title: Development of a multi-biomarker disease activity test for rheumatoid arthritis.
abstract: BACKGROUND
  Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment.
  
  
  OBJECTIVE
  To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis.
  
  
  METHODS
  Candidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing.
  
  
  RESULTS
  130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities.
  
  
  CONCLUSIONS
  We followed a stepwise approach to develop a quantitative serum-based measure of RA disease activity, based on 12-biomarkers, which was consistently associated with clinical disease activity levels.
authors.affiliation: Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Centola
authors.forename: Guy
authors.initials: G
authors.lastname: Cavet
authors.forename: Yijing
authors.initials: Y
authors.lastname: Shen
authors.forename: Saroja
authors.initials: S
authors.lastname: Ramanujan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Knowlton
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Swan
authors.forename: Mary
authors.initials: M
authors.lastname: Turner
authors.forename: Chris
authors.initials: C
authors.lastname: Sutton
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Smith
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Haney
authors.forename: David
authors.initials: D
authors.lastname: Chernoff
authors.forename: Lyndal K
authors.initials: LK
authors.lastname: Hesterberg
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
authors.forename: Peter C
authors.initials: PC
authors.lastname: Taylor
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shadick
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Curtis
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D012372:ROC Curve; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D002097:C-Reactive Protein