Comparative Evaluation of Median Versus Youden Index Dichotomization Methods: Exposure–Response Analysis of Mycophenolic Acid and Acyl-Glucuronide Metabolite
- 4 Downloads
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.
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 http://www.clinicaltrials.gov (NCT00270712).
- 1.Linnet K, Brandt E. Assessing diagnostic tests once an optimal cut-off point has been selected. Clin Chem. 1986;32(7):1341–6.Google Scholar
- 7.Schutz E, Shipkova M, Armstrong VW, Wieland E, Oellerich M. Identification of a pharmacologically active metabolite of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Clin Chem. 1999;45(3):419–22.Google Scholar
- 8.Shipkova M, Armstrong VW, Wieland E, Niedmann PD, Schutz E, Brenner-Weiss G, Voihsel M, Braun F, Oellerich M. Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Br J Pharmacol. 1999;126(5):1075–82. https://doi.org/10.1038/sj.bjp.0702399.CrossRefGoogle Scholar
- 11.Dupuis R, Yuen A, Innocenti F. The Influence of Ugt Polymorphisms as Biomarkers in Solid Organ Transplantation. Clin Chim Acta. 2012;413(17–18):1318–1325. https://doi.org/10.1016/j.cca.2012.01.031.
- 14.Nowak I, Shaw LM. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem. 1995;41(7):1011–7.Google Scholar
- 16.Van Gelder T, Hilbrands L, Vanrenterghem Y, Weimar W, De Fijter J, Squifflet J, Hene R, Verpooten G, Navarro M, Hale M. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation1. Transplantation. 1999;68(2):261–6.CrossRefGoogle Scholar
- 18.Oellerich M, Shipkova M, Schütz E, Wieland E, Weber L, Tönshoff B, Armstrong VW, Recipients GSGoMMTiPRT. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: implications for therapeutic drug monitoring. Ther Drug Monit. 2000;22(1):20–6.CrossRefGoogle Scholar
- 19.Mourad M, Malaise J, Eddour DC, De Meyer M, König J, Schepers R, Squifflet JP, Wallemacq P. Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem. 2001;47(1):88–94.Google Scholar
- 24.Team RC. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2014.Google Scholar
- 26.Wickham H, Francois R. Dplyr: a grammar of data manipulation. R package version. 2014;03:02.Google Scholar
- 27.Kuypers D, Vanrenterghem Y, Squifflet J-P, Mourad M, Abramowicz D, Oellerich M, Armstrong V, Shipkova M, Daems J. Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil. Ther Drug Monit. 2003;25(5):609–22.CrossRefGoogle Scholar
- 31.Kuypers DR, de Jonge H, Naesens M, de Loor H, Halewijck E, Dekens M, Vanrenterghem Y. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients. Clin Ther. 2008;30(4):673–83.CrossRefGoogle Scholar
- 33.Buxhofer-Ausch V, Steurer M, Sormann S, Schloegl E, Schimetta W, Gisslinger B, Ruckser R, Gastl G, Gisslinger H. Influence of platelet and white blood cell counts on major thrombosis-analysis from a patient registry in essential thrombocythemia. Eur J Haematol. 2016;97(6):511–6.CrossRefGoogle Scholar
- 34.Ryan CJ, Rosenthal M, Ng S, Alumkal J, Picus J, Gravis G, Fizazi K, Forget F, Machiels JP, Srinivas S, Zhu M, Tang R, Oliner KS, Jiang Y, Loh E, Dubey S, Gerritsen WR. Targeted met inhibition in castration-resistant prostate cancer: a randomized phase ii study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. Clin Cancer Res. 2013;19(1):215–24. https://doi.org/10.1158/1078-0432.ccr-12-2605.CrossRefGoogle Scholar
- 36.White KT, Moorthy M, Akinkuolie AO, Demler O, Ridker PM, Cook NR, Mora S. Identifying an optimal cut-point for the diagnosis of hypertriglyceridemia in the nonfasting state. Clin Chem. 2015;2015:241752.Google Scholar