Null Distribution Of Test Statistic Research Articles

FPLS-DC: functional partial least squares through distance covariance for imaging genetics.

Imaging genetics integrates imaging and genetic techniques to examine how genetic variations influence the function and structure of organs like the brain or heart, providing insights into their impact on behavior and disease phenotypes. The use of organ-wide imaging endophenotypes has increasingly been used to identify potential genes associated with complex disorders. However, analyzing organ-wide imaging data alongside genetic data presents two significant challenges: high dimensionality and complex relationships. To address these challenges, we propose a novel, nonlinear inference framework designed to partially mitigate these issues. We propose a functional partial least squares through distance covariance (FPLS-DC) framework for efficient genome wide analyses of imaging phenotypes. It consists of two components. The first component utilizes the FPLS-derived base functions to reduce image dimensionality while screening genetic markers. The second component maximizes the distance correlation between genetic markers and projected imaging data, which is a linear combination of the FPLS-basis functions, using simulated annealing algorithm. In addition, we proposed an iterative FPLS-DC method based on FPLS-DC framework, which effectively overcomes the influence of inter-gene correlation on inference analysis. We efficiently approximate the null distribution of test statistics using a gamma approximation. Compared to existing methods, FPLS-DC offers computational and statistical efficiency for handling large-scale imaging genetics. In real-world applications, our method successfully detected genetic variants associated with the hippocampus, demonstrating its value as a statistical toolbox for imaging genetic studies. The FPLS-DC method we propose opens up new research avenues and offers valuable insights for analyzing functional and high-dimensional data. In addition, it serves as a useful tool for scientific analysis in practical applications within the field of imaging genetics research. The R package FPLS-DC is available in Github: https://github.com/BIG-S2/FPLSDC.

Limitation of permutation-based differential correlation analysis.

The comparison of biological systems, through the analysis of molecular changes under different conditions, has played a crucial role in the progress of modern biological science. Specifically, differential correlation analysis (DCA) has been employed to determine whether relationships between genomic features differ across conditions or outcomes. Because ascertaining the null distribution of test statistics to capture variations in correlation is challenging, several DCA methods utilize permutation which can loosen parametric (e.g., normality) assumptions. However, permutation is often problematic for DCA due to violating the assumption that samples are exchangeable under the null. Here, we examine the limitations of permutation-based DCA and investigate instances where the permutation-based DCA exhibits poor performance. Experimental results show that the permutation-based DCA often fails to control the type I error under the null hypothesis of equal correlation structures.

Statistical inference of heterogeneous treatment effect based on single-index model

The heterogeneous treatment effect (HTE) is estimated by using the semiparametric regression method. Firstly, a flexible semiparametric single-index model is considered by assuming the nonparametric link function and the interaction between treatment and covariates, and the index parameter vector and the unknown link function are estimated by using the rMAVE method. Then a HTE estimator can be obtained based on the estimators of index parameter vector and the link function. The consistency and asymptotic normality of the HTE estimator are established under some regularity conditions. Secondly, a hypothesis test is developed for the existence of HTE, and the bootstrap procedure is utilized to evaluate the null distribution of test statistic. Finally, simulation studies and a real data analysis are conducted to assess the performance of our proposed method.

Random rotation for identifying differentially expressed genes with linear models following batch effect correction.

Data generated from high-throughput technologies such as sequencing, microarray and bead-chip technologies are unavoidably affected by batch effects (BEs). Large effort has been put into developing methods for correcting these effects. Often, BE correction and hypothesis testing cannot be done with one single model, but are done successively with separate models in data analysis pipelines. This potentially leads to biased P-values or false discovery rates due to the influence of BE correction on the data. We present a novel approach for estimating null distributions of test statistics in data analysis pipelines where BE correction is followed by linear model analysis. The approach is based on generating simulated datasets by random rotation and thereby retains the dependence structure of genes adequately. This allows estimating null distributions of dependent test statistics, and thus the calculation of resampling-based P-values and false-discovery rates following BE correction while maintaining the alpha level. The described methods are implemented as randRotation package on Bioconductor: https://bioconductor.org/packages/randRotation/. p.hettegger@gmail.com. Supplementary data are available at Bioinformatics online.

