We discuss problems the null hypothesis significance testing (NHST) paradigm poses for replication and more broadly in the biomedical and social sciences as well as how these problems remain unresolved by proposals involving modified p-value thresholds, confidence intervals, and Bayes factors. We then discuss our own proposal, which is to abandon statistical significance. We recommend dropping the NHST paradigm—and the p-value thresholds intrinsic to it—as the default statistical paradigm for research, publication, and discovery in the biomedical and social sciences. Specifically, we propose that the p-value be demoted from its threshold screening role and instead, treated continuously, be considered along with currently subordinate factors (e.g., related prior evidence, plausibility of mechanism, study design and data quality, real world costs and benefits, novelty of finding, and other factors that vary by research domain) as just one among many pieces of evidence. We have no desire to “ban” p-values or other purely statistical measures. Rather, we believe that such measures should not be thresholded and that, thresholded or not, they should not take priority over the currently subordinate factors. We also argue that it seldom makes sense to calibrate evidence as a function of p-values or other purely statistical measures. We offer recommendations for how our proposal can be implemented in the scientific publication process as well as in statistical decision making more broadly.     

Hadamard matrix methods in identifying differentially expressed genes from microarray experiments

Identifying differentially expressed genes is a basic objective in microarray experiments. Many statistical methods for detecting differentially expressed genes in multiple-slide experiments have been proposed. However, sometimes with limited experimental resources, only a single cDNA array or two Oligonuleotide arrays could be made or only insufficient replicated arrays could be conducted. Many current statistical models cannot be used because of the non-availability of replicated data. Simply using fold changes is also unreliable and inefficient [Chen et al. 1997. Ratio-based decisions and the quantitative analysis of cDNA microarray images. J. Biomed. Optics 2, 364–374; Newton et al. 2001. On differential variability of expression ratios: improving statistical inference about gene expression changes from microarray data. J. Comput. Biol. 8, 37–52; Pan et al. 2002. How many replicates of arrays are required to detect gene expression changes in microarray experiments? a mixture model approach. Genome Biol. 3, research0022.1-0022.10]. We propose a new method. If the log-transformed ratios for the expressed genes as well as unexpressed genes have equal variance, we use a Hadamard matrix to construct a t-test from a single array data. Basically, we test whether each doubtful gene has significantly differential expression compared to the unexpressed genes. We form some new random variables corresponding to the rows of a Hadamard matrix using the algebraic sum of gene expressions. A one-sample t-test is constructed and the p-value is calculated for each doubtful gene based on these random variables. By using any method for multiple testing, adjusted p-values could be obtained from original p-values and significance of doubtful genes can be determined. When the variance of expressed genes differs from the variance of unexpressed genes, we construct a z-statistic based on the result from application of Hadamard matrix and find the confidence interval to retain the null hypothesis. Using the interval, we determine differentially expressed genes. This method is also useful for multiple microarrays, especially when sufficient replicated data are not available for a traditional t-test. We apply our methodology to ApoAI data. The results appear to be promising. They not only confirm the early known differentially expressed genes, but also indicate more genes to be differentially expressed.     

Hierarchical Bayesian meta-analysis models for cross-platform microarray studies

The development of new technologies to measure gene expression has been calling for statistical methods to integrate findings across multiple-platform studies. A common goal of microarray analysis is to identify genes with differential expression between two conditions, such as treatment versus control. Here, we introduce a hierarchical Bayesian meta-analysis model to pool gene expression studies from different microarray platforms: spotted DNA arrays and short oligonucleotide arrays. The studies have different array design layouts, each with multiple sources of data replication, including repeated experiments, slides and probes. Our model produces the gene-specific posterior probability of differential expression, which is the basis for inference. In simulations combining two and five independent studies, our meta-analysis model outperformed separate analyses for three commonly used comparison measures; it also showed improved receiver operating characteristic curves. When combining spotted DNA and CombiMatrix short oligonucleotide array studies of Geobacter sulfurreducens, our meta-analysis model discovered more genes for fixed thresholds of posterior probability of differential expression and Bayesian false discovery than individual study analyses. We also examine an alternative model and compare models using the deviance information criterion.     

An improved two-stage procedure to compare hazard curves

Qiu and Sheng has proposed a powerful and robust two-stage procedure to compare two hazard rate functions. In this paper we improve their method by using the Fisher test to combine the asymptotically independent p-values obtained from the two stages of their procedure. In addition, we extend the procedure to situations with multiple hazard rate functions. Our comprehensive simulation study shows that the proposed method has a good performance in terms of controlling the type I error rate and of detecting power. Three real data applications are considered for illustrating the use of the new method.     

Revisiting retesting in the estimation of proportions by group testing

In the estimation of a proportion p by group testing (pooled testing), retesting of units within positive groups has received little attention due to the minimal gain in precision compared to testing additional units. If acquisition of additional units is impractical or too expensive, and testing is not destructive, we show that retesting can be a useful option. We propose the retesting of a random grouping of units from positive groups, and compare it with nested halving procedures suggested by others. We develop an estimator of p for our proposed method, and examine its variance properties. Using simulation we compare retesting methods across a range of group testing situations, and show that for most realistic scenarios, our method is more efficient.     

