OBJECTIVE: At OMERACT 8 a framework for levels of evidence was proposed for the validation of biomarkers as surrogate outcome measures. We aimed to adapt this scheme in order to apply it in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers.

METHODS: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). This formed the basis for discussions among OMERACT 9 participants.

RESULTS: The proposed framework was accepted by consensus. In the study design domain a requirement for both prospective observational studies and randomized controlled trials (RCT) in different drug classes was noted. A template for determining the level of statistical strength was proposed. The addition of a new domain on biomarker assay performance was considered essential, and participants suggested that for any biomarker this domain should be addressed first, i.e., before starting clinical validation studies. Participants agreed on most elements of a longitudinal study design template. Where consensus was lacking the working group has drafted solutions that constitute a basis for prospective validation studies.

CONCLUSION: The OMERACT 9 Soluble Biomarker Group has successfully formulated a levels of evidence scheme and a study design template that will provide guidance to conduct validation studies in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in RA, PsA, and AS.

The Bath ankylosing spondylitis metrology index (BASMI; range 0-10) has gained widespread use in daily clinical practice as an objective measure of spinal stiffness not only in patients with ankylosing spondylitis (AS) but also in patients with other spondylarthropathies (SpA). We examined intra-rater and inter-rater reproducibility of BASMI scoring in 30 Danish patients with SpA (median age 40 years, range 22-56 years) fulfilling the European Spondylarthropathy Study Group criteria, 25 of them satisfying the modified New York Criteria for AS. Measurements were performed twice on two different days (median interval 7 days, range 4-11) by a trained physiotherapist (PT) and by an untrained nurse who had undergone a single 1-h training session with the PT. The median BASMI score obtained by the PT on the two test days was 3.5 (range 1-8) and 3.0 (range 1-8), respectively (NS). Test-retest BASMI scores from the PT were significantly correlated (r(s) = 0.95, p < 0.0001). The 95% likely range for the difference between a patient's BASMI scores from two tests was +/-1.4 corresponding to a minimal detectable difference of +/-2 in the individual patient as the scale consists of intervals of 1. Similar results were achieved by the nurse. BASMI scores obtained by the two raters were significantly inter-correlated (r(s) = 0.95, p < 0.0001). The mean difference between paired BASMI scores obtained by the nurse and the PT on test day 1 was -0.2 with a minimal detectable difference of +/-2. A similar result was found using data from test day 2. In conclusion, a change in BASMI less than 2 may be due solely to expected random measurement error. A single 1-h training session allowed an untrained nurse to obtain BASMI results almost identical to those of an experienced PT.