Validity of clinical associations of biomarkers in translational research studies: the case of systemic autoimmune diseases

INTRODUCTION: Validity of biomarkers may be affected if studies do not include certain features in their design. We evaluated whether translational research studies of potential biomarkers incorporated design features important for valid clinical associations. METHODS: We searched 10 journals for translational studies in six systemic autoimmune diseases published in 2004 through 2009. We included studies that reported associations between laboratory markers and the presence of disease, measures of disease activity, or prognosis. We examined the following design features: age, sex, and race matching; control for effects of treatment on expression of the biomarker; inclusion of patients with both early and late disease, or both active and inactive disease; longitudinal or cross-sectional design; and use of validated activity and damage measures. RESULTS: Among 170 articles, 156 articles examined potential biomarkers for diagnosis, 37 for disease activity assessment, and nine for prognosis; 67 were studies of rheumatoid arthritis (RA); 48, of systemic lupus erythematosus; and 41, of other diseases. Gene-expression profiles were the most commonly examined potential biomarkers (n = 51). Fewer than one half of studies incorporated study-design features important for valid clinical associations. Only 47.4% of studies of biomarkers for diagnosis had groups that were age-matched, 45.5% were sex-matched, and 35.3% controlled for treatment. Studies that examined biomarkers in histologic samples and studies of RA were less likely to include important design features. CONCLUSIONS: Fewer than one half of translational studies of potential biomarkers incorporated design features needed for valid interpretation of clinical associations. Attention to these features could reduce false-positive and false-negative associations.