@article{RoeblitzWeber2013, author = {R{\"o}blitz, Susanna and Weber, Marcus}, title = {Fuzzy spectral clustering by PCCA+: application to Markov state models and data classification}, volume = {7}, journal = {Advances in Data Analysis and Classification}, number = {2}, doi = {10.1007/s11634-013-0134-6}, pages = {147 -- 179}, year = {2013}, language = {en} } @misc{Meisel2012, type = {Master Thesis}, author = {Meisel, Kristin}, title = {Mathematische Modellierung der Knochenremodellierung}, year = {2012}, language = {de} } @article{HaackFackeldeyRoeblitzetal.2013, author = {Haack, Fiete and Fackeldey, Konstantin and R{\"o}blitz, Susanna and Scharkoi, Olga and Weber, Marcus and Schmidt, Burkhard}, title = {Adaptive spectral clustering with application to tripeptide conformation analysis}, volume = {139}, journal = {The Journal of Chemical Physics}, doi = {10.1063/1.4830409}, pages = {110 -- 194}, year = {2013}, language = {en} } @inproceedings{SchaeferPloentzkeRoeblitz2016, author = {Sch{\"a}fer, Stefan and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {Mathematical Modelling of Follicular Maturation in Cows and Women}, booktitle = {49. Jahrestagung der Physiologie und Pathologie der Fortpflanzung und gleichzeitig 41. Veterin{\"a}r-Humanmedizinische Gemeinschaftstagung 2016, Leipzig.}, year = {2016}, language = {en} } @article{KlebanovSikorskiSchuetteetal.2021, author = {Klebanov, Ilja and Sikorski, Alexander and Sch{\"u}tte, Christof and R{\"o}blitz, Susanna}, title = {Objective priors in the empirical Bayes framework}, volume = {48}, journal = {Scandinavian Journal of Statistics}, number = {4}, publisher = {Wiley Online Library}, doi = {10.1111/sjos.12485}, pages = {1212 -- 1233}, year = {2021}, abstract = {When dealing with Bayesian inference the choice of the prior often remains a debatable question. Empirical Bayes methods offer a data-driven solution to this problem by estimating the prior itself from an ensemble of data. In the nonparametric case, the maximum likelihood estimate is known to overfit the data, an issue that is commonly tackled by regularization. However, the majority of regularizations are ad hoc choices which lack invariance under reparametrization of the model and result in inconsistent estimates for equivalent models. We introduce a nonparametric, transformation-invariant estimator for the prior distribution. Being defined in terms of the missing information similar to the reference prior, it can be seen as an extension of the latter to the data-driven setting. This implies a natural interpretation as a trade-off between choosing the least informative prior and incorporating the information provided by the data, a symbiosis between the objective and empirical Bayes methodologies.}, language = {en} } @misc{OmariPloentzkeRoeblitz2019, author = {Omari, Mohamed and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {A pharmacokinetic-pharmacodynamic model for single dose administration of Dexamethasone in dairy cows}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-75043}, year = {2019}, abstract = {We present a mechanistic pharmacokinetic-pharmacodynamic model to simulate the effect of dexamethasone on the glucose metabolism in dairy cows. The coupling of the pharmacokinetic model to the pharmacodynamic model is based on mechanisms underlying homeostasis regulation by dexamethasone. In particular, the coupling takes into account the predominant role of dexamethasone in stimulating glucagon secretion, glycogenolysis and lipolysis and in impairing the sensitivity of cells to insulin. Simulating the effect of a single dose of dexamethasone on the physiological behaviour of the system shows that the adopted mechanisms are able to induce a temporary hyperglycemia and hyperinsulinemia, which captures the observed data in non-lactating cows. In lactating cows, the model simulations show that a single dose of dexamethasone reduces the lipolytic effect, owing to the reduction of glucose uptake by the mammary gland.}, language = {en} } @article{OmariLangePloentzkeetal.2020, author = {Omari, Mohamed and Lange, Alexander and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {Model-based exploration of the impact of glucose metabolism on the estrous cycle dynamics in dairy cows}, volume = {15}, journal = {Biology Direct}, doi = {10.1186/s13062-019-0256-7}, year = {2020}, language = {en} } @article{WeberFischerDamerauetal.2020, author = {Weber, Marie-Christin and Fischer, Lisa and Damerau, Alexandra and Ponomarev, Igor and Pfeiffenberger, Moritz and Gaber, Timo and G{\"o}tschel, Sebastian and Lang, Jens and R{\"o}blitz, Susanna and Buttgereit, Frank and Ehrig, Rainald and Lang, Annemarie}, title = {Macroscale mesenchymal condensation to study cytokine-driven cellular and matrix-related changes during cartilage degradation}, volume = {12}, journal = {Biofabrication}, number = {4}, doi = {10.1088/1758-5090/aba08f}, year = {2020}, abstract = {Understanding the pathophysiological processes of cartilage degradation requires adequate model systems to develop therapeutic strategies towards osteoarthritis (OA). Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific disease aspects. This study aimed to combine in vitro and in silico modeling based on a tissue-engineering approach using mesenchymal condensation to mimic cytokine-induced cellular and matrix-related changes during cartilage degradation. Thus, scaffold-free cartilage-like constructs (SFCCs) were produced based on self-organization of mesenchymal stromal cells (mesenchymal condensation) and i) characterized regarding their cellular and matrix composition or secondly ii) treated with interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) for 3 weeks to simulate OA-related matrix degradation. In addition, an existing mathematical model based on partial differential equations was optimized and transferred to the underlying settings to simulate distribution of IL-1β, type II collagen degradation and cell number reduction. By combining in vitro and in silico methods, we aim to develop a valid, efficient alternative approach to examine and predict disease progression and effects of new therapeutics.}, language = {en} } @article{AlvesEhrigRaffaltetal.2020, author = {Alves, S{\´o}nia and Ehrig, Rainald and Raffalt, Peter C. and Bender, Alwina and Duda, Georg and Agres, Alison N.}, title = {Quantifying Asymmetry in Gait: A Weighted Universal Symmetry Index to Evaluate 3D Ground Reaction Forces}, journal = {Frontiers in Bioengineering and Biotechnology}, year = {2020}, abstract = {Though gait asymmetry is used as a metric of functional recovery in clinical rehabilitation, there is no consensus on an ideal method for its evaluation. Various methods have been proposed but are limited in scope, as they can often use only positive signals or discrete values extracted from time-scale data as input. By defining five symmetry axioms, a framework for benchmarking existing methods was established and a new method was described here for the first time: the weighted universal symmetry index (wUSI), which overcomes limitations of other methods. Both existing methods and the wUSI were mathematically compared to each other and in respect to their ability to fulfill the proposed symmetry axioms. Eligible methods that fulfilled these axioms were then applied using both discrete and continuous approaches to ground reaction force (GRF) data collected from healthy gait, both with and without artificially induced asymmetry using a single instrumented elbow crutch. The wUSI with a continuous approach was the only symmetry method capable of determining GRF asymmetries in different walking conditions in all three planes of motion. When used with a continuous approach, the wUSI method was able to detect asymmetries while avoiding artificial inflation, a common problem reported in other methods. In conclusion, the wUSI is proposed as a universal method to quantify three-dimensional GRF asymmetries, which may also be expanded to other biomechanical signals.}, language = {en} } @article{FischerEhrigSchaeferetal.2021, author = {Fischer, Sophie and Ehrig, Rainald and Sch{\"a}fer, Stefan and Tronci, Enrico and Mancini, Toni and Egli, Marcel and Ille, Fabian and Kr{\"u}ger, Tillmann H. C. and Leeners, Brigitte and R{\"o}blitz, Susanna}, title = {Mathematical Modelling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation}, volume = {12}, journal = {Frontiers in Endocrinology}, doi = {10.3389/fendo.2021.613048}, year = {2021}, abstract = {New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle which is especially useful when time for assisted reproductive technology is limited, e.g. for emergency fertility preservation in cancer patients. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts ("waves") of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modelling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.