Cross-Tissue Transcriptomic Analysis Leveraging Machine Learning Approaches Identifies New Biomarkers for Rheumatoid Arthritis
Dmitry Rychkov, Jessica Neely, Tomiko Oskotsky, Steven Yu, Noah Perlmutter, Joanne Nititham, Alexander Carvidi, Melissa A. Krueger, Andrew Gross, Lindsey A. Criswell, Judith F. Ashouri, Marina Sirota
Abstract
There is an urgent need to identify biomarkers for diagnosis and disease activity monitoring in rheumatoid arthritis (RA). We leveraged publicly available microarray gene expression data in the NCBI GEO database for whole blood (N=1,885) and synovial (N=284) tissues from RA patients and healthy controls. We developed a robust machine learning feature selection pipeline with validation on five independent datasets culminating in 13 genes: TNFAIP6 , S100A8 , TNFSF10 , DRAM1 , LY96 , QPCT , KYNU , ENTPD1 , CLIC1 , ATP6V0E1 , HSP90AB1 , NCL and CIRBP which define the RA score and demonstrate its clinical utility: the score tracks the disease activity DAS28 (p = 7e-9), distinguishes osteoarthritis (OA) from RA (OR 0.57, p = 8e-10) and polyJIA from healthy controls (OR 1.15, p = 2e-4) and monitors treatment effect in RA (p = 2e-4). Finally, the immunoblotting analysis of six proteins on an independent cohort confirmed two proteins, TNFAIP6 /TSG6 and HSP90AB1 /HSP90.