Differential network connectivity analysis for microbiome data adjusted for clinical covariates using jackknife pseudo-values.

ABSTRACT

BACKGROUND: A recent breakthrough in differential network (DN) analysis of microbiome data has been realized with the advent of next-generation sequencing technologies. The DN analysis disentangles the microbial co-abundance among taxa by comparing the network properties between two or more graphs under different biological conditions. However, the existing methods to the DN analysis for microbiome data do not adjust for other clinical differences between subjects. RESULTS: We propose a Statistical Approach via Pseudo-value Information and Estimation for Differential Network Analysis (SOHPIE-DNA) that incorporates additional covariates such as continuous age and categorical BMI. SOHPIE-DNA is a regression technique adopting jackknife pseudo-values that can be implemented readily for the analysis. We demonstrate through simulations that SOHPIE-DNA consistently reaches higher recall and F1-score, while maintaining similar precision and accuracy to existing methods (NetCoMi and MDiNE). Lastly, we apply SOHPIE-DNA on two real datasets from the American Gut Project and the Diet Exchange Study to showcase the utility. The analysis of the Diet Exchange Study is to showcase that SOHPIE-DNA can also be used to incorporate the temporal change of connectivity of taxa with the inclusion of additional covariates. As a result, our method has found taxa that are related to the prevention of intestinal inflammation and severity of fatigue in advanced metastatic cancer patients. CONCLUSION: SOHPIE-DNA is the first attempt of introducing the regression framework for the DN analysis in microbiome data. This enables the prediction of characteristics of a connectivity of a network with the presence of additional covariate information in the regression. The R package with a vignette of our methodology is available through the CRAN repository ( https//CRAN.R-project.org/package=SOHPIE ), named SOHPIE (pronounced as Sofie). The source code and user manual can be found at https//github.com/sjahnn/SOHPIE-DNA .