title: Stratification and partial ascertainment of biomarker value in biomarker-driven clinical trials.
abstract: This article examines the role of stratification of treatment assignment with regard to biomarker value in clinical trials that accept biomarker-positive and -negative patients but have a primary objective of evaluating treatment effect separately for the marker-positive subset. It also examines the issue of incomplete ascertainment of biomarker value and how this affects inference about treatment effect for the biomarker-positive subset of patients. I find that stratifying the randomization for the biomarker ensures that all patients will have tissue collected but is not necessary for the validity of inference for the biomarker-positive subset if there is complete ascertainment. If there is not complete ascertainment of biomarker values, it is important to establish that ascertainment is independent of treatment assignment. Having a large proportion of cases with biomarker ascertainment is not necessary for establishing internal validity of the treatment evaluation in biomarker-positive patients; independence of ascertainment and treatment is the important factor. Having a large proportion of cases with biomarker ascertainment makes it more likely that biomarker-positive patients with ascertainment are representative of the biomarker-positive patients in the clinical trial (with and without ascertainment), but since the patients in the clinical trial are a convenience sample of the population of patients potentially eligible for the trial, requiring a large proportion of cases with ascertainment does not facilitate generalizability of conclusions.
authors.affiliation: a National Cancer Institute , Rockville , Maryland , USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Simon
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D006801:Humans; D015233:Models, Statistical; D011237:Predictive Value of Tests; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data*; D012107:Research Design; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers
keywords: Ascertainment; Biomarker; Clinical trials; Stratification