title: Analysis of clustered competing risks data using subdistribution hazard models with multivariate frailties.
abstract: Competing risks data often exist within a center in multi-center randomized clinical trials where the treatment effects or baseline risks may vary among centers. In this paper, we propose a subdistribution hazard regression model with multivariate frailty to investigate heterogeneity in treatment effects among centers from multi-center clinical trials. For inference, we develop a hierarchical likelihood (or h-likelihood) method, which obviates the need for an intractable integration over the frailty terms. We show that the profile likelihood function derived from the h-likelihood is identical to the partial likelihood, and hence it can be extended to the weighted partial likelihood for the subdistribution hazard frailty models. The proposed method is illustrated with a dataset from a multi-center clinical trial on breast cancer as well as with a simulation study. We also demonstrate how to present heterogeneity in treatment effects among centers by using a confidence interval for the frailty for each individual center and how to perform a statistical test for such heterogeneity using a restricted h-likelihood.
authors.affiliation: Department of Asset Management, Daegu Haany University, Gyeongsan, South Korea idha1353@pknu.ac.kr.
authors.forename: Il Do
authors.initials: ID
authors.lastname: Ha
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Christian
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Jong-Hyeon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Statistics, Seoul National University, Seoul, South Korea.
authors.forename: Junwoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Statistics, Seoul National University, Seoul, South Korea.
authors.forename: Youngjo
authors.initials: Y
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy; D003198:Computer Simulation; D006801:Humans; D016013:Likelihood Functions; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D013629:Tamoxifen
keywords: competing risks; hierarchical likelihood; multivariate frailty; random treatment-by-center interaction; subdistribution hazard