Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction: Standards for Study Design

TLDR

Research methods for biomarker evaluation lag behind those for therapeutic treatments, and although a phased approach and reporting guidelines exist, a comprehensive set of design guidelines has not been delineated. The authors propose a nested case–control design with prospective specimen collection to evaluate biomarkers for diagnosis, screening, or prognosis, detailing clinical context, performance criteria, test, and sample size. The design involves prospective specimen collection and blinded assays on randomly selected case and control subjects from a relevant cohort. Adhering to these rigorous standards would eliminate common biases in biomarker research.

Abstract

Research methods for biomarker evaluation lag behind those for evaluating therapeutic treatments. Although a phased approach to development of biomarkers exists and guidelines are available for reporting study results, a coherent and comprehensive set of guidelines for study design has not been delineated. We describe a nested case–control study design that involves prospective collection of specimens before outcome ascertainment from a study cohort that is relevant to the clinical application. The biomarker is assayed in a blinded fashion on specimens from randomly selected case patients and control subjects in the study cohort. We separately describe aspects of the design that relate to the clinical context, biomarker performance criteria, the biomarker test, and study size. The design can be applied to studies of biomarkers intended for use in disease diagnosis, screening, or prognosis. Common biases that pervade the biomarker research literature would be eliminated if these rigorous standards were followed.