title: Diagnosis of rheumatoid arthritis: multivariate analysis of biomarkers.
abstract: OBJECTIVE
  To test if a combination of biomarkers can increase the classification power of autoantibodies to cyclic citrullinated peptides (anti-CCP) in the diagnosis of rheumatoid arthritis (RA) depending on the diagnostic situation.
  
  
  METHODS
  Biomarkers were subject to three inclusion/exclusion criteria (discrimination between RA patients and healthy blood donors, ability to identify anti-CCP-negative RA patients, specificity in a panel with major non-rheumatological diseases) before univariate ranking and multivariate analysis was carried out using a modelling panel (n = 906). To enable the evaluation of the classification power in different diagnostic settings the disease controls (n = 542) were weighted according to the admission rates in rheumatology clinics modelling a clinic panel or according to the relative prevalences of musculoskeletal disorders in the general population seen by general practitioners modelling a GP panel.
  
  
  RESULTS
  Out of 131 biomarkers considered originally, we evaluated 32 biomarkers in this study, of which only seven passed the three inclusion/exclusion criteria and were combined by multivariate analysis using four different mathematical models. In the modelled clinic panel, anti-CCP was the lead marker with a sensitivity of 75.8% and a specificity of 94.0%. Due to the lack in specificity of the markers other than anti-CCP in this diagnostic setting, any gain in sensitivity by any marker combination is off-set by a corresponding loss in specificity. In the modelled GP panel, the best marker combination of anti-CCP and interleukin (IL)-6 resulted in a sensitivity gain of 7.6% (85.9% vs. 78.3%) at a minor loss in specificity of 1.6% (90.3% vs. 91.9%) compared with anti-CCP as the best single marker.
  
  
  CONCLUSIONS
  Depending on the composition of the sample panel, anti-CCP alone or anti-CCP in combination with IL-6 has the highest classification power for the diagnosis of established RA.
authors.affiliation: Department of Marker Discovery/Proteomics, Roche Professional Diagnostics, Roche Diagnostics GmbH, Penzberg, Germany. norbert.wild@roche.com
authors.forename: Norbert
authors.initials: N
authors.lastname: Wild
authors.forename: Johann
authors.initials: J
authors.lastname: Karl
authors.forename: Veit P
authors.initials: VP
authors.lastname: Grunert
authors.forename: Raluca I
authors.initials: RI
authors.lastname: Schmitt
authors.forename: Ursula
authors.initials: U
authors.lastname: Garczarek
authors.forename: Friedemann
authors.initials: F
authors.lastname: Krause
authors.forename: Fritz
authors.initials: F
authors.lastname: Hasler
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Bayer
authors.forename: Matthias
authors.initials: M
authors.lastname: Thun
authors.forename: Derek L
authors.initials: DL
authors.lastname: Mattey
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sharif
authors.forename: Werner
authors.initials: W
authors.lastname: Zolg
mesh_terms: D000974:Antibodies, Antinuclear / Q000032:analysis*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis*; D015415:Biomarkers / Q000032:analysis*; D002956:Citrulline / Q000276:immunology; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010456:Peptides, Cyclic / Q000276:immunology*; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D000685:Serum Amyloid A Protein / Q000032:analysis
chemical_list: D000974:Antibodies, Antinuclear; D015415:Biomarkers; D010456:Peptides, Cyclic; D000685:Serum Amyloid A Protein; C487763:cyclic citrullinated peptide; D002956:Citrulline