Modelling time-varying covariates effect on survival via functional data analysis: application to the MRC BO06 trial in osteosarcoma
Statistical Methods & Applications, vol. 32, pp. 271–298
Abstract
Abstract Time-varying covariates are of great interest in clinical research since they represent dynamic patterns which reflect disease progression. In cancer studies biomarkers values change as functions of time and chemotherapy treatment is modified by delaying a course or reducing the dose intensity, according to patient’s toxicity levels. In this work, a Functional covariate Cox Model (FunCM) to study the association between time-varying processes and a time-to-event outcome is proposed. FunCM first exploits functional data analysis techniques to represent time-varying processes in terms of functional data. Then, information related to the evolution of the functions over time is incorporated into functional regression models for survival data through functional principal component analysis. FunCM is compared to a standard time-varying covariate Cox model, commonly used despite its limiting assumptions that covariate values are constant in time and measured without errors. Data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma are analysed. Time-varying covariates related to alkaline phosphatase levels, white blood cell counts and chemotherapy dose during treatment are investigated. The proposed method allows to detect differences between patients with different biomarkers and treatment evolutions, and to include this information in the survival model. These aspects are seldom addressed in the literature and could provide new insights into the clinical research.
Authors 3
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Leiden University · Politecnico di Milano · University of Milano-Bicocca
Affiliation as printed
CHRP - National Center for Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, 20126, Milan, Italy
MOX - Laboratory for Modeling and Scientific Computing, Department of Mathematics, 20133, Politecnico di Milano, Milan, Italy
Mathematical Institute, Leiden University, Leiden, The Netherlands
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Politecnico di Milano · University of Milano-Bicocca · Human Technopole
Affiliation as printed
CHDS - Centre for Health Data Science, Human Technopole, 20157, Milan, Italy
CHRP - National Center for Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, 20126, Milan, Italy
MOX - Laboratory for Modeling and Scientific Computing, Department of Mathematics, 20133, Politecnico di Milano, Milan, Italy
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Leiden University · Leiden University Medical Center · Princess Máxima Center
Affiliation as printed
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
Mathematical Institute, Leiden University, Leiden, The Netherlands
Trial and Data Center, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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