}, language = {en} } @article{LangVolkamerBehmetal.2018, author = {Lang, Annemarie and Volkamer, Andrea and Behm, Laura and R{\"o}blitz, Susanna and Ehrig, Rainald and Schneider, Marlon and Geris, Lisbet and Wichard, Joerg and Buttgereit, Frank}, title = {In silico Methods - Computational Alternatives to Animal Testing}, volume = {35}, journal = {ALTEX}, number = {1}, doi = {10.14573/altex.1712031}, pages = {126 -- 128}, year = {2018}, abstract = {A seminar and interactive workshop on "In silico Methods - Computational Alternatives to Animal Testing" was held in Berlin, Germany, organized by Annemarie Lang, Frank Butt- gereit and Andrea Volkamer at the Charit{\´e}-Universit{\"a}tsmedizin Berlin, on August 17-18, 2017. During the half-day seminar, the variety and applications of in silico methods as alternatives to animal testing were presented with room for scientific discus- sions with experts from academia, industry and the German fed- eral ministry (Fig. 1). Talks on computational systems biology were followed by detailed information on predictive toxicology in order to display the diversity of in silico methods and the potential to embrace them in current approaches (Hartung and Hoffmann, 2009; Luechtefeld and Hartung, 2017). The follow- ing interactive one-day Design Thinking Workshop was aimed at experts, interested researchers and PhD-students interested in the use of in silico as alternative methods to promote the 3Rs (Fig. 2). Forty participants took part in the seminar while the workshop was restricted to sixteen participants.}, language = {en} } @misc{HelfmannDjurdjevacConradDjurdjevacetal.2019, author = {Helfmann, Luzie and Djurdjevac Conrad, Natasa and Djurdjevac, Ana and Winkelmann, Stefanie and Sch{\"u}tte, Christof}, title = {From interacting agents to density-based modeling with stochastic PDEs}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-73456}, year = {2019}, abstract = {Many real-world processes can naturally be modeled as systems of interacting agents. However, the long-term simulation of such agent-based models is often intractable when the system becomes too large. In this paper, starting from a stochastic spatio-temporal agent-based model (ABM), we present a reduced model in terms of stochastic PDEs that describes the evolution of agent number densities for large populations. We discuss the algorithmic details of both approaches; regarding the SPDE model, we apply Finite Element discretization in space which not only ensures efficient simulation but also serves as a regularization of the SPDE. Illustrative examples for the spreading of an innovation among agents are given and used for comparing ABM and SPDE models.}, language = {en} } @misc{OmariLangePloentzkeetal.2019, author = {Omari, Mohamed and Lange, Alexander and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {A Mathematical Model for the Influence of Glucose-Insulin Dynamics on the Estrous Cycle in Dairy Cows}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-73475}, year = {2019}, abstract = {Nutrition plays a crucial role in regulating reproductive hormones and follicular development in cattle. This is visible particularly during the time of negative energy balance at the onset of milk production after calving. Here, elongated periods of anovulation have been observed, resulting from alterations in luteiniz- ing hormone concentrations, likely caused by lower glucose and insulin concen- trations in the blood. The mechanisms that result in a reduced fertility are not completely understood, although a close relationship to the glucose-insulin metabolism is widely supported. Following this idea, a mathematical model of the hormonal network combining reproductive hormones and hormones that are coupled to the glucose compartments within the body of the cow was developed. The model is built on ordinary differential equations and relies on previously introduced models on the bovine estrous cycle and the glucose-insulin dynam- ics. Necessary modifications and coupling mechanisms are thoroughly discussed. Depending on the composition and the amount of food, in particular the glu- cose content in the dry matter, the model quantifies reproductive hormones and follicular development over time. Simulation results for different nutritional regimes in lactating and non-lactating dairy cows are examined and compared with experimental studies. Regarding its applicability, this work is an early attempt towards developing in silico feeding strategies and may eventually help refining and reducing animal experiments.}, language = {en} } @article{WeberFischerDamerauetal.2019, author = {Weber, Marie-Christin and Fischer, Lisa and Damerau, Alexandra and Ponomarev, Igor and Pfeiffenberger, Moritz and Gaber, Timo and G{\"o}tschel, Sebastian and Lang, Jens and R{\"o}blitz, Susanna and Buttgereit, Frank and Ehrig, Rainald and Lang, Annemarie}, title = {In vitro and in silico modeling of cellular and matrix-related changes during the early phase of osteoarthritis}, journal = {BioRxiv}, doi = {10.1101/725317}, year = {2019}, abstract = {Understanding the pathophysiological processes of osteoarthritis (OA) require adequate model systems. Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific parts of the disease. This study aimed to combine in vitro and in silico modeling to describe cellular and matrix-related changes during the early phase of OA. We developed an in vitro OA model based on scaffold-free cartilage-like constructs (SFCCs), which was mathematically modeled using a partial differential equation (PDE) system to resemble the processes during the onset of OA. SFCCs were produced from mesenchymal stromal cells and analyzed weekly by histology and qPCR to characterize the cellular and matrix-related composition. To simulate the early phase of OA, SFCCs were treated with interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and examined after 3 weeks or cultivated another 3 weeks without inflammatory cytokines to validate the regeneration potential. Mathematical modeling was performed in parallel to the in vitro experiments. SFCCs expressed cartilage-specific markers, and after stimulation an increased expression of inflammatory markers, matrix degrading enzymes, a loss of collagen II (Col-2) and a reduced cell density was observed which could be partially reversed by retraction of stimulation. Based on the PDEs, the distribution processes within the SFCCs, including those of IL-1β, Col-2 degradation and cell number reduction was simulated. By combining in vitro and in silico methods, we aimed to develop a valid, efficient alternative approach to examine and predict disease progression and new therapeutic strategies.}, language = {en} } @article{LangFischerWeberetal.2019, author = {Lang, Annemarie and Fischer, Lisa and Weber, Marie-Christin and Gaber, Timo and Ehrig, Rainald and R{\"o}blitz, Susanna and Buttgereit, Frank}, title = {Combining in vitro simulation and in silico modelling towards a sophisticated human osteoarthritis model}, volume = {27}, journal = {Osteoarthritis and Cartilage}, doi = {10.1016/j.joca.2019.02.277}, pages = {S183}, year = {2019}, abstract = {Our project aimed at building an in silico model based on our recently developed in vitro osteoarthritis (OA) model seeking for refinement of the model to enhance validity and translatability towards the more sophisticated simulation of OA. In detail, the previously 3D in vitro model is based on 3D chondrogenic constructs generated solely from human bone marrow derived mesenchymal stromal cells (hMSCs). Besides studying the normal state of the model over 3 weeks, the in vitro model was treated with interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) to mimic an OA-like environment.}, language = {en} } @article{HelfmannDjurdjevacConradDjurdjevacetal.2021, author = {Helfmann, Luzie and Djurdjevac Conrad, Natasa and Djurdjevac, Ana and Winkelmann, Stefanie and Sch{\"u}tte, Christof}, title = {From interacting agents to density-based modeling with stochastic PDEs}, volume = {16}, journal = {Communications in Applied Mathematics and Computational Science}, number = {1}, arxiv = {http://arxiv.org/abs/1905.13525}, doi = {10.2140/camcos.2021.16.1}, pages = {1 -- 32}, year = {2021}, abstract = {Many real-world processes can naturally be modeled as systems of interacting agents. However, the long-term simulation of such agent-based models is often intractable when the system becomes too large. In this paper, starting from a stochastic spatio-temporal agent-based model (ABM), we present a reduced model in terms of stochastic PDEs that describes the evolution of agent number densities for large populations. We discuss the algorithmic details of both approaches; regarding the SPDE model, we apply Finite Element discretization in space which not only ensures efficient simulation but also serves as a regularization of the SPDE. Illustrative examples for the spreading of an innovation among agents are given and used for comparing ABM and SPDE models.