 Efficient Optimization of Stimuli for Model-Based Design of Experiments to Resolve Dynamical UncertaintyThembi Mdluli, Gregery T Buzzard and Ann E Rundell PLOS Computational Biology, 2015, vol. 11, issue 9, 1-23 Abstract: This model-based design of experiments (MBDOE) method determines the input magnitudes of an experimental stimuli to apply and the associated measurements that should be taken to optimally constrain the uncertain dynamics of a biological system under study. The ideal global solution for this experiment design problem is generally computationally intractable because of parametric uncertainties in the mathematical model of the biological system. Others have addressed this issue by limiting the solution to a local estimate of the model parameters. Here we present an approach that is independent of the local parameter constraint. This approach is made computationally efficient and tractable by the use of: (1) sparse grid interpolation that approximates the biological system dynamics, (2) representative parameters that uniformly represent the data-consistent dynamical space, and (3) probability weights of the represented experimentally distinguishable dynamics. Our approach identifies data-consistent representative parameters using sparse grid interpolants, constructs the optimal input sequence from a greedy search, and defines the associated optimal measurements using a scenario tree. We explore the optimality of this MBDOE algorithm using a 3-dimensional Hes1 model and a 19-dimensional T-cell receptor model. The 19-dimensional T-cell model also demonstrates the MBDOE algorithm’s scalability to higher dimensions. In both cases, the dynamical uncertainty region that bounds the trajectories of the target system states were reduced by as much as 86% and 99% respectively after completing the designed experiments in silico. Our results suggest that for resolving dynamical uncertainty, the ability to design an input sequence paired with its associated measurements is particularly important when limited by the number of measurements.Author Summary: Many mathematical models that have been developed for biological systems are limited because the complex systems are not well understood, the parameters are not known, and available data is limited and noisy. On the other hand, experiments to support model development are limited in terms of costs and time, feasible inputs and feasible measurements. MBDOE combines the mathematical models with experiment design to strategically design optimal experiments to obtain data that will contribute to the understanding of the systems. Our approach extends current capabilities of existing MBDOE techniques to make them more useful for scientists to resolve the trajectories of the system under study. It identifies the optimal conditions for stimuli and measurements that yield the most information about the system given the practical limitations. Exploration of the input space is not a trivial extension to MBDOE methods used for determining optimal measurements due to the nonlinear nature of many biological system models. The exploration of the system dynamics elicited by different inputs requires a computationally efficient and tractable approach. Our approach plans optimal experiments to reduce dynamical uncertainty in the output of selected target states of the biological system. Date: 2015 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1004488 DOI: 10.1371/journal.pcbi.1004488 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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