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The poolr package provides an implementation of a variety of methods for pooling (i.e., combining) p values, including Fisher's method, Stouffer's method, the inverse chisquare method, the binomial test, the Bonferroni method, and Tippett's method. More importantly, the methods can be adjusted to account for dependence among the tests from which the p values have been derived assuming multivariate normality among the test statistics. All methods can be adjusted based on an estimate of the effective number of tests or by using an empirically-derived null distribution based on pseudo replicates that mimics a proper permutation test. For the Fisher, Stouffer, and inverse chi-square methods, the test statistics can also be directly generalized to account for dependence, leading to Brown's method, Strube's method, and the generalized inverse chi-square method. In this paper, we describe the various methods, discuss their implementation in the package, illustrate their use based on several examples, and compare the poolr package with several other packages that can be used to combine p values.

Controlling the type I error rate while retaining sufficient power is a major concern in genome-wide association studies, which nowadays often examine more than a million single-nucleotide polymorphisms (SNPs) simultaneously. Methods such as the Bonferroni correction can lead to a considerable decrease in power due to the large number of tests conducted. Shifting the focus to higher functional structures (e.g., genes) can reduce the loss of power. This can be accomplished via the combination of p -values of SNPs that belong to the same structural unit to test their joint null hypothesis. However, standard methods for this purpose (e.g., Fisher's method) do not account for the dependence among the tests due to linkage disequilibrium (LD). In this paper, we review various adjustments to methods for combining p -values that take LD information explicitly into consideration and evaluate their performance in a simulation study based on data from the HapMap project. The results illustrate the importance of incorporating LD information into the methods for controlling the type I error rate at the desired level. Furthermore, some methods are more successful in controlling the type I error rate than others. Among them, Brown's method was the most robust technique with respect to the characteristics of the genes and outperformed the Bonferroni method in terms of power in many scenarios. Examining the genetic factors of a phenotype of interest at the gene-rather than SNP-level can provide researchers benefits in terms of the power of the study. While doing so, one should be careful to account for LD in SNPs belonging to the same gene, for which Brown's method seems the most robust technique. [ABSTRACT FROM AUTHOR]

Controlling the type I error rate while retaining sufficient power is a major concern in genome-wide association studies, which nowadays often examine more than a million single-nucleotide polymorphisms (SNPs) simultaneously. Methods such as the Bonferroni correction can lead to a considerable decrease in power due to the large number of tests conducted. Shifting the focus to higher functional structures (e.g., genes) can reduce the loss of power. This can be accomplished via the combination of p-values of SNPs that belong to the same structural unit to test their joint null hypothesis. However, standard methods for this purpose (e.g., Fisher’s method) do not account for the dependence among the tests due to linkage disequilibrium (LD). In this paper, we review various adjustments to methods for combining p-values that take LD information explicitly into consideration and evaluate their performance in a simulation study based on data from the HapMap project. The results illustrate the importance of incorporating LD information into the methods for controlling the type I error rate at the desired level. Furthermore, some methods are more successful in controlling the type I error rate than others. Among them, Brown’s method was the most robust technique with respect to the characteristics of the genes and outperformed the Bonferroni method in terms of power in many scenarios. Examining the genetic factors of a phenotype of interest at the gene-rather than SNP-level can provide researchers benefits in terms of the power of the study. While doing so, one should be careful to account for LD in SNPs belonging to the same gene, for which Brown’s method seems the most robust technique.

Summary: Statistical methodology plays a crucial role in drug regulation. Decisions by the US Food and Drug Administration or European Medicines Agency are typically made based on multiple primary studies testing the same medical product, where the two‐trials rule is the standard requirement, despite shortcomings. A new approach is proposed for this task based on the harmonic mean of the squared study‐specific test statistics. Appropriate scaling ensures that, for any number of independent studies, the null distribution is a χ2‐distribution with 1 degree of freedom. This gives rise to a new method for combining one‐sided p‐values and calculating confidence intervals for the overall treatment effect. Further properties are discussed and a comparison with the two‐trials rule is made, as well as with alternative research synthesis methods. An attractive feature of the new approach is that a claim of success requires each study to be convincing on its own to a certain degree depending on the overall level of significance and the number of studies. The new approach is motivated by and applied to data from five clinical trials investigating the effect of carvedilol for the treatment of patients with moderate to severe heart failure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article summarizes and discusses the existing p-value pooling approaches and compares their performances in the context of panel unit root tests. When the data are free of contemporaneous correlation, most tests achieve very high power. However, in the presence of contemporaneous correlation, most tests suffer from moderate to severe size distortions. When the panel contains both stationary and nonstationary series, the power of tests increases as the cross-sectional units grows. Among all the tests under study, the mean-of-Z test yields the highest power for the benchmark model, while the Fisher test is most robust for complicated model structures. [ABSTRACT FROM AUTHOR]

Despite the great success of genome-wide association studies (GWAS) in identification of the common genetic variants associated with complex diseases, the current GWAS have focused on single-SNP analysis. However, single-SNP analysis often identifies only a few of the most significant SNPs that account for a small proportion of the genetic variants and offers only a limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis of 13 published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single-SNP analysis, but also detected new genes in which each single SNP conferred a small disease risk; however, their joint actions were implicated in the development of diseases. The results also showed that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases, which were confirmed by a gene-set-rich analysis using gene expression data. [ABSTRACT FROM AUTHOR]

Prediction of biological functions of genes is an important issue in basic biology research and has applications in drug discoveries and gene therapies. Previous studies have shown either gene expression data or protein-protein interaction data alone can be used for predicting gene functions. In particular, clustering gene expression profiles has been widely used for gene function prediction. In this paper, we first propose a new method for gene function prediction using protein-protein interaction data, which will facilitate combining prediction results based on clustering gene expression profiles. We then propose a new method to combine the prediction results based on either source of data by weighting on the evidence provided by each. Using protein-protein interaction data downloaded from the GRID database, published gene expression profiles from 300 microarray experiments for the yeast S. cerevisiae, we show that this new combined analysis provides improved predictive performance over that of using either data source alone in a cross-validated analysis of the MIPS gene annotations. Finally, we propose a logistic regression method that is flexible enough to combine information from any number of data sources while maintaining computational feasibility. [ABSTRACT FROM AUTHOR]