}, language = {en} } @article{BoerStoetzelRoeblitzetal.2011, author = {Boer, H. Marike T. and St{\"o}tzel, Claudia and R{\"o}blitz, Susanna and Deuflhard, Peter and Veerkamp, Roel F. and Woelders, Henri}, title = {A simple mathematical model of the bovine estrous cycle}, volume = {278}, journal = {Journal of Theoretical Biology}, number = {1}, doi = {10.1016/j.jtbi.2011.02.021}, pages = {20 -- 31}, year = {2011}, language = {en} } @article{BoerRoeblitzStoetzeletal.2011, author = {Boer, H. Marike T. and R{\"o}blitz, Susanna and St{\"o}tzel, Claudia and Veerkamp, Roel F. and Kemp, Bas and Woelders, Henri}, title = {Mechanisms regulating follicle wave patterns in the bovine estrous cycle investigated with a mathematical model}, volume = {94}, journal = {Journal of Dairy Science}, number = {12}, doi = {10.3168/jds.2011-4400}, pages = {5987 -- 6000}, year = {2011}, language = {en} } @incollection{BoerStoetzelRoeblitzetal.2012, author = {Boer, H. Marike T. and St{\"o}tzel, Claudia and R{\"o}blitz, Susanna and Woelders, Henri}, title = {A differential equation model to investigate the dynamics of the bovine estrous cycle}, volume = {736}, booktitle = {Advances in Systems Biology}, doi = {10.1007/978-1-4419-7210-1_35}, pages = {597 -- 606}, year = {2012}, language = {en} } @article{BoerApriMolenaaretal.2012, author = {Boer, H. Marike T. and Apri, Mochamad and Molenaar, Jaap and St{\"o}tzel, Claudia and Veerkamp, Roel F. and Woelders, Henri}, title = {Candidate mechanisms underlying atypical progesterone profiles as deduced from parameter perturbations in a mathematical model of the bovine estrous cycle}, volume = {95}, journal = {Journal of Dairy Science}, number = {7}, doi = {10.3168/jds.2011-5241}, pages = {3837 -- 3851}, year = {2012}, language = {en} } @book{DeuflhardRoeblitz2015, author = {Deuflhard, Peter and R{\"o}blitz, Susanna}, title = {A guide to numerical modelling in systems biology}, volume = {12}, publisher = {Springer}, isbn = {978-3-319-20058-3}, doi = {10.1007/978-3-319-20059-0}, year = {2015}, language = {en} } @article{MoualeuNgangueRoeblitzEhrigetal.2015, author = {Moualeu-Ngangue, Dany Pascal and R{\"o}blitz, Susanna and Ehrig, Rainald and Deuflhard, Peter}, title = {Parameter Identification in a Tuberculosis Model for Cameroon}, journal = {PLOS ONE}, doi = {10.1371/journal.pone.0120607}, year = {2015}, abstract = {A deterministic model of tuberculosis in Cameroon is designed and analyzed with respect to its transmission dynamics. The model includes lack of access to treatment and weak diagnosis capacity as well as both frequency- and density-dependent transmissions. It is shown that the model is mathematically well-posed and epidemiologically reasonable. Solutions are non-negative and bounded whenever the initial values are non-negative. A sensitivity analysis of model parameters is performed and the most sensitive ones are identified by means of a state-of-the-art Gauss-Newton method. In particular, parameters representing the proportion of individuals having access to medical facilities are seen to have a large impact on the dynamics of the disease. The model predicts that a gradual increase of these parameters could significantly reduce the disease burden on the population within the next 15 years.}, language = {en} } @inproceedings{KraemerHerrmannBoethetal.2015, author = {Kr{\"a}mer, Martin and Herrmann, Karl-Heinz and Boeth, Heide and Tycowicz, Christoph von and K{\"o}nig, Christian and Zachow, Stefan and Ehrig, Rainald and Hege, Hans-Christian and Duda, Georg and Reichenbach, J{\"u}rgen}, title = {Measuring 3D knee dynamics using center out radial ultra-short echo time trajectories with a low cost experimental setup}, booktitle = {ISMRM (International Society for Magnetic Resonance in Medicine), 23rd Annual Meeting 2015, Toronto, Canada}, year = {2015}, language = {en} } @inproceedings{HajizadehSchuetzListetal.2015, author = {Hajizadeh, Maryam and Sch{\"u}tz, Pascal and List, Renate and Boeth, Heide and Ehrig, Rainald and Postolka, Barbara and Freeman, Michael A. R. and Taylor, William R.}, title = {Interpretation of tibio-femoral kinematics critically depends upon the kinematic analysis approach}, booktitle = {ISB 2015, 25th congress of the International Society of Biomechanics, Glasgow}, year = {2015}, language = {en} } @inproceedings{EhrigDierkesSchaeferetal.2016, author = {Ehrig, Rainald and Dierkes, Thomas and Sch{\"a}fer, Stefan and R{\"o}blitz, Susanna and Tronci, Enrico and Mancini, Toni and Salvo, Ivano and Alimguzhin, Vadim and Mari, Federico and Melatti, Igor and Massini, Annalisa and Kr{\"u}ger, Tillmann H. C. and Egli, Marcel and Ille, Fabian and Leeners, Brigitte}, title = {An integrative approach for model driven computation of treatments in reproductive medicine}, booktitle = {BIOMAT - Proceedings of the 15th International Symposium on Mathematical and Computational Biology, Rorkee, India}, year = {2016}, language = {en} } @inproceedings{PloentzkeBergStoetzeletal.2015, author = {Pl{\"o}ntzke, Julia and Berg, Mascha and St{\"o}tzel, Claudia and R{\"o}blitz, Susanna}, title = {A systems biology approach to bovine fertility and metabolism: Introduction of a glucose insulin model}, booktitle = {15th International Symposium on Mathematical and Computational Biology, Rorkee, India}, year = {2015}, language = {en} } @misc{StoetzelApriRoeblitz2014, author = {St{\"o}tzel, Claudia and Apri, Mochamad and R{\"o}blitz, Susanna}, title = {A reduced ODE model of the bovine estrous cycle}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-51594}, year = {2014}, abstract = {This work deals with the reduction of a previously developed ODE model for the bovine estrous cycle. After applying a method for exploring the parameter space by Apri et al. (2012), we perform structure-based reduction steps and several system specific adaptations. Overall, the original model consisting of 15 ODEs and 60 parameters is reduced to a model of 10 odes and 38 parameters. The reduced model qualitatively reproduces the state trajectories of the original model.}, language = {en} } @inproceedings{ManciniSalvoMarietal.2014, author = {Mancini, Toni and Salvo, Ivano and Mari, Federico and Melatti, Igor and Massini, Annalisa and Sinisi, Stefano and Tronci, Enrico and Davi, Francesco and Dierkes, Thomas and Ehrig, Rainald and R{\"o}blitz, Susanna and Leeners, Brigitte and Kr{\"u}ger, Tillmann H. C. and Egli, Marcel and Ille, Fabian}, title = {Patient-Specific Models from Inter-Patient Biological Models and Clinical Records}, booktitle = {Proceedings of the 14th Conference on Formal Methods in Computer-Aided Design (FMCAD 2014)}, pages = {207 -- 214}, year = {2014}, language = {en} } @article{BoethDudaHinzmannetal.2015, author = {Boeth, Heide and Duda, Georg and Hinzmann, Daniel and Hermann, Sandra and Taylor, William R. and Ehrig, Rainald and Witaschek, Tom and Buttgereit, Frank}, title = {A Novel Approach to Quantify Morning Stiffness in Patients with Rheumatoid Arthritis}, journal = {Annual European Congress of Rheumatology, EULAR 2015, Rome}, year = {2015}, language = {en} } @article{StoetzelEhrigBoeretal.2014, author = {St{\"o}tzel, Claudia and Ehrig, Rainald and Boer, H. Marike T. and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {Exploration of different wave patterns in a model of the bovine estrous cycle by Fourier analysis}, journal = {BIOMAT - Proceedings of the 14th International Symposium on Mathematical and Computational Biology, Bedlewo, Poland}, year = {2014}, abstract = {Cows typically have different numbers of follicular waves during their hormonal cycle. Understanding the underlying regulations leads to insights into the reasons for declined fertility, a phenomenon that has been observed during the last decades. We present a systematic approach based on Fourier analysis to examine how parameter changes in a model of the bovine estrous cycle lead to different wave patterns. Even without any biological considerations, this allows to detect the responsible model parameters that control the type of periodicity of the solution, thus supporting experimental planning of animal scientists.}, language = {en} } @phdthesis{Stoetzel2014, author = {St{\"o}tzel, Claudia}, title = {Numerical and Discrete Modeling of Reproductive Endocrinological Networks}, year = {2014}, abstract = {This thesis deals with the mathematical modeling of endocrinological networks that are underlying the female hormone cycle. These networks consist of a variety of biological mechanisms in different parts of the organism. Their interaction leads to periodic changes of various substances that are necessary for reproduction. In every cycle, hormones are secreted from the hypothalamic-pituitary-gonadal axis into the bloodstream, where they distribute and influence several functions in the body. Their most important task in reproduction is to regulate processes in the ovaries, where follicles and corpus luteum develop. These produce steroids that are released into the blood and from therein regulate the processes in the hypothalamic-pituitary-gonadal axis. The hormonal cycle is thus a result of a large feedback loop, whose self-regulation is a complex interplay of multiple components. For the modeling of these processes, a high abstraction level is required, which can be realized by various modeling approaches. In this work, some of these approaches are implemented. The first step in all approaches is the representation of the most important mechanisms in a flowchart. In the next step, this can be implemented as a system of ordinary differential equations using Hill functions, as a piecewise defined affine differential equation model, or directly as a purely regulatory model. Using this approach, a differential equation model for the hormonal cycle of cows is developed. This is compared with a more advanced model of the menstrual cycle in humans. Both models are validated by comparing simulations