TY - JOUR T1 - Efficient parameterization of large-scale dynamic models based on relative measurements JF - bioRxiv DO - 10.1101/579045 SP - 579045 AU - Leonard Schmiester AU - Yannik Schälte AU - Fabian Fröhlich AU - Jan Hasenauer AU - Daniel Weindl Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/03/16/579045.abstract N2 - Motivation Mechanistic models of biochemical reaction networks facilitate the quantitative understanding of biological processes and the integration of heterogeneous datasets. However, some biological processes require the consideration of comprehensive reaction networks and therefore large-scale models. Parameter estimation for such models poses great challenges, in particular when the data are on a relative scale.Results Here, we propose a novel hierarchical approach combining (i) the efficient analytic evaluation of optimal scaling, offset, and error model parameters with (ii) the scalable evaluation of objective function gradients using adjoint sensitivity analysis. We evaluate the properties of the methods by parameterizing a pan-cancer ordinary differential equation model (> 1000 state variables, > 4000 parameters) using relative protein, phospho-protein and viability measurements. The hierarchical formulation improves optimizer performance considerably. Furthermore, we show that this approach allows estimating error model parameters with negligible computational overhead when no experimental estimates are available, pro-viding an unbiased way to weight heterogeneous data. Overall, our hierarchical formulation is applicable to a wide range of models, and allows for the efficient parameterization of large-scale models based on heterogeneous relative measurements.Contact jan.hasenauer{at}helmholtz-muenchen.deSupplementary information Supplementary information are available at bioRxiv online. Supplementary code and data are available online at http://doi.org/10.5281/zenodo.2593839 and http://doi.org/10.5281/zenodo.2592186. ER -