Hass, H. | bioRxiv Science

bioRxiv2018

Benchmark Problems for Dynamic Modeling of Intracellular Processes

MotivationDynamic models are used in systems biology to study and understand cellular processes like gene regulation or signal transduction. Frequently, ordinary differential equation (ODE) models are used to model the time and dose dependency of the abundances of molecular compounds as well as interactions and translocations. A multitude of computational approaches have been developed within recent years. However, many of these approaches lack proper testing in application settings because a comprehensive set of benchmark problems is yet missing.\n\nResultsWe present a collection of 20 ODE models developed given experimental data as benchmark problems in order to evaluate new and existing methodologies, e.g. for parameter estimation or uncertainty analysis. In addition to the equations of the dynamical system, the benchmark collection provides experimental measurements as well as observation functions and assumptions about measurement noise distributions and parameters. The presented benchmark models comprise problems of different size, complexity and numerical demands. Important characteristics of the models and methodological requirements are summarized, estimated parameters are provided, and some example studies were performed for illustrating the capabilities of the presented benchmark collection.\n\nAvailabilityThe models are provided in several standardized formats, including an easy-to-use human readable form and machine-readable SBML files. The data is provided as Excel sheets. All files are available at https://github.com/Benchmarking-Initiative/Benchmark-Models, with MATLAB code to process and simulate the models.\n\nContactjan.hasenauer@helmholtz-muenchen.de, ckreutz@fdm.uni-freiburg.de

systems biology↗

bioRxiv2017

Predicting Ligand-Dependent Tumors From Multi-Dimensional Signaling Features

Targeted therapies have shown significant patient benefit in about 5-10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great benefit in unselected patient populations. Using a novel approach of applying Bagged Decision Trees (BDT) to high-dimensional signaling features derived from a computational model, we can predict ligand dependent proliferation across a set of 58 cell lines. This mechanistic, multi-pathway model that features receptor heterodimerization, was trained on seven cancer cell lines and can predict signaling across two independent cell lines by adjusting only the receptor expression levels for each cell line. Interestingly, for patient samples the predicted tumor growth response correlates with high growth factor expression in the tumor microenvironment, which argues for a co-evolution of both factors in vivo.\n\nSummaryPrediction of ligand-induced growth of cancer cell lines, which correlates with ligand-blocking antibody efficacy, could be significantly improved by learning from features of a mechanistic signaling model, and was applied to reveal a correlation between growth factor expression and predicted response in patient samples.

systems biology↗