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Summary In this paper, we develop a systematic theory for high-dimensional analysis of variance in multivariate linear regression, where the dimension and the number of coefficients can both grow with the sample size. We propose a new U-type statistic to test linear hypotheses and establish a high-dimensional Gaussian approximation result under fairly mild moment assumptions. Our general framework and theory can be used to deal with the classical one-way multivariate analysis of variance, and the nonparametric one-way multivariate analysis of variance in high dimensions. To implement the test procedure, we introduce a sample-splitting-based estimator of the second moment of the error covariance and discuss its properties. A simulation study shows that our proposed test outperforms some existing tests in various settings. 

Abstract Differential abundance analysis is at the core of statistical analysis of microbiome data. The compositional nature of microbiome sequencing data makes false positive control challenging. Here, we show that the compositional effects can be addressed by a simple, yet highly flexible and scalable, approach. The proposed method, LinDA, only requires fitting linear regression models on the centered log-ratio transformed data, and correcting the bias due to compositional effects. We show that LinDA enjoys asymptotic FDR control and can be extended to mixed-effect models for correlated microbiome data. Using simulations and real examples, we demonstrate the effectiveness of LinDA. 

Motivated by the increasing use of kernel-based metrics for high-dimensional and large-scale data, we study the asymptotic behaviour of kernel two-sample tests when the dimension and sample sizes both diverge to infinity. We focus on the maximum mean discrepancy using an isotropic kernel, which includes maximum mean discrepancy with the Gaussian kernel and the Laplace kernel, and the energy distance as special cases. We derive asymptotic expansions of the kernel two-sample statistics, based on which we establish a central limit theorem under both the null hypothesis and the local and fixed alternatives. The new nonnull central limit theorem results allow us to perform asymptotic exact power analysis, which reveals a delicate interplay between the moment discrepancy that can be detected by the kernel two-sample tests and the dimension-and-sample orders. The asymptotic theory is further corroborated through numerical studies.

 

Due to the sparsity and high dimensionality, microbiome data are routinely summarized into pairwise distances capturing the compositional differences. Many biological insights can be gained by analyzing the distance matrix in relation to some covariates. A microbiome sampling method that characterizes the inter-sample relationship more reproducibly is expected to yield higher statistical power. Traditionally, the intraclass correlation coefficient (ICC) has been used to quantify the degree of reproducibility for a univariate measurement using technical replicates. In this work, we extend the traditional ICC to distance measures and propose a distance-based ICC (dICC). We derive the asymptotic distribution of the sample-based dICC to facilitate statistical inference. We illustrate dICC using a real dataset from a metagenomic reproducibility study.

dICC is implemented in the R CRAN package GUniFrac.

Supplementary data are available at Bioinformatics online.

 

Abstract Summary PERMANOVA (permutational multivariate analysis of variance based on distances) has been widely used for testing the association between the microbiome and a covariate of interest. Statistical significance is established by permutation, which is computationally intensive for large sample sizes. As large-scale microbiome studies, such as American Gut Project (AGP), become increasingly popular, a computationally efficient version of PERMANOVA is much needed. To achieve this end, we derive the asymptotic distribution of the PERMANOVA pseudo-F statistic and provide analytical P-value calculation based on chi-square approximation. We show that the asymptotic P-value is close to the PERMANOVA P-value even under a moderate sample size. Moreover, it is more accurate and an order-of-magnitude faster than the permutation-free method MDMR. We demonstrated the use of our procedure D-MANOVA on the AGP dataset. Availability and implementation D-MANOVA is implemented by the dmanova function in the CRAN package GUniFrac. Supplementary information Supplementary data are available at Bioinformatics online. 

One challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.