title: Personalized Medicine Enrichment Design for DHA Supplementation Clinical Trial.
abstract: Personalized medicine aims to match patient subpopulation to the most beneficial treatment. The purpose of this study is to design a prospective clinical trial in which we hope to achieve the highest level of confirmation in identifying and making treatment recommendations for subgroups, when the risk levels in the control arm can be ordered. This study was motivated by our goal to identify subgroups in a DHA (docosahexaenoic acid) supplementation trial to reduce preterm birth (gestational age<37 weeks) rate. We performed a meta-analysis to obtain informative prior distributions and simulated operating characteristics to ensure that overall Type I error rate was close to 0.05 in designs with three different models: independent, hierarchical, and dynamic linear models. We performed simulations and sensitivity analysis to examine the subgroup power of models and compared results to a chi-square test. We performed simulations under two hypotheses: a large overall treatment effect and a small overall treatment effect. Within each hypothesis, we designed three different subgroup effects scenarios where resulting subgroup rates are linear, flat, or nonlinear. When the resulting subgroup rates are linear or flat, dynamic linear model appeared to be the most powerful method to identify the subgroups with a treatment effect. It also outperformed other methods when resulting subgroup rates are nonlinear and the overall treatment effect is big. When the resulting subgroup rates are nonlinear and the overall treatment effect is small, hierarchical model and chi-square test did better. Compared to independent and hierarchical models, dynamic linear model tends to be relatively robust and powerful when the control arm has ordinal risk subgroups.
authors.affiliation: Department of Biostatistics, The University of Kansas Medical Center, School of Medicine, Mail Stop 1026, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Biostatistics, The University of Kansas Medical Center, School of Medicine, Mail Stop 1026, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Mayo
authors.affiliation: Department of Dietetics and Nutrition, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Carlson
authors.affiliation: Department of Biostatistics, The University of Kansas Medical Center, School of Medicine, Mail Stop 1026, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
authors.forename: Byron J
authors.initials: BJ
authors.lastname: Gajewski
keywords: enrichment design; overall Type I error; power; subgroup analysis