title: Establishment of reference intervals for osteoarthritis-related soluble biomarkers: the FNIH/OARSI OA Biomarkers Consortium.
abstract: OBJECTIVE
  To establish reference intervals for osteoarthritis (OA)-related biomarkers used in the Foundation for the National Institutes of Health (FNIH) OA Biomarkers Consortium Project.
  
  
  METHODS
  A total of 129 'multijoint controls' were selected from 2722 African-American and Caucasian men and women in the Johnston County Osteoarthritis Project. The majority (79%) of those eligible (with biospecimens and baseline data) also had one or more follow-up evaluations 5-15 years later. Multijoint controls were selected to be free of radiographic hand, hip, knee and lumbar spine osteoarthritis (OA), to have no knee or hip symptoms, and minimal hand and spine symptoms at all available time points. Eighteen biomarkers were evaluated in serum (s) and/or urine (u) by ELISA. Reference intervals and partitioning by gender and race were performed with EP Evaluator software.
  
  
  RESULTS
  Controls were 64% women, 33% African-Americans, mean age 59 years and mean body mass index 29 kg/m2. Three biomarkers were associated with age: sHyaluronan (positively), sN-terminal propeptide of collagen IIA (positively) and sCol2-3/4 C-terminal cleavage product of types I and II collagen (negatively). Exploratory analyses suggested that separate reference intervals may be warranted on the basis of gender for uC-terminal cross-linked telopeptide of type II collagen (uCTXII), sMatrix metalloproteinase-3, uNitrated type II collagen degradation fragment (uCol2-1 NO2) and sHyaluronan, and on the basis of race for uCTXII, sCartilage oligomeric matrix protein, sC-terminal cross-linked telopeptide of type I collagen and uCol2-1 NO2.
  
  
  CONCLUSIONS
  To our knowledge, this represents the best and most stringent control group ever assayed for OA-related biomarkers. These well-phenotyped controls, representing a similar age demographic to that of the OA Initiative-FNIH main study sample, provide a context for interpretation of OA subject biomarker data. The freely available data set also provides a reference for future human studies.
authors.affiliation: Division of Rheumatology, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: LabCorp Clinical Trials, San Leandro, California, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hargrove
authors.affiliation: Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David J
authors.identifier: http://orcid.org/0000-0003-3197-752X
authors.initials: DJ
authors.lastname: Hunter
authors.affiliation: Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Renner
authors.affiliation: Department of Medicine, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Jordan
mesh_terms: D000367:Age Factors; D000368:Aged; D000375:Aging / Q000097:blood / Q000652:urine; D000465:Algorithms; D015415:Biomarkers / Q000097:blood / Q000378:metabolism* / Q000652:urine; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood / Q000175:diagnosis* / Q000652:urine; D010147:Pain Measurement / Q000379:methods; D012016:Reference Values; D013048:Specimen Handling / Q000379:methods
chemical_list: D015415:Biomarkers
keywords: Disease Activity; Knee Osteoarthritis; Osteoarthritis