Abstract
IntroductionValidity 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.MethodsWe 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.ResultsAmong 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.ConclusionsFewer 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.
Highlights
Validity of biomarkers may be affected if studies do not include certain features in their design
We evaluated whether the authors reported any one of three possible methods to control for confounding by treatment: enrollment of treatment-naïve patients; testing whether biomarker expression differed between groups of patients taking different medications; or providing a reference from the literature regarding associations between the potential biomarker and any medication
Studies of biomarkers for disease activity assessment We examined eight study-design features (Table 1), including whether patients with active and inactive disease were matched for age, sex, and race, or whether a statistical adjustment was made for these factors, and whether the authors reported any one of three possible methods to control for confounding by treatment
Summary
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. Dramatic recent progress in immunology has resulted in the recognition of new pathways mediating inflammation and tissue damage in systemic autoimmune diseases. These discoveries have led to the identification of biochemical, molecular, or genetic markers that indicate normal and pathogenic biologic processes or pharmacologic responses [1]. One goal of translational research is to test whether these markers, characterized as biomarkers, have clinical application in improving diagnostic. Laboratory scientists may not always design early translational studies with features that guard against confounding and information bias but may rather test samples of convenience. To know whether a biomarker is associated with a disease, matching patients and healthy controls on age and sex would be important
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