On the conditional test of order restricted multivariate normal mean vectors: simulation study and application

Multivariate isotonic regression theory plays an important role in the field of testing statistical hypotheses under order restriction for several vector valued parameters and this problem may arise in several situations. Sasabuchi et al. derived a likelihood ratio type test for homogeneity of order restricted mean vectors under a multivariate normality assumption with unknown and common covariance matrices; however, its null distribution depends on the unknown covariance matrix. In order to overcome this difficulty, in the present paper we propose a test that conditions on the sufficient statistic for the covariance matrix. We remove the dependence of the null distribution of test statistic proposed by Sasabuchi et al. on the unknown value of covariance matrix and present a condition on a sufficient statistic for covariance matrix under the null hypothesis. A method based on Markov Chain Monte Carlo sampling is used to calculate the value of the test. We evaluate the operating characteristics of the proposed test through simulation studies. Our extensive simulation studies demonstrate that the power of this new test is generally higher than the test proposed by Sasabuchi et al. and also by Sasabuchi. A real data example is presented.

Exact tests for outliers in Laplace samples

The exact null distributions of test statistics used for testing up to upper outliers in a two-parameter Laplace sample are investigated. Two types of test statistics, namely, the modified Murphy’s test for k upper normal outliers and the general Dixon-type test statistic discussed by Childs, are considered. Utilizing the result of conditional independence of blocked ordered data established by Iliopoulos and Balakrishnan, together with the computational algorithm of Huffer and Lin for distributions of linear combinations of exponential variables, exact critical values of test statistics for testing discordancy of k upper outliers in two-parameter Laplace samples are obtained. For illustration, some examples with pertinent computational details are finally presented.

Power analysis for RNA-Seq differential expression studies using generalized linear mixed effects models

BackgroundPower analysis becomes an inevitable step in experimental design of current biomedical research. Complex designs allowing diverse correlation structures are commonly used in RNA-Seq experiments. However, the field currently lacks statistical methods to calculate sample size and estimate power for RNA-Seq differential expression studies using such designs. To fill the gap, simulation based methods have a great advantage by providing numerical solutions, since theoretical distributions of test statistics are typically unavailable for such designs.ResultsIn this paper, we propose a novel simulation based procedure for power estimation of differential expression with the employment of generalized linear mixed effects models for correlated expression data. We also propose a new procedure for power estimation of differential expression with the use of a bivariate negative binomial distribution for paired designs. We compare the performance of both the likelihood ratio test and Wald test under a variety of simulation scenarios with the proposed procedures. The simulated distribution was used to estimate the null distribution of test statistics in order to achieve the desired false positive control and was compared to the asymptotic Chi-square distribution. In addition, we applied the procedure for paired designs to the TCGA breast cancer data set.ConclusionsIn summary, we provide a framework for power estimation of RNA-Seq differential expression under complex experimental designs. Simulation results demonstrate that both the proposed procedures properly control the false positive rate at the nominal level.

General linear hypothesis testing in functional response model

In this paper, the general linear hypothesis testing and variable selection problems in functional response model are considered. The globalizing pointwise F test and the -test as well as the variable selection methods based on multiple hypothesis testing are adapted to this model. The asymptotic null distributions and consistency under local alternatives of test statistics are established under some standard regularity conditions. Based on these results and nonparametric bootstrap approach, different methods are proposed to approximate the null distribution of test statistics. The performance of the new testing and variable selection procedures is compared with that of the known methods in numerical experiments based on real data set. The results suggest that the new methods often outperform the known ones in terms of size control, power and ability to detect significant variables.

Goftte: A R package for assessing goodness-of-fit in proportional (sub) distributions hazards regression models

Background and objectiveIn this paper, we introduce a new R package goftte for goodness-of-fit assessment based on cumulative sums of model residuals useful for checking key assumptions in the Cox regression and Fine and Gray regression models. MethodsMonte-Carlo methods are used to approximate the null distribution of cumulative sums of model residuals. To limit the computational burden, the main routines used to approximate the null distributions are implemented in a parallel C++ programming environment. Numerical studies are carried out to evaluate the empirical type I error rates of the different testing procedures. The package and the documentation are available to users from CRAN R repositories. ResultsResults from simulation studies suggested that all statistical tests implemented in goftte yielded excellent control of the type I error rate even with modest sample sizes with high censoring rates. ConclusionsAs compared to other R packages goftte provides new useful method for testing functionals, such as Anderson-Darling type test statistics for checking assumptions about proportional (sub-) distribution hazards. Approximations for the null distributions of test statistics have been validated through simulation experiments. Future releases will provide similar tools for checking model assumptions in multiplicative intensity models for recurrent data. The package may help to spread the use of recent advocated goodness-of-fit techniques in semiparametric regression for time-to-event data.

EAMA: Empirically adjusted meta-analysis for large-scale simultaneous hypothesis testing in genomic experiments.

