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Establishment of reference intervals for osteoarthritis-related soluble biomarkers: the FNIH/OARSI OA Biomarkers Consortium
  1. Virginia B Kraus1,
  2. David E Hargrove2,
  3. David J Hunter3,
  4. Jordan B Renner4,
  5. Joanne M Jordan5
  1. 1Division of Rheumatology, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
  2. 2LabCorp Clinical Trials, San Leandro, California, USA
  3. 3Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, Sydney, New South Wales, Australia
  4. 4Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  5. 5Department of Medicine, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr Virginia Byers Kraus, Duke Molecular Physiology Institute, Box 104775, 300 N Duke St, Durham, NC 27701, USA; vbk{at}


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.

  • Knee Osteoarthritis
  • Osteoarthritis
  • Disease Activity

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  • Handling editor Tore K Kvien

  • Twitter Follow David Hunter at @ProfDavidHunter

  • Contributors VBK, JMJ, DEH and DJH designed the study. DEH performed all biomarker analyses. JBR performed all radiographic grading. All authors helped to draft the manuscript and reviewed and approved it for submission.

  • Funding The Johnston County Osteoarthritis Project has been in part from the Centers for Disease Control and Prevention (CDC) and the Association of Schools of Public Health (ASPH) S043 and S3486 and the National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS) Multidisciplinary Clinical Research Center (MCRC) P60 AR49465.

  • Competing interests DEH is an employee of LabCorp Clinical Trials and was blinded to all clinical data during performance of biomarker assays.

  • Ethics approval UNC Chapel Hill IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The biomarker data reported in this study are freely available on the Osteoarthritis Initiative (OAI) website (

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