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.

Fig. 1

Exposure–response plot of the MPA exposure metrics versus acute rejection. For each patient, acute rejection was coded using a binary system of [0] and [1]. The [0] value indicated that the patient did not develop the event, and the [1] value indicated that the patient had developed the event. The dashed blue and solid red vertical lines in each plot represent the cut-off values suggested by the Youden index and the median, respectively. MPA mycophenolic acid, acyl-MPAG acyl-glucuronide metabolite of MPA, AUC_ss area under the curve at steady-state, C_max,ss maximum concentration at steady-state, C_min,ss minimum concentration at steady-state

Fig. 2

Exposure response plot of the MPA exposure metrics versus leukopenia. For each patient, leukopenia was coded using a binary system of [0] and [1]. The [0] value indicated that the patient did not develop the event, and the [1] value indicated that the patient had developed the event. The dashed blue and solid red vertical lines in each plot represent the cut-off values suggested by the Youden index and the median, respectively. MPA mycophenolic acid, acyl-MPAG acyl-glucuronide metabolite of MPA, AUC_ss area under the curve at steady-state, C_max,ss maximum concentration at steady-state, C_min,ss minimum concentration at steady-state