Replicability of Differentially Expressed Genes Versus Biological Pathways Biomarkers in Diagnosing Sepsis

It is generally believed that biological pathways representing curated gene sets are not only more interpretable, but also more replicable and reproducible than gene signatures. With the falling costs of next generation sequencing, we are approaching a point where the cost fully sequencing the transcriptome is competitive with quantifying a targeted gene expression signature which opens up the possibility of pathway signatures for infectious disease. In this work, we evaluated if pathway based signatures are really more reproducible than gene signatures (improvement between 0.83 and over 1 million fold), and amend a meta-analysis framework known for generating highly reproducible gene signatures to instead produce pathway signatures (AUC improves from 0.854 to 0.964 and 0.556 to 0.677 between gene and pathway signatures in independent validation data). We conclude that pathway based signatures show clinical promise for the diagnosis of infectious disease, and there is a growing need for methods considering such signatures.