A novel gene and pathway-level subtyping analysis scheme to understand biological mechanisms in complex disease: a case study in rheumatoid arthritis

Abstract

Complex diseases have heterogeneous underlying molecular mechanisms. In order to improve the diagnosis and treatment of disease, it is vital to stratify patients into homogeneous subgroups that share a similar disease etiology. In this study, we performed gene-level subtyping analysis on two independent Rheumatoid Arthritis gene expression cohorts from different ethnic groups to discover the possible disease mechanisms associated with each subtype. Also, a novel pathway-level analysis is proposed to increase the subtyping robustness and facilitate biological interpretation. This approach could stratify RA patients into two robust and homogeneous groups with differing activation of central signal transduction pathways and pro-inflammatory cytokines in the pathogenesis of RA. Such a methodology can help understand disease mechanisms at play in different patient sub-populations and also potentially explain why some patients don't respond to anti-TNF treatment.