Virtual Patient Simulation Using Copula Modeling
Clinical Pharmacology & Therapeutics, vol. 115, pp. 795–804
Abstract
Virtual patient simulation is increasingly performed to support model-based optimization of clinical trial designs or individualized dosing strategies. Quantitative pharmacological models typically incorporate individual-level patient characteristics, or covariates, which enable the generation of virtual patient cohorts. The individual-level patient characteristics, or covariates, used as input for such simulations should accurately reflect the values seen in real patient populations. Current methods often make unrealistic assumptions about the correlation between patient's covariates or require direct access to actual data sets with individual-level patient data, which may often be limited by data sharing limitations. We propose and evaluate the use of copulas to address current shortcomings in simulation of patient-associated covariates for virtual patient simulations for model-based dose and trial optimization in clinical pharmacology. Copulas are multivariate distribution functions that can capture joint distributions, including the correlation, of covariate sets. We compare the performance of copulas to alternative simulation strategies, and we demonstrate their utility in several case studies. Our work demonstrates that copulas can reproduce realistic patient characteristics, both in terms of individual covariates and the dependence structure between different covariates, outperforming alternative methods, in particular when aiming to reproduce high-dimensional covariate sets. In conclusion, copulas represent a versatile and generalizable approach for virtual patient simulation which preserve relationships between covariates, and offer an open science strategy to facilitate re-use of patient data sets.
Authors 6
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Laura B. Zwep Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research Leiden University Leiden The Netherlands
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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Tingjie Guo Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research Leiden University Leiden The Netherlands
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Statistics Ludwig Maximilian University of Munich Munich Germany
Department of Statistics, Ludwig Maximilian University of Munich, Munich, Germany
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Catherijne A. J. Knibbe Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Leiden University · St. Antonius Ziekenhuis
Affiliation as printed
Department of Clinical Pharmacy St. Antonius Hospital Nieuwegein The Netherlands
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research Leiden University Leiden The Netherlands
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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Affiliation as printed
Department of Statistics Stanford University Stanford California USA
LUXs Data Science Leiden The Netherlands
Department of Statistics Stanford University Stanford California USA
LUXs Data Science, Leiden, The Netherlands
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J. G. Coen van Hasselt corresponding Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research Leiden University Leiden The Netherlands
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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