Unfolding and De-confounding: Biologically meaningful causal inference from longitudinal multi-omic networks usingMETALICA

Abstract

A key challenge in the analysis of microbiome data is the integration of multi-omic datasets and the discovery of interactions between microbial taxa, their expressed genes, and the metabolites they consume and/or produce. In an effort to improve the state-of-the-art in inferring biologically meaningful multi-omic interactions, we sought to address some of the most fundamental issues in causal inference from longitudinal multi-omics microbiome data sets. We developed METALICA, a suite of tools and techniques that can infer interactions between microbiome entities. METALICA introduces novelunrollingandde-confoundingtechniques used to uncover multi-omic entities that are believed to act as confounders for some of the relationships that may be inferred using standard causal inferencing tools. The results lend support to predictions about biological models and processes by which microbial taxa interact with each other in a microbiome. Theunrollingprocess helps to identify putative intermediaries (genes and/or metabolites) to explain the interactions between microbes; thede-confoundingprocess identifies putative common causes that may lead to spurious relationships to be inferred. METALICA was applied to the networks inferred by existing causal discovery and network inference algorithms applied to a multi-omics data set resulting from a longitudinal study of IBD microbiomes. The most significant unrollings and de-confoundings were manually validated using the existing literature and databases.ImportanceWe have developed a suite of tools and techniques capable of inferring interactions between microbiome entities. METALICAintroduces novel techniques called unrolling and de-confounding that are employed to uncover multi-omic entities considered to be confounders for some of the relationships that may be inferred using standard causal inferencing tools. To evaluate our method, we conducted tests on the Inflammatory Bowel Disease (IBD) dataset from the iHMP longitudinal study, which we pre-processed in accordance with our previous work.