with measured values, and by studying external influences such as drug administration. For the example of the bovine estrous cycle, continuous analysis methods are used to investigate stability, follicular wave patterns, and robustness with respect to parameter perturbations. Furthermore, the model is substantially reduced while preserving the main simulation results. To take a look at alternative modeling approaches, corresponding discrete models are derived, exemplified for the bovine model. For a piecewise affine version of the model, parameter constraints for the continuous model are calculated. Stability is analyzed globally for a purely discrete model. In addition, core discrete models are derived, which retain the dynamic properties of the original model.}, language = {en} } @article{MoualeuNgangueBowongKurths2014, author = {Moualeu-Ngangue, Dany Pascal and Bowong, Samuel and Kurths, J{\"u}rgen}, title = {Parameter Estimation of a Tuberculosis Model in a Patchy Environment: Case of Cameroon}, journal = {BIOMAT - Proceedings of the 12th International Symposium on Mathematical and Computational Biology, Toronto, 2013}, doi = {10.1142/9789814602228_0021}, year = {2014}, language = {en} } @article{DierkesOrtmann2015, author = {Dierkes, Thomas and Ortmann, Karl Michael}, title = {On the efficient utilisation of duration}, volume = {60}, journal = {Insurance: Mathematics and Economics}, doi = {10.1016/j.insmatheco.2014.11.002}, pages = {29 -- 37}, year = {2015}, abstract = {In this article we present a new approach to estimate the change of the present value of a given cashflow pattern caused by an interest rate shift. Our approximation is based on analysing the evolution of the present value function through a linear differential equation. The outcome is far more accurate than the standard approach achieved by a Taylor expansion. Furthermore, we derive an approximation formula of second order that produces nearly accurate results. In particular, we prove that our method is superior to any known alternative approximation formula based on duration. In order to demonstrate the power of this improved approximation we apply it to coupon bonds, level annuities, and level perpetuities. We finally generalise the approach to a non-flat term structure. As for applications in insurance, we estimate the change of the discounted value of future liabilities due to a proportional shift in the set of capital accumulation factors. These findings are of particular importance to capital adequacy calculations with respect to interest rate stress scenarios that are part of regulatory solvency requirements.}, language = {en} } @misc{Guenther2014, type = {Master Thesis}, author = {G{\"u}nther, Matthias}, title = {Implementation and verification of methods for the validation of knee joint kinematics}, pages = {55}, year = {2014}, language = {en} } @masterthesis{Burtscher2016, type = {Bachelor Thesis}, author = {Burtscher, Felicia}, title = {Algorithmic approaches to the change-point problem for ovulation detection in the human menstrual cycle}, pages = {80}, year = {2016}, language = {en} } @article{GuptaGramatkeEinspanieretal.2017, author = {Gupta, Pooja and Gramatke, Annika and Einspanier, Ralf and Sch{\"u}tte, Christof and von Kleist, Max and Sharbati, Jutta}, title = {In silico cytotoxicity assessment on cultured rat intestinal cells deduced from cellular impedance measurements}, volume = {41}, journal = {Toxicology in Vitro}, issn = {1438-0064}, pages = {179 -- 188}, year = {2017}, abstract = {Early and reliable identification of chemical toxicity is of utmost importance. At the same time, reduction of animal testing is paramount. Therefore, methods that improve the interpretability and usability of in vitro assays are essential. xCELLigence's real-time cell analyzer (RTCA) provides a novel, fast and cost effective in vitro method to probe compound toxicity. We developed a simple mathematical framework for the qualitative and quantitative assessment of toxicity for RTCA measurements. Compound toxicity, in terms of its 50\% inhibitory concentration IC50 on cell growth, and parameters related to cell turnover were estimated on cultured IEC-6 cells exposed to 10 chemicals at varying concentrations. Our method estimated IC50 values of 113.05, 7.16, 28.69 and 725.15 μM for the apparently toxic compounds 2-acetylamino-fluorene, aflatoxin B1, benzo-[a]-pyrene and chloramphenicol in the tested cell line, in agreement with literature knowledge. IC50 values of all apparent in vivo non-toxic compounds were estimated to be non-toxic by our method. Corresponding estimates from RTCA's in-built model gave false positive (toxicity) predictions in 5/10 cases. Taken together, our proposed method reduces false positive predictions and reliably identifies chemical toxicity based on impedance measurements. The source code for the developed method including instructions is available at https://git.zib.de/bzfgupta/toxfit/tree/master.