Developing Tools to Evaluate Non-linear Mixed Effect Models: 20 Years on the npde Adventure

Abstract

This article revisits 20 years of our work in developing evaluation tools adapted to non-linear mixed effect models. These hierarchical models involve a large number of assumptions concerning the structural evolution of the outcomes, the link between different outcomes, the variabilities in the parameters and model evaluation aims at assessing these various components, both to help guide the model building and to communicate on model adequacy for a given purpose. During our career, we have developed and extended simulation-based evaluation tools called normalised prediction discrepancies (npd) and normalised prediction distribution errors (npde), providing informative diagnostics through graphs and tests.

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Contributions

The two (female) authors of this article (F. Mentré and E. Comets) have been the main architects for the development of npde. The original idea of prediction discrepancies was proposed by France Mentré with her PhD student Florence Mesnil for non-parametric mixed effect models and extended to general parametric models with Sylvie Escolano. Emmanuelle Comets got involved in the definition of npde and co-supervised the PhD of Karl Brendel, who also conducted in collaboration with Céline Dartois a survey of how population PK and PD analyses were evaluated. The extension of npde to BLQ data was the methodological topic of Tram (Thi Huyen) Nguyen, another female PhD student supervised by France Mentré. Tram was also the first author for the collaborative white paper by the ISoP group (29). Emmanuelle Comets supervised the PhD of Marc Cerou, our second male PhD student on the topic, who extended npd to models involving time-to-event and categorical outcomes (manuscript under preparation). Finally, we also would like to acknowledge the contribution since January 2020 of our engineer, Romain Leroux, for the latest version of the npde library. France Mentré was awarded the prestigious Lewis Sheiner lecturer award from the University of California and the International Society of Pharmacometrics in 2013, recalling in her lecture the prominent part of model evaluation in her career (2).

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Correspondence to Emmanuelle Comets.

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Comets, E., Mentré, F. Developing Tools to Evaluate Non-linear Mixed Effect Models: 20 Years on the npde Adventure. AAPS J 23, 75 (2021). https://doi.org/10.1208/s12248-021-00597-7

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KEY WORDS

  • mixed effect models
  • model diagnostics
  • model evaluation
  • NLMEM
  • npde