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

  • Malek OkourEmail author
  • Pamala A. Jacobson
  • Ajay Israni
  • Richard C. Brundage
Original Research Article


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.


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.


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.


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.


Compliance with Ethical Standards


The study was supported by Grants (U19-AI070119 and U01-AI058013) from the National Institute of Allergy and Infectious Disease (PJ, AI).

Conflict of interest

The authors have no conflicts of interest.

Ethics approval

All procedures in this clinical study data were in accordance with the 1964 Helsinki declaration (and its amendments). For the clinical study, institutional Review Board approval was obtained at each participating center and all patients provided informed, written consents prior to enrollment. The clinical study is registered at (NCT00270712).

Supplementary material

13318_2019_550_MOESM1_ESM.docx (382 kb)
Supplementary material 1 (DOCX 382 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Clinical Pharmacology Modeling and Simulation (CPMS)GlaxoSmithKlineCollegevilleUSA
  2. 2.Department of Experimental and Clinical Pharmacology, College of PharmacyUniversity of MinnesotaMinneapolisUSA
  3. 3.Hennepin Health and Minnesota Medical Research FoundationMinneapolisUSA

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