BZINB Model-Based Pathway Analysis and Module Identification Facilitates Integration of Microbiome and Metabolome Data

Bridget M Lin; Hunyong Cho; Chuwen Liu; Jeff Roach; Apoena Aguiar Ribeiro; Kimon Divaris; Di Wu

doi:10.3390/microorganisms11030766

BZINB Model-Based Pathway Analysis and Module Identification Facilitates Integration of Microbiome and Metabolome Data

Microorganisms. 2023 Mar 16;11(3):766. doi: 10.3390/microorganisms11030766.

Authors

Bridget M Lin¹, Hunyong Cho¹, Chuwen Liu¹, Jeff Roach², Apoena Aguiar Ribeiro³, Kimon Divaris^{4

5}, Di Wu^{1

6

7}

Affiliations

¹ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Research Computing, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Division of Diagnostic Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Division of Pediatric and Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

Integration of multi-omics data is a challenging but necessary step to advance our understanding of the biology underlying human health and disease processes. To date, investigations seeking to integrate multi-omics (e.g., microbiome and metabolome) employ simple correlation-based network analyses; however, these methods are not always well-suited for microbiome analyses because they do not accommodate the excess zeros typically present in these data. In this paper, we introduce a bivariate zero-inflated negative binomial (BZINB) model-based network and module analysis method that addresses this limitation and improves microbiome-metabolome correlation-based model fitting by accommodating excess zeros. We use real and simulated data based on a multi-omics study of childhood oral health (ZOE 2.0; investigating early childhood dental caries, ECC) and find that the accuracy of the BZINB model-based correlation method is superior compared to Spearman's rank and Pearson correlations in terms of approximating the underlying relationships between microbial taxa and metabolites. The new method, BZINB-iMMPath, facilitates the construction of metabolite-species and species-species correlation networks using BZINB and identifies modules of (i.e., correlated) species by combining BZINB and similarity-based clustering. Perturbations in correlation networks and modules can be efficiently tested between groups (i.e., healthy and diseased study participants). Upon application of the new method in the ZOE 2.0 study microbiome-metabolome data, we identify that several biologically-relevant correlations of ECC-associated microbial taxa with carbohydrate metabolites differ between healthy and dental caries-affected participants. In sum, we find that the BZINB model is a useful alternative to Spearman or Pearson correlations for estimating the underlying correlation of zero-inflated bivariate count data and thus is suitable for integrative analyses of multi-omics data such as those encountered in microbiome and metabolome studies.

Keywords: caries; clustering; correlation; counts; metabolomics; microbiome; multi-omics; network; pathways; zero-inflation.

Grants and funding

R03 DE028983/DE/NIDCR NIH HHS/United States