Detecting sparse microbial association signals adaptively from longitudinal microbiome data based on generalized estimating equations.

The association between the compositions of microbial communities and various host phenotypes is an important research topic. Microbiome association research addresses multiple domains, such as human disease and diet. Statistical methods for testing microbiome-phenotype associations have been studied recently to determine their ability to assess longitudinal microbiome data. However, existing methods fail to detect sparse association signals in longitudinal microbiome data. In this paper, we developed a novel method, namely aGEEMIHC, which is a data-driven adaptive microbiome higher criticism analysis based on generalized estimating equations to detect sparse microbial association signals from longitudinal microbiome data. aGEEMiHC adopts generalized estimating equations framework that fully considers the correlation among different observations from the same subject in longitudinal data. To be robust to diverse correlation structures for longitudinal data, aGEEMiHC integrates multiple microbiome higher criticism analyses based on generalized estimating equations with different working correlation structures. Extensive simulation experiments demonstrate that aGEEMiHC can control the type I error correctly and achieve superior performance according to a statistical power comparison. We also applied it to longitudinal microbiome data with various types of host phenotypes to demonstrate the stability of our method. aGEEMiHC is also utilized for real longitudinal microbiome data, and we found a significant association between the gut microbiome and Crohn's disease. In addition, our method ranks the significant factors associated with the host phenotype to provide potential biomarkers.

A powerful adaptive microbiome-based association test for microbial association signals with diverse sparsity levels.

The dysbiosis of microbiome may have negative effects on a host phenotype. The microbes related to the host phenotype are regarded as microbial association signals. Recently, statistical methods based on microbiome-phenotype association tests have been extensively developed to detect these association signals. However, the currently available methods do not perform well to detect microbial association signals when dealing with diverse sparsity levels (i.e., sparse, low sparse, non-sparse). Actually, the real association patterns related to different host phenotypes are not unique. Here, we propose a powerful and adaptive microbiome-based association test to detect microbial association signals with diverse sparsity levels, designated as MiATDS. In particular, we define probability degree to measure the associations between microbes and the host phenotype and introduce the adaptive weighted sum of powered score tests by considering both probability degree and phylogenetic information. We design numerous simulation experiments for the task of detecting association signals with diverse sparsity levels to prove the performance of the method. We find that type I error rates can be well-controlled and MiATDS shows superior efficiency on the power. By applying to real data analysis, MiATDS displays reliable practicability too. The R package is available at https://github.com/XiaoyunHuang33/MiATDS.