title: Rational selection of experimental readout and intervention sites for reducing uncertainties in computational model predictions.
abstract: BACKGROUND
  Understanding the dynamics of biological processes can substantially be supported by computational models in the form of nonlinear ordinary differential equations (ODE). Typically, this model class contains many unknown parameters, which are estimated from inadequate and noisy data. Depending on the ODE structure, predictions based on unmeasured states and associated parameters are highly uncertain, even undetermined. For given data, profile likelihood analysis has been proven to be one of the most practically relevant approaches for analyzing the identifiability of an ODE structure, and thus model predictions. In case of highly uncertain or non-identifiable parameters, rational experimental design based on various approaches has shown to significantly reduce parameter uncertainties with minimal amount of effort.
  
  
  RESULTS
  In this work we illustrate how to use profile likelihood samples for quantifying the individual contribution of parameter uncertainty to prediction uncertainty. For the uncertainty quantification we introduce the profile likelihood sensitivity (PLS) index. Additionally, for the case of several uncertain parameters, we introduce the PLS entropy to quantify individual contributions to the overall prediction uncertainty. We show how to use these two criteria as an experimental design objective for selecting new, informative readouts in combination with intervention site identification. The characteristics of the proposed multi-criterion objective are illustrated with an in silico example. We further illustrate how an existing practically non-identifiable model for the chlorophyll fluorescence induction in a photosynthetic organism, D. salina, can be rendered identifiable by additional experiments with new readouts.
  
  
  CONCLUSIONS
  Having data and profile likelihood samples at hand, the here proposed uncertainty quantification based on prediction samples from the profile likelihood provides a simple way for determining individual contributions of parameter uncertainties to uncertainties in model predictions. The uncertainty quantification of specific model predictions allows identifying regions, where model predictions have to be considered with care. Such uncertain regions can be used for a rational experimental design to render initially highly uncertain model predictions into certainty. Finally, our uncertainty quantification directly accounts for parameter interdependencies and parameter sensitivities of the specific prediction.
authors.affiliation: Department Process Systems Engineering (PSE), Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, Magdeburg, D-39106, Germany. flassig@mpi-magdeburg.mpg.de.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Flassig
authors.affiliation: Department Process Systems Engineering (PSE), Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, Magdeburg, D-39106, Germany. migal@mpi-magdeburg.mpg.de.
authors.forename: Iryna
authors.initials: I
authors.lastname: Migal
authors.affiliation: Department Process Systems Engineering (PSE), Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, Magdeburg, D-39106, Germany. van_der_zalm@mpi-magdeburg.mpg.de.
authors.forename: Esther van
authors.initials: Ev
authors.lastname: der Zalm
authors.affiliation: Department Process Systems Engineering (PSE), Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, Magdeburg, D-39106, Germany. rihko@mpi-magdeburg.mpg.de.
authors.forename: Liisa
authors.initials: L
authors.lastname: Rihko-Struckmann
authors.affiliation: Department Process Systems Engineering (PSE), Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, Magdeburg, D-39106, Germany. sundmacher@mpi-magdeburg.mpg.de.|Department Process Systems Engineering, Otto von Guericke University Magdeburg, Universitätsplatz 2, Magdeburg, D-39106, Germany. sundmacher@mpi-magdeburg.mpg.de.
authors.forename: Kai
authors.initials: K
authors.lastname: Sundmacher
mesh_terms: D002734:Chlorophyll / Q000737:chemistry; D000460:Chlorophyta / Q000737:chemistry; D003198:Computer Simulation; D016013:Likelihood Functions; D008954:Models, Biological; D035501:Uncertainty
chemical_list: D002734:Chlorophyll