title: Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system.
abstract: A deterministic biologically based dose-response model for the thyroidal system in a near-term pregnant woman and the fetus was recently developed to evaluate quantitatively thyroid hormone perturbations. The current work focuses on conducting a quantitative global sensitivity analysis on this complex model to identify and characterize the sources and contributions of uncertainties in the predicted model output. The workflow and methodologies suitable for computationally expensive models, such as the Morris screening method and Gaussian Emulation processes, were used for the implementation of the global sensitivity analysis. Sensitivity indices, such as main, total and interaction effects, were computed for a screened set of the total thyroidal system descriptive model input parameters. Furthermore, a narrower sub-set of the most influential parameters affecting the model output of maternal thyroid hormone levels were identified in addition to the characterization of their overall and pair-wise parameter interaction quotients. The characteristic trends of influence in model output for each of these individual model input parameters over their plausible ranges were elucidated using Gaussian Emulation processes. Through global sensitivity analysis we have gained a better understanding of the model behavior and performance beyond the domains of observation by the simultaneous variation in model inputs over their range of plausible uncertainties. The sensitivity analysis helped identify parameters that determine the driving mechanisms of the maternal and fetal iodide kinetics, thyroid function and their interactions, and contributed to an improved understanding of the system modeled. We have thus demonstrated the use and application of global sensitivity analysis for a biologically based dose-response model for sensitive life-stages such as pregnancy that provides richer information on the model and the thyroidal system modeled compared to local sensitivity analysis.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration Jefferson, AR, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Lumen
authors.affiliation: Health and Safety Laboratory Buxton, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: McNally
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration Jefferson, AR, USA.
authors.forename: Nysia
authors.initials: N
authors.lastname: George
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration Jefferson, AR, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Fisher
authors.affiliation: Health and Safety Laboratory Buxton, UK.
authors.forename: George D
authors.initials: GD
authors.lastname: Loizou
keywords: BBDR; PBPK; global sensitivity analysis; iodide; modeling; pregnancy; thyroid; thyroid hormones