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ABSTRACT We introduce a novel meta-analysis framework to combine dependent tests under a general setting, and utilize it to synthesize various microbiome association tests that are calculated from the same dataset. Our development builds upon the classical meta-analysis methods of aggregating P-values and also a more recent general method of combining confidence distributions, but makes generalizations to handle dependent tests. The proposed framework ensures rigorous statistical guarantees, and we provide a comprehensive study and compare it with various existing dependent combination methods. Notably, we demonstrate that the widely used Cauchy combination method for dependent tests, referred to as the vanilla Cauchy combination in this article, can be viewed as a special case within our framework. Moreover, the proposed framework provides a way to address the problem when the distributional assumptions underlying the vanilla Cauchy combination are violated. Our numerical results demonstrate that ignoring the dependence among the to-be-combined components may lead to a severe size distortion phenomenon. Compared to the existing P-value combination methods, including the vanilla Cauchy combination method and other methods, the proposed combination framework is flexible and can be adapted to handle the dependence accurately and utilizes the information efficiently to construct tests with accurate size and enhanced power. The development is applied to the microbiome association studies, where we aggregate information from multiple existing tests using the same dataset. The combined tests harness the strengths of each individual test across a wide range of alternative spaces, enabling more efficient and meaningful discoveries of vital microbiome associations. 

Abstract A critical task in microbiome data analysis is to explore the association between a scalar response of interest and a large number of microbial taxa that are summarized as compositional data at different taxonomic levels. Motivated by fine‐mapping of the microbiome, we propose a two‐step compositional knockoff filter to provide the effective finite‐sample false discovery rate (FDR) control in high‐dimensional linear log‐contrast regression analysis of microbiome compositional data. In the first step, we propose a new compositional screening procedure to remove insignificant microbial taxa while retaining the essential sum‐to‐zero constraint. In the second step, we extend the knockoff filter to identify the significant microbial taxa in the sparse regression model for compositional data. Thereby, a subset of the microbes is selected from the high‐dimensional microbial taxa as related to the response under a prespecified FDR threshold. We study the theoretical properties of the proposed two‐step procedure, including both sure screening and effective false discovery control. We demonstrate these properties in numerical simulation studies to compare our methods to some existing ones and show power gain of the new method while controlling the nominal FDR. The potential usefulness of the proposed method is also illustrated with application to an inflammatory bowel disease data set to identify microbial taxa that influence host gene expressions.