Three Recommendations for Improving the Use of p-Values

ABSTRACT

Researchers commonly use p-values to answer the question: How strongly does the evidence favor the alternative hypothesis relative to the null hypothesis? p-Values themselves do not directly answer this question and are often misinterpreted in ways that lead to overstating the evidence against the null hypothesis. Even in the “post p?<?0.05 era,” however, it is quite possible that p-values will continue to be widely reported and used to assess the strength of evidence (if for no other reason than the widespread availability and use of statistical software that routinely produces p-values and thereby implicitly advocates for their use). If so, the potential for misinterpretation will persist. In this article, we recommend three practices that would help researchers more accurately interpret p-values. Each of the three recommended practices involves interpreting p-values in light of their corresponding “Bayes factor bound,” which is the largest odds in favor of the alternative hypothesis relative to the null hypothesis that is consistent with the observed data. The Bayes factor bound generally indicates that a given p-value provides weaker evidence against the null hypothesis than typically assumed. We therefore believe that our recommendations can guard against some of the most harmful p-value misinterpretations. In research communities that are deeply attached to reliance on “p?<?0.05,” our recommendations will serve as initial steps away from this attachment. We emphasize that our recommendations are intended merely as initial, temporary steps and that many further steps will need to be taken to reach the ultimate destination: a holistic interpretation of statistical evidence that fully conforms to the principles laid out in the ASA statement on statistical significance and p-values.     

Asymmetry models for square contingency tables: exact tests via algebraic statistics

Square contingency tables with the same row and column classification occur frequently in a wide range of statistical applications, e.g. whenever the members of a matched pair are classified on the same scale, which is usually ordinal. Such tables are analysed by choosing an appropriate loglinear model. We focus on the models of symmetry, triangular, diagonal and ordinal quasi symmetry. The fit of a specific model is tested by the chi-squared test or the likelihood-ratio test, where p-values are calculated from the asymptotic chi-square distribution of the test statistic or, if this seems unjustified, from the exact conditional distribution. Since the calculation of exact p-values is often not feasible, we propose alternatives based on algebraic statistics combined with MCMC methods.     

Testing Conditional Mean Independence Under Symmetry

Conditional mean independence (CMI) is one of the most widely used assumptions in the treatment effect literature to achieve model identification. We propose a Kolmogorov–Smirnov-type statistic to test CMI under a specific symmetry condition. We also propose a bootstrap procedure to obtain the p-values and critical values that are required to carry out the test. Results from a simulation study suggest that our test can work very well even in small to moderately sized samples. As an empirical illustration, we apply our test to a dataset that has been used in the literature to estimate the return on college education in China, to check whether the assumption of CMI is supported by the dataset and show the plausibility of the extra symmetry condition that is necessary for this new test.     

Estimating the proportion of true null hypotheses using the pattern of observed p-values

Estimating the proportion of true null hypotheses, π₀, has attracted much attention in the recent statistical literature. Besides its apparent relevance for a set of specific scientific hypotheses, an accurate estimate of this parameter is key for many multiple testing procedures. Most existing methods for estimating π₀ in the literature are motivated from the independence assumption of test statistics, which is often not true in reality. Simulations indicate that most existing estimators in the presence of the dependence among test statistics can be poor, mainly due to the increase of variation in these estimators. In this paper, we propose several data-driven methods for estimating π₀ by incorporating the distribution pattern of the observed p-values as a practical approach to address potential dependence among test statistics. Specifically, we use a linear fit to give a data-driven estimate for the proportion of true-null p-values in (λ, 1] over the whole range [0, 1] instead of using the expected proportion at 1?λ. We find that the proposed estimators may substantially decrease the variance of the estimated true null proportion and thus improve the overall performance.     

A modified combination test for the analysis of a clinical trial when a protocol amendment changed the inclusion criteria

Protocol amendments are often necessary in clinical trials. They can change the entry criteria and, therefore, the population. Simply analysing the pooled data is not acceptable. Instead, each phase should be analysed separately and a combination test such as Fisher's test should be applied to the resulting p-values. In this situation, an asymmetric decision rule is not appropriate. Therefore, we propose a modification of Bauer and Köhne's test. We compare this new test with the tests of Liptak, Fisher, Bauer/Köhne and Edgington. In case of differences in variance only or only small differences in mean, Liptak's Z-score approach is the best, and the new test keeps up with the rest and is in most cases slightly superior. In other situations, the new test and the Z-score approach are not preferable. But no big differences in populations are usually to be expected due to amendments. Then, the new method is a recommendable alternative.     

On two approximations to the F-distribution: Application to testing for intraclass correlation in family studies

Two approximations to the F-distribution are evaluated in the context of testing for intraclass correlation in the analysis of family data. The evaluation is based on a computation of empirical significance levels and a comparison between p-values associated with these approximations and the corresponding exact p-values. It is found that the approximate methods may give very unsatisfactory results, and exact methods are therefore recommended for general use.     

Testing Homogeneity of Inverse Gaussian Scale Parameters Based on Generalized Likelihood Ratio

This article presents a new procedure for testing homogeneity of scale parameters from k independent inverse Gaussian populations. Based on the idea of generalized likelihood ratio method, a new generalized p-value is derived. Some simulation results are presented to compare the performance of the proposed method and existing methods. Numerical results show that the proposed test has good size and power performance.     

Saddlepoint <Emphasis Type="Italic">p</Emphasis>-values and confidence intervals for a class of two sample permutation tests for current status and panel count data

The current status and panel count data frequently arise from cancer and tumorigenicity studies when events currently occur. A common and widely used class of two sample tests, for current status and panel count data, is the permutation class. We manipulate the double saddlepoint method to calculate the exact mid-p-values of the underlying permutation distributions of this class of tests. Permutation simulations are replaced by analytical saddlepoint computations which provide extremely accurate mid-p-values that are exact for most practical purposes and almost always more accurate than normal approximations. The method is illustrated using two real tumorigenicity panel count data. To compare the saddlepoint approximation with the normal asymptotic approximation, a simulation study is conducted. The speed and accuracy of the saddlepoint method facilitate the calculation of the confidence interval for the treatment effect. The inversion of the mid-p-values to calculate the confidence interval for the mean rate of development of the recurrent event is discussed.