Why do pathway methods work better than they should?

FEBS Letters, vol. 594, pp. 4189–4200

Abstract

Pathway analysis methods are frequently applied to cancer gene expression data to identify dysregulated pathways. These methods often infer pathway activity based on the expression of genes belonging to a given pathway, even though the proteins ultimately determine the activity of a given pathway. Furthermore, the association between gene expression levels and protein activities is not well-characterized. Here, we posit that pathway-based methods are effective not because of the correlation between expression and activity of members of a given pathway, but because pathway gene sets overlap with the genes regulated by transcription factors (TFs). Thus, pathway-based methods do not inform about the activity of the pathway of interest but rather reflect changes in TF activities.

Authors 2

1. Bence Szalai corresponding

   Semmelweis University

   Affiliation as printed

   Department of Physiology Faculty of Medicine Semmelweis University Budapest Hungary

   Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary

2. Julio Sáez-Rodríguez corresponding Aachen Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Faculty of Medicine

   RWTH Aachen University · Heidelberg University

   Affiliation as printed

   Institute of Computational Biomedicine Faculty of Medicine Heidelberg University Germany

   Joint Research Centre for Computational Biomedicine (JRC‐COMBINE) Faculty of Medicine RWTH Aachen University Germany

   Institute of Computational Biomedicine, Faculty of Medicine, Heidelberg University, Germany

   Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Faculty of Medicine, RWTH Aachen University, Germany