Comparative Evaluation of Median Versus Youden Index Dichotomization Methods: Exposure–Response Analysis of Mycophenolic Acid and Acyl-Glucuronide Metabolite

Malek Okour, Pamala A Jacobson, Ajay Israni, Richard Brundage

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Abstract

Background and Objectives: Dichotomization of pharmacokinetic exposure measures in exposure–response relationship studies provides results that are interpretable in clinical care. Several methods exist in the literature on how to define the cut-off values needed for the dichotomization process. Commonly, the sample median is utilized to define the dichotomizing value; however, statistical methods based on the exposure metric and its association with the outcome are argued to result in a more proper definition of the optimal cut-point. The Youden index is a recommended statistical method to define the cut-off value. The current analysis objective is to compare the dichotomization results based on the Youden index versus median methods. Methods: Utilizing mycophenolic acid (MPA) exposure data and its related acute rejection and leukopenia outcome variables, the current study compared the MPA exposure–response relationship outcomes when MPA exposure is dichotomized via the Youden index versus median methods. Univariate logistic models were utilized to quantify the relationships between MPA exposure, including total MPA, unbound MPA, and the acyl-glucuronide metabolite of MPA, and the probabilities of acute rejection and leukopenia. Results: The overall trend of the results of the logistic models demonstrated a general similarity in the inferred exposure–response associations when considering either the Youden index-based or the median-based dichotomization methods. Conclusion: The results demonstrated in this analysis suggest that both the Youden index and the median methods provide similar conclusions when dichotomization of a continuous variable is considered. However, confirmation of these conclusions comes from future powered studies that include a larger number of subjects.

Original languageEnglish (US)
Pages (from-to)629-638
Number of pages10
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
Volume44
Issue number5
DOIs
StatePublished - Oct 1 2019

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Mycophenolic Acid
Leukopenia
Logistic Models
mycophenolic acid glucuronide
Pharmacokinetics

PubMed: MeSH publication types

  • Journal Article

Cite this

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title = "Comparative Evaluation of Median Versus Youden Index Dichotomization Methods: Exposure–Response Analysis of Mycophenolic Acid and Acyl-Glucuronide Metabolite",
abstract = "Background and Objectives: Dichotomization of pharmacokinetic exposure measures in exposure–response relationship studies provides results that are interpretable in clinical care. Several methods exist in the literature on how to define the cut-off values needed for the dichotomization process. Commonly, the sample median is utilized to define the dichotomizing value; however, statistical methods based on the exposure metric and its association with the outcome are argued to result in a more proper definition of the optimal cut-point. The Youden index is a recommended statistical method to define the cut-off value. The current analysis objective is to compare the dichotomization results based on the Youden index versus median methods. Methods: Utilizing mycophenolic acid (MPA) exposure data and its related acute rejection and leukopenia outcome variables, the current study compared the MPA exposure–response relationship outcomes when MPA exposure is dichotomized via the Youden index versus median methods. Univariate logistic models were utilized to quantify the relationships between MPA exposure, including total MPA, unbound MPA, and the acyl-glucuronide metabolite of MPA, and the probabilities of acute rejection and leukopenia. Results: The overall trend of the results of the logistic models demonstrated a general similarity in the inferred exposure–response associations when considering either the Youden index-based or the median-based dichotomization methods. Conclusion: The results demonstrated in this analysis suggest that both the Youden index and the median methods provide similar conclusions when dichotomization of a continuous variable is considered. However, confirmation of these conclusions comes from future powered studies that include a larger number of subjects.",
author = "Malek Okour and Jacobson, {Pamala A} and Ajay Israni and Richard Brundage",
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T1 - Comparative Evaluation of Median Versus Youden Index Dichotomization Methods

T2 - Exposure–Response Analysis of Mycophenolic Acid and Acyl-Glucuronide Metabolite

AU - Okour, Malek

AU - Jacobson, Pamala A

AU - Israni, Ajay

AU - Brundage, Richard

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N2 - Background and Objectives: Dichotomization of pharmacokinetic exposure measures in exposure–response relationship studies provides results that are interpretable in clinical care. Several methods exist in the literature on how to define the cut-off values needed for the dichotomization process. Commonly, the sample median is utilized to define the dichotomizing value; however, statistical methods based on the exposure metric and its association with the outcome are argued to result in a more proper definition of the optimal cut-point. The Youden index is a recommended statistical method to define the cut-off value. The current analysis objective is to compare the dichotomization results based on the Youden index versus median methods. Methods: Utilizing mycophenolic acid (MPA) exposure data and its related acute rejection and leukopenia outcome variables, the current study compared the MPA exposure–response relationship outcomes when MPA exposure is dichotomized via the Youden index versus median methods. Univariate logistic models were utilized to quantify the relationships between MPA exposure, including total MPA, unbound MPA, and the acyl-glucuronide metabolite of MPA, and the probabilities of acute rejection and leukopenia. Results: The overall trend of the results of the logistic models demonstrated a general similarity in the inferred exposure–response associations when considering either the Youden index-based or the median-based dichotomization methods. Conclusion: The results demonstrated in this analysis suggest that both the Youden index and the median methods provide similar conclusions when dichotomization of a continuous variable is considered. However, confirmation of these conclusions comes from future powered studies that include a larger number of subjects.

AB - Background and Objectives: Dichotomization of pharmacokinetic exposure measures in exposure–response relationship studies provides results that are interpretable in clinical care. Several methods exist in the literature on how to define the cut-off values needed for the dichotomization process. Commonly, the sample median is utilized to define the dichotomizing value; however, statistical methods based on the exposure metric and its association with the outcome are argued to result in a more proper definition of the optimal cut-point. The Youden index is a recommended statistical method to define the cut-off value. The current analysis objective is to compare the dichotomization results based on the Youden index versus median methods. Methods: Utilizing mycophenolic acid (MPA) exposure data and its related acute rejection and leukopenia outcome variables, the current study compared the MPA exposure–response relationship outcomes when MPA exposure is dichotomized via the Youden index versus median methods. Univariate logistic models were utilized to quantify the relationships between MPA exposure, including total MPA, unbound MPA, and the acyl-glucuronide metabolite of MPA, and the probabilities of acute rejection and leukopenia. Results: The overall trend of the results of the logistic models demonstrated a general similarity in the inferred exposure–response associations when considering either the Youden index-based or the median-based dichotomization methods. Conclusion: The results demonstrated in this analysis suggest that both the Youden index and the median methods provide similar conclusions when dichotomization of a continuous variable is considered. However, confirmation of these conclusions comes from future powered studies that include a larger number of subjects.

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