title: Investigating association between behavior, corticosterone, heart rate, and blood pressure in rats using surrogate marker evaluation methodology.
abstract: The drug development process involves identifying a compound and assessing its merit through rigorous pre-clinical and clinical trials. The pre-clinical stage is designed to assess the chemical properties of the new drug, as well as to determine the steps for synthesis and purification. In this stage of drug development, circumstances might dictate the use of alternative endpoints than the originally anticipated clinically relevant endpoint. In this regard, identification and evaluation of surrogate endpoints is of paramount importance. The validation methods make it possible to quantify degrees of association between the clinically relevant endpoint, also termed the true endpoint, and the alternative, surrogate endpoint. In this paper, we adapt the surrogate marker evaluation methodology of Alonso et al. (2003); (2006), developed for the case of two longitudinal outcomes, to the situation where either a longitudinal surrogate and cross sectional true endpoint is recorded, or vice versa. The work is motivated by a preclinical experiment conducted to assess association between corticosterone (CORT), heart rate, and blood pressure in rats, the data from which are then subjected to analysis. It was found that there is a weak relationship between CORT and behavior, and between CORT on the one hand and heart rate and blood pressure on the other hand, but a reasonably high degree of association was registered between heart rate and behavior.
authors.affiliation: Center for Statistics, Hasselt University, Diepenbeek, Belgium.
authors.forename: Abel
authors.initials: A
authors.lastname: Tilahun
authors.forename: John T
authors.initials: JT
authors.lastname: Maringwa
authors.forename: Helena
authors.initials: H
authors.lastname: Geys
authors.forename: Ariel
authors.initials: A
authors.lastname: Alonso
authors.forename: Leen
authors.initials: L
authors.lastname: Raeymaekers
authors.forename: Geert
authors.initials: G
authors.lastname: Molenberghs
authors.forename: Gerd
authors.initials: G
authors.lastname: Van Den Kieboom
authors.forename: Pim
authors.initials: P
authors.lastname: Drinkenburg
authors.forename: Luc
authors.initials: L
authors.lastname: Bijnens
mesh_terms: D000465:Algorithms; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000097:blood*; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D020407:Internet; D016014:Linear Models; D015233:Models, Statistical; D011619:Psychotropic Drugs / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D012984:Software; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D015415:Biomarkers; D011619:Psychotropic Drugs; D003345:Corticosterone