Correcting for sparsity and non-independence in glycomic data through a system biology framework

Glycans are fundamental cellular building blocks, involved in many organismal functions. Advances in glycomics are elucidating the roles of glycans, but it remains challenging to properly analyze large glycomics datasets, since the data are sparse (each sample often has only a few measured glycans) and detected glycans are non-independent (sharing many intermediate biosynthetic steps). We address these challenges with GlyCompare, a glycomic data analysis approach that leverages shared biosynthetic pathway intermediates to correct for sparsity and non-independence in glycomics. Specifically, quantities of measured glycans are propagated to intermediate glycan substructures, which enables direct comparison of different glycoprofiles and increases statistical power. Using GlyCompare, we studied diverse N-glycan profiles from glycoengineered erythropoietin. We obtained biologically meaningful clustering of mutant cell glycoprofiles and identified knockout-specific effects of fucosyltransferase mutants on tetra-antennary structures. We further analyzed human milk oligosaccharide profiles and identified novel impacts that the mothers secretor-status on fucosylation and sialylation. Our substructure-oriented approach will enable researchers to take full advantage of the growing power and size of glycomics data.