Journal of Pharmacokinetics and Pharmacodynamics

, Volume 40, Issue 4, pp 537–544

Mixed-effects beta regression for modeling continuous bounded outcome scores using NONMEM when data are not on the boundaries

  • Xu Steven Xu
  • Mahesh N. Samtani
  • Adrian Dunne
  • Partha Nandy
  • An Vermeulen
  • Filip De Ridder
  • The Alzheimer’s Disease Neuroimaging Initiative
Short Report

DOI: 10.1007/s10928-013-9318-0

Cite this article as:
Xu, X.S., Samtani, M.N., Dunne, A. et al. J Pharmacokinet Pharmacodyn (2013) 40: 537. doi:10.1007/s10928-013-9318-0

Abstract

Beta regression models have been recommended for continuous bounded outcome scores that are often collected in clinical studies. Implementing beta regression in NONMEM presents difficulties since it does not provide gamma functions required by the beta distribution density function. The objective of the study was to implement mixed-effects beta regression models in NONMEM using Nemes’ approximation to the gamma function and to evaluate the performance of the NONMEM implementation of mixed-effects beta regression in comparison to the commonly used SAS approach. Monte Carlo simulations were conducted to simulate continuous outcomes within an interval of (0, 70) based on a beta regression model in the context of Alzheimer’s disease. Six samples per subject over a 3 years period were simulated at 0, 0.5, 1, 1.5, 2, and 3 years. One thousand trials were simulated and each trial had 250 subjects. The simulation–reestimation exercise indicated that the NONMEM implementation using Laplace and Nemes’ approximations provided only slightly higher bias and relative RMSE (RRMSE) compared to the commonly used SAS approach with adaptive Gaussian quadrature and built-in gamma functions, i.e., the difference in bias and RRMSE for fixed-effect parameters, random effects on intercept, and the precision parameter were <1–3 %, while the difference in the random effects on the slope was <3–7 % under the studied simulation conditions. The mixed-effect beta regression model described the disease progression for the cognitive component of the Alzheimer’s disease assessment scale from the Alzheimer’s Disease Neuroimaging Initiative study. In conclusion, with Nemes’ approximation of the gamma function, NONMEM provided comparable estimates to those from SAS for both fixed and random-effect parameters. In addition, the NONMEM run time for the mixed beta regression models appeared to be much shorter compared to SAS, i.e., 1–2 versus 20–40 s for the model and data used in the manuscript.

Supplementary material

10928_2013_9318_MOESM1_ESM.ppt (110 kb)
Supplementary Fig. 1. Histograms for the simulated data from a randomly selected simulation at different times when the precision parameter for the mixed-effects beta regression (τ) was set to 3 (1a), 5 (1b), and 7 (1c)
10928_2013_9318_MOESM2_ESM.ppt (110 kb)
Supplementary material 2 (PPT 107 kb)
10928_2013_9318_MOESM3_ESM.ppt (110 kb)
Supplementary material 3 (PPT 106 kb)
10928_2013_9318_MOESM4_ESM.ppt (107 kb)
Supplementary Fig. 2. Histograms for the ADAS-cog scores from the patients with Alzheimer’s Disease in the ADNI study

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Xu Steven Xu
    • 1
  • Mahesh N. Samtani
    • 1
  • Adrian Dunne
    • 2
  • Partha Nandy
    • 1
  • An Vermeulen
    • 2
  • Filip De Ridder
    • 2
  • The Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Model-Based Drug DevelopmentJanssen Research & DevelopmentRaritanUSA
  2. 2.Model-Based Drug DevelopmentJanssen Research & DevelopmentBeerseBelgium