Causal effects in microbiomes using interventional calculus

Abstract

Causal inference in biomedical research allows us to shift the paradigm from investigating associational relationships to causal ones. Inferring causal relationships can help in understanding the inner workings of biological processes. Association patterns can be coincidental and may lead to wrong conclusions about causality in complex systems. Microbiomes are highly complex, diverse, and dynamic environments. Microbes are key players in human health and disease. Hence knowledge of critical causal relationships among the entities in a microbiome, and the impact of internal and external factors on microbial abundance and their interactions are essential for understanding disease mechanisms and making appropriate treatment recommendations. In this paper, we employ causal inference techniques to understand causal relationships between various entities in a microbiome, and to use the resulting causal network to make useful computations. We introduce a novel pipeline for microbiome analysis, which includes adding an outcome or “disease” variable, and then computing the causal network, referred to as a “disease network”, with the goal of identifying disease-relevant causal factors from the microbiome. Internventional techniques are then applied to the resulting network, allowing us to compute a measure called the causal effect of one or more microbial taxa on the outcome variable or the condition of interest. Finally, we propose a measure called causal influence that quantifies the total influence exerted by a microbial taxon on the rest of the microiome. Our pipeline is robust, sensitive, different from traditional approaches, and able to predict interventional effects without any controlled experiments. The pipeline can be used to identify potential eubiotic and dysbiotic microbial taxa in a microbiome. We validate our results using synthetic data sets and using results on real data sets that were previously published.