title: Validation of surrogate markers in multiple randomized clinical trials with repeated measurements: canonical correlation approach.
abstract: Part of the recent literature on the evaluation of biomarkers as surrogate endpoints starts from a multitrial context, which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between the surrogate and true endpoints (Buyse et al., 2000, Biostatistics1, 49-67). These authors concentrated on cross-sectional continuous responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. A challenge in this setting is the formulation of a simple and meaningful concept of "surrogacy."Alonso et al. (2003, Biometrical Journal45, 931-945) proposed the variance reduction factor (VRF) to evaluate surrogacy at the individual level. They also showed how and when this concept should be extended to study surrogacy at the trial level. Here, we approach the problem from the natural canonical correlation perspective. We define a class of canonical correlation functions that can be used to study surrogacy at the trial and individual level. We show that the VRF and the R2 measure defined by Buyse et al. (2000) follow as special cases. Simulations are conducted to evaluate the performance of different members of this family. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia.
authors.affiliation: Center for Statistics, Limburgs Universitair Centrum, Transnationale Universiteit Limburg, Universitaire Campus, B3590 Diepenbeek, Belgium. ariel.alonso@luc.ac.be
authors.forename: Ariel
authors.initials: A
authors.lastname: Alonso
authors.forename: Helena
authors.initials: H
authors.lastname: Geys
authors.forename: Geert
authors.initials: G
authors.lastname: Molenberghs
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kenward
authors.forename: Tony
authors.initials: T
authors.lastname: Vangeneugden
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D001699:Biometry; D023381:Endpoint Determination / Q000706:statistics & numerical data; D006801:Humans; D008137:Longitudinal Studies; D015201:Meta-Analysis as Topic; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D018967:Risperidone / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers; D018967:Risperidone