title: The Limitations of Model-Based Experimental Design and Parameter Estimation in Sloppy Systems.
abstract: We explore the relationship among experimental design, parameter estimation, and systematic error in sloppy models. We show that the approximate nature of mathematical models poses challenges for experimental design in sloppy models. In many models of complex biological processes it is unknown what are the relevant physical mechanisms that must be included to explain system behaviors. As a consequence, models are often overly complex, with many practically unidentifiable parameters. Furthermore, which mechanisms are relevant/irrelevant vary among experiments. By selecting complementary experiments, experimental design may inadvertently make details that were ommitted from the model become relevant. When this occurs, the model will have a large systematic error and fail to give a good fit to the data. We use a simple hyper-model of model error to quantify a model's discrepancy and apply it to two models of complex biological processes (EGFR signaling and DNA repair) with optimally selected experiments. We find that although parameters may be accurately estimated, the discrepancy in the model renders it less predictive than it was in the sloppy regime where systematic error is small. We introduce the concept of a sloppy system-a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. We explore the limits of accurate parameter estimation in sloppy systems and argue that identifying underlying mechanisms controlling system behavior is better approached by considering a hierarchy of models of varying detail rather than focusing on parameter estimation in a single model.
authors.affiliation: Department of Physics & Astronomy, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Andrew
authors.identifier: 0000-0001-7249-8950
authors.initials: A
authors.lastname: White
authors.affiliation: Department of Physics & Astronomy, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Malachi
authors.initials: M
authors.lastname: Tolman
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Thames
authors.affiliation: Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Hubert Rodney
authors.initials: HR
authors.lastname: Withers
authors.affiliation: Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Mason
authors.affiliation: Department of Physics & Astronomy, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Mark K
authors.identifier: 0000-0001-9529-9399
authors.initials: MK
authors.lastname: Transtrum
mesh_terms: D000465:Algorithms; D000818:Animals; D004260:DNA Repair; D066246:ErbB Receptors; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D012107:Research Design; D015398:Signal Transduction; D014916:Whole-Body Irradiation
chemical_list: D066246:ErbB Receptors