Recent developments in high throughput genomic assays have opened up the possibility of testing hundreds and thousands of genes simultaneously. However, adhering to the regular statistical assumptions regarding the null distributions of test statistics in such large-scale multiple testing frameworks has the potential of leading to incorrect significance testing results and biased inference. This problem gets worse when one combines results from different independent genomic experiments with a possibility of ending up with gross false discoveries of significant genes. In this article, we develop a meta-analysis method of combining p-values from different independent experiments involving large-scale multiple testing frameworks, through empirical adjustments of the individual test statistics and p-values. Even though, it is based on various existing ideas, this specific combination is novel and potentially useful. Through simulation studies and real genomic datasets we show that our method outperforms the standard meta-analysis approach of significance testing in terms of accurately identifying the truly significant set of genes.

Bootstrap approach to test the homogeneity of order restricted mean vectors when the covariance matrices are unknown

ABSTRACTTesting homogeneity of multivariate normal mean vectors under an order restriction when the covariance matrices are unknown, arbitrary positive definite and unequal are considered. This problem of testing has been studied to some extent, for example, by Kulatunga and Sasabuchi (1984) when the covariance matrices are known and also Sasabuchi et al. (2003) and Sasabuchi (2007) when the covariance matrices are unknown but common. In this paper, a test statistic is proposed and because of the main advantage of the bootstrap test is that it avoids the derivation of the complex null distribution analytically, a bootstrap test statistic is derived and since the proposed test statistic is location invariance the bootstrap p-value defined logical and some steps are presented to estimate it. Our numerical studies via Monte Carlo simulation show that the proposed bootstrap test can correctly control the type I error rates. The power of the test for some of the p-dimensional normal distributions is computed by Monte Carlo simulation. Also, the null distribution of test statistic is estimated using kernel density. Finally, the bootstrap test is illustrated using a real data.

Minimum distance estimators for count data based on the probability generating function with applications

This paper studies properties of parameter estimators obtained by minimizing a distance between the empirical probability generating function and the probability generating function of a model for count data. Specifically, it is shown that, under certain not restrictive conditions, the resulting estimators are consistent and, suitably normalized, asymptotically normal. These properties hold even if the model is misspecified. Three applications of the obtained results are considered. First, we revisit the goodness-of-fit problem for count data and propose a weighted bootstrap estimator of the null distribution of test statistics based on the above cited distance. Second, we give a probability generating function version of the model selection test problem for separate, overlapping and nested families of distributions. Finally, we provide an application to the problem of testing for separate families of distributions. All applications are illustrated with numerical examples.

Sampling for Conditional Inference on Contingency Tables

ABSTRACTWe propose new sequential importance sampling methods for sampling contingency tables with given margins. The proposal for each method is based on asymptotic approximations to the number of tables with fixed margins. These methods generate tables that are very close to the uniform distribution. The tables, along with their importance weights, can be used to approximate the null distribution of test statistics and calculate the total number of tables. We apply the methods to a number of examples and demonstrate an improvement over other methods in a variety of real problems. Supplementary materials are available online.

Partially functional linear varying coefficient model

In this paper, we introduce a new partially functional linear varying coefficient model, where the response is a scalar and some of the covariates are functional. By means of functional principal components analysis and local linear smoothing techniques, we obtain the estimators of coefficient functions of both function-valued variable and real-valued variables. Then the rates of convergence of the proposed estimators and the mean squared prediction error are established under some regularity conditions. Moreover, we develop a hypothesis test for the model and employ the bootstrap procedure to evaluate the null distribution of test statistic and the p-value of the test. At last, we illustrate the finite sample performance of our methods with some simulation studies and a real data application.

Parametric and permutation testing for multivariate monotonic alternatives

We are firstly interested in testing the homogeneity of k mean vectors against two-sided restricted alternatives separately in multivariate normal distributions. This problem is a multivariate extension of Bartholomew (in Biometrica 46:328---335, 1959b) and an extension of Sasabuchi et al. (in Biometrica 70:465---472, 1983) and Kulatunga and Sasabuchi (in Mem. Fac. Sci., Kyushu Univ. Ser. A: Mathematica 38:151---161, 1984) to two-sided ordered hypotheses. We examine the problem of testing under two separate cases. One case is that covariance matrices are known, the other one is that covariance matrices are unknown but common. For the general case that covariance matrices are known the test statistic is obtained using the likelihood ratio method. When the known covariance matrices are common and diagonal, the null distribution of test statistic is derived and its critical values are computed at different significance levels. A Monte Carlo study is also presented to estimate the power of the test. A test statistic is proposed for the case when the common covariance matrices are unknown. Since it is difficult to compute the exact p-value for this problem of testing with the classical method when the covariance matrices are completely unknown, we first present a reformulation of the test statistic based on the orthogonal projections on the closed convex cones and then determine the upper bounds for its p-values. Also we provide a general nonparametric solution based on the permutation approach and nonparametric combination of dependent tests.

Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma.

ATIC, SHMT2, and SLC46A1 have essential roles in one-carbon (1-C) transfer. The authors examined whether associations between ovarian carcinoma and 15 variants in these genes are modified by regular multivitamin use, a source of 1-C donors, among Caucasian participants from two US case–control studies. Using a phased study design, variant-by-multivitamin interactions were tested, and associations between variants and ovarian carcinoma were reported stratified by multivitamin supplement use. Per-allele risk associations were modified by multivitamin use at six variants among 655 cases and 920 controls (Phase 1). In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6–0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1–2.0). The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. A multi-variant analysis was also performed by comparing the observed likelihood ratio test statistic from adjusted models with and without the two ATIC variant-by-multivitamin interaction terms with a null distribution of test statistics generated by permuting case status 10,000 times. The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the null hypothesis of no association. In summary, there is little statistical evidence that the 15 variants are independently associated with risk of ovarian carcinoma. However, the statistical interaction of ATIC variants with regular multivitamin intake, when evaluated at both the SNP and gene level, may support these findings as relevant to ovarian health and disease processes.

A family of test statistics for trend change in mean residual life with unknown turning point using censored data

In this paper, we develop a family of test statistics for testing exponentiality against increasing then decreasing mean residual life alternatives to accommodate the randomly censored data when neither the change point nor the proportion is known. We establish the asymptotic null distribution of test statistics. Monte Carlo simulations are conducted to investigate the speed of convergence of test statistics to the asymptotic null distribution and study the performance of test statistics by the power of tests.

A permutation-based multiple testing method for time-course microarray experiments

BackgroundTime-course microarray experiments are widely used to study the temporal profiles of gene expression. Storey et al. (2005) developed a method for analyzing time-course microarray studies that can be applied to discovering genes whose expression trajectories change over time within a single biological group, or those that follow different time trajectories among multiple groups. They estimated the expression trajectories of each gene using natural cubic splines under the null (no time-course) and alternative (time-course) hypotheses, and used a goodness of fit test statistic to quantify the discrepancy. The null distribution of the statistic was approximated through a bootstrap method. Gene expression levels in microarray data are often complicatedly correlated. An accurate type I error control adjusting for multiple testing requires the joint null distribution of test statistics for a large number of genes. For this purpose, permutation methods have been widely used because of computational ease and their intuitive interpretation.ResultsIn this paper, we propose a permutation-based multiple testing procedure based on the test statistic used by Storey et al. (2005). We also propose an efficient computation algorithm. Extensive simulations are conducted to investigate the performance of the permutation-based multiple testing procedure. The application of the proposed method is illustrated using the Caenorhabditis elegans dauer developmental data.ConclusionOur method is computationally efficient and applicable for identifying genes whose expression levels are time-dependent in a single biological group and for identifying the genes for which the time-profile depends on the group in a multi-group setting.

The Null Distributions of Test Statistics in Genomewide Association Studies

Genomewide association (GWA) studies assay hundreds of thousands of single nucleotide polymorphisms (SNPs) simultaneously across the entire genome and associate them with diseases, other biological or clinical traits. The association analysis usually tests each SNP as an independent entity and ignores the biological information such as linkage disequilibrium. Although the Bonferroni correction and other approaches have been proposed to address the issue of multiple comparisons as a result of testing many SNPs, there is a lack of understanding of the distribution of an association test statistic when an entire genome is considered together. In other words, there are extensive efforts in hypothesis testing, and almost no attempt in estimating the density under the null hypothesis. By estimating the true null distribution, we can apply the result directly to hypothesis testing; better assess the existing approaches of multiple comparisons; and evaluate the impact of linkage disequilibrium on the GWA studies. To this end, we estimate the empirical null distribution of an association test statistic in GWA studies using simulated population data. We further propose a convenient and accurate method based on adaptive spline to estimate the empirical value in GWA studies and validate our findings using a real data set. Our method enables us to fully characterize the null distribution of an association test that not only can be used to test the null hypothesis of no association, but also provide important information about the impact of density of the genetic markers on the significance of the tests. Our method does not require users to perform computationally intensive permutations, and hence provides a timely solution to an important and difficult problem in GWA studies.

Goodness of fit and homogeneity tests on the basis of N-distances

In this paper we propose an application of N-distance theory [Klebanov, L.B., 2005. N-distances and their applications. Karolinum, Prague] for testing simple hypotheses of goodness of fit and homogeneity. The asymptotic null distribution of test statistics is established and coincides with the distribution of infinite quadratic form of independent standard normal random variables. A construction of multivariate free-of-distribution homogeneity test is considered. The power of proposed criteria is compared with classical tests using Monte-Carlo simulations.