Parameter estimation in nonlinear mixed effect models based on ordinary differential equations: An optimal control approach
Résumé
We present a parameter estimation method for nonlinear mixed effect
models based on ordinary differential equations (NLME-ODEs). The method
presented here aims at regularizing the estimation problem in presence
of model misspecifications, practical identifiability issues and unknown
initial conditions. For doing so, we define our estimator as the minimizer
of a cost function which incorporates a possible gap between the assumed
model at the population level and the specific individual dynamic.
The cost function computation leads to formulate and solve optimal
control problems at the subject level. This control theory approach
allows to bypass the need to know or estimate initial conditions for
each subject and it regularizes the estimation problem in presence
of poorly identifiable parameters. Comparing to maximum likelihood,
we show on simulation examples that our method improves estimation
accuracy in possibly partially observed systems with unknown initial
conditions or poorly identifiable parameters with or without model
error. We conclude this work with a real application on antibody concentration
data after vaccination against Ebola virus coming from phase 1 trials.
We use the estimated model discrepancy at the subject level to analyze
the presence of model misspecification.
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