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Evaluation of estimation methods and power of tests of discrete covariates in repeated time-to-event parametric models: application to Gaucher patients treated by imiglucerase

Published inThe AAPS journal, vol. 16, no. 3, p. 415-423
Publication date2014
Abstract

Analysis of repeated time-to-event data is increasingly performed in pharmacometrics using parametric frailty models. The aims of this simulation study were (1) to assess estimation performance of Stochastic Approximation Expectation Maximization (SAEM) algorithm in MONOLIX, Adaptive Gaussian Quadrature (AGQ), and Laplace algorithm in PROC NLMIXED of SAS and (2) to evaluate properties of test of a dichotomous covariate on occurrence of events. The simulation setting is inspired from an analysis of occurrence of bone events after the initiation of treatment by imiglucerase in patients with Gaucher Disease (GD). We simulated repeated events with an exponential model and various dropout rates: no, low, or high. Several values of baseline hazard model, variability, number of subject, and effect of covariate were studied. For each scenario, 100 datasets were simulated for estimation performance and 500 for test performance. We evaluated estimation performance through relative bias and relative root mean square error (RRMSE). We studied properties of Wald and likelihood ratio test (LRT). We used these methods to analyze occurrence of bone events in patients with GD after starting an enzyme replacement therapy. SAEM with three chains and AGQ algorithms provided good estimates of parameters much better than SAEM with one chain and Laplace which often provided poor estimates. Despite a small number of repeated events, SAEM with three chains and AGQ gave small biases and RRMSE. Type I errors were closed to 5%, and power varied as expected for SAEM with three chains and AGQ. Probability of having at least one event under treatment was 19.1%.

Keywords
  • Adolescent
  • Adult
  • Algorithms
  • Child
  • Child, Preschool
  • Computer Simulation
  • Female
  • Gaucher Disease/drug therapy
  • Glucosylceramidase/pharmacokinetics/therapeutic use
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Models, Statistical
  • Reproducibility of Results
  • Young Adult
Affiliation Not a UNIGE publication
Citation (ISO format)
VIGAN, Marie, STIRNEMANN, Jérôme, MENTRÉ, France. Evaluation of estimation methods and power of tests of discrete covariates in repeated time-to-event parametric models: application to Gaucher patients treated by imiglucerase. In: The AAPS journal, 2014, vol. 16, n° 3, p. 415–423. doi: 10.1208/s12248-014-9575-x
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Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal1550-7416
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