Microbiome compositional data analysis for survival studies.

The growing interest in studying the relationship between the human microbiome and our health has also extended to time-to-event studies where researchers explore the connection between the microbiome and the occurrence of a specific event of interest. The analysis of microbiome obtained through high throughput sequencing techniques requires the use of specialized Compositional Data Analysis (CoDA) methods designed to accommodate its compositional nature. There is a limited availability of statistical tools for microbiome analysis that incorporate CoDA, and this is even more pronounced in the context of survival analysis. To fill this methodological gap, we present coda4microbiome for survival studies, a new methodology for the identification of microbial signatures in time-to-event studies. The algorithm implements an elastic-net penalized Cox regression model adapted to compositional covariates. We illustrate coda4microbiome algorithm for survival studies with a case study about the time to develop type 1 diabetes for non-obese diabetic mice. Our algorithm identified a bacterial signature composed of 21 genera associated with diabetes development. coda4microbiome for survival studies is integrated in the R package coda4microbiome as an extension of the existing functions for cross-sectional and longitudinal studies.

coda4microbiome: compositional data analysis for microbiome cross-sectional and longitudinal studies.

BACKGROUND: One of the main challenges of microbiome analysis is its compositional nature that if ignored can lead to spurious results. Addressing the compositional structure of microbiome data is particularly critical in longitudinal studies where abundances measured at different times can correspond to different sub-compositions. RESULTS: We developed coda4microbiome, a new R package for analyzing microbiome data within the Compositional Data Analysis (CoDA) framework in both, cross-sectional and longitudinal studies. The aim of coda4microbiome is prediction, more specifically, the method is designed to identify a model (microbial signature) containing the minimum number of features with the maximum predictive power. The algorithm relies on the analysis of log-ratios between pairs of components and variable selection is addressed through penalized regression on the "all-pairs log-ratio model", the model containing all possible pairwise log-ratios. For longitudinal data, the algorithm infers dynamic microbial signatures by performing penalized regression over the summary of the log-ratio trajectories (the area under these trajectories). In both, cross-sectional and longitudinal studies, the inferred microbial signature is expressed as the (weighted) balance between two groups of taxa, those that contribute positively to the microbial signature and those that contribute negatively. The package provides several graphical representations that facilitate the interpretation of the analysis and the identified microbial signatures. We illustrate the new method with data from a Crohn's disease study (cross-sectional data) and on the developing microbiome of infants (longitudinal data). CONCLUSIONS: coda4microbiome is a new algorithm for identification of microbial signatures in both, cross-sectional and longitudinal studies. The algorithm is implemented as an R package that is available at CRAN ( https://cran.r-project.org/web/packages/coda4microbiome/ ) and is accompanied with a vignette with a detailed description of the functions. The website of the project contains several tutorials: https://malucalle.github.io/coda4microbiome/.

Variable selection in microbiome compositional data analysis.

Though variable selection is one of the most relevant tasks in microbiome analysis, e.g. for the identification of microbial signatures, many studies still rely on methods that ignore the compositional nature of microbiome data. The applicability of compositional data analysis methods has been hampered by the availability of software and the difficulty in interpreting their results. This work is focused on three methods for variable selection that acknowledge the compositional structure of microbiome data: selbal, a forward selection approach for the identification of compositional balances, and clr-lasso and coda-lasso, two penalized regression models for compositional data analysis. This study highlights the link between these methods and brings out some limitations of the centered log-ratio transformation for variable selection. In particular, the fact that it is not subcompositionally consistent makes the microbial signatures obtained from clr-lasso not readily transferable. Coda-lasso is computationally efficient and suitable when the focus is the identification of the most associated microbial taxa. Selbal stands out when the goal is to obtain a parsimonious model with optimal prediction performance, but it is computationally greedy. We provide a reproducible vignette for the application of these methods that will enable researchers to fully leverage their potential in microbiome studies.