TreeKernel: interpretable kernel machine tests for interactions between -omics and clinical predictors with applications to metabolomics and COPD phenotypes

Abstract

Abstract Background In this paper, we are interested in interactions between a high-dimensional -omics dataset and clinical covariates. The goal is to evaluate the relationship between a phenotype of interest and a high-dimensional omics pathway, where the effect of the omics data depends on subjects’ clinical covariates (age, sex, smoking status, etc.). For instance, metabolic pathways can vary greatly between sexes which may also change the relationship between certain metabolic pathways and a clinical phenotype of interest. We propose partitioning the clinical covariate space and performing a kernel association test within those partitions. To illustrate this idea, we focus on hierarchical partitions of the clinical covariate space and kernel tests on metabolic pathways. Results We see that our proposed method outperforms competing methods in most simulation scenarios. It can identify different relationships among clinical groups with higher power in most scenarios while maintaining a proper Type I error rate. The simulation studies also show a robustness to the grouping structure within the clinical space. We also apply the method to the COPDGene study and find several clinically meaningful interactions between metabolic pathways, the clinical space, and lung function. Conclusion TreeKernel provides a simple and interpretable process for testing for relationships between high-dimensional omics data and clinical outcomes in the presence of interactions within clinical cohorts. The method is broadly applicable to many studies.

Keywords

• Kernel functions
• Kernel methods
• Kernel interactions
• Metabolomics
• Metabolic pathways