}, language = {en} } @misc{WinkelmannSchuette2017, author = {Winkelmann, Stefanie and Sch{\"u}tte, Christof}, title = {Hybrid Models for Chemical Reaction Networks: Multiscale Theory and Application to Gene Regulatory Systems}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-64264}, year = {2017}, abstract = {Well-mixed stochastic chemical kinetics are properly modelled by the chemical master equation (CME) and associated Markov jump processes in molecule number space. If the reactants are present in large amounts, however, corresponding simulations of the stochastic dynamics become computationally expensive and model reductions are demanded. The classical model reduction approach uniformly rescales the overall dynamics to obtain deterministic systems characterized by ordinary differential equations, the well-known mass action reaction rate equations. For systems with multiple scales there exist hybrid approaches that keep parts of the system discrete while another part is approximated either using Langevin dynamics or deterministically. This paper aims at giving a coherent overview of the different hybrid approaches, focusing on their basic concepts and the relation between them. We derive a novel general description of such hybrid models that allows to express various forms by one type of equation. We also check in how far the approaches apply to model extensions of the CME for dynamics which do not comply with the central well-mixed condition and require some spatial resolution. A simple but meaningful gene expression system with negative self-regulation is analysed to illustrate the different approximation qualities of some of the hybrid approaches discussed.}, language = {en} } @article{HengartnerKruegerGeraedtsetal.2017, author = {Hengartner, Michael and Kr{\"u}ger, Tillmann H. C. and Geraedts, Kirsten and Tronci, Enrico and Mancini, Toni and Ille, Fabian and Egli, Marcel and R{\"o}blitz, Susanna and Ehrig, Rainald and Saleh, Lanja and Spanaus, Katharina and Schippert, Cordula and Zhang, Yuanyuan and Leeners, Brigitte}, title = {Negative affect is unrelated to fluctuations in hormone levels across the menstrual cycle: evidence from a multisite observational study across two successive cycles}, volume = {99}, journal = {Journal of Psychosomatic Research}, doi = {10.1016/j.jpsychores.2017.05.018}, pages = {21 -- 27}, year = {2017}, language = {en} } @misc{LangeSchwiegerPloentzkeetal.2017, author = {Lange, Alexander and Schwieger, Robert and Pl{\"o}ntzke, Julia and Sch{\"a}fer, Stefan and R{\"o}blitz, Susanna}, title = {Follicular competition: the selection of dominant follicles as a synergistic effect}, issn = {1438-0064}, doi = {https://doi.org/10.1007/s00285-018-1284-0}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-63863}, year = {2017}, abstract = {The estrous cycle of mono-ovulatory species such as cows or humans, is known to show two or more waves of follicular growth and decline between two successive ovulations. Within each wave, there is one dominant follicle escorted by subordinate follicles of varying number. Under the surge of the luteinizing hormone a growing dominant follicle ovulates. Rarely the number of ovulating follicles exceeds one. In the biological literature, the change of hormonal concentrations and individually varying numbers of follicular receptors are made responsible for the selection of exactly one dominant follicle, yet a clear cause has not been identified. In this paper, we suggest a synergistic explanation based on competition, formulated by a parsimoniously defined system of ordinary differential equations (ODEs) that quantifies the time evolution of multiple follicles and their competitive interaction during one wave. Not discriminating between follicles, growth and decline are given by fixed rates. Competition is introduced via a growth-suppressing term, equally supported by all follicles. We prove that the number of dominant follicles is determined exclusively by the ratio of follicular growth and competition. This number turns out to be independent of the number of subordinate follicles. The asymptotic behavior of the corresponding dynamical system is investigated rigorously, where we demonstrate that the omega-limit set only contains fixed points. When also including follicular decline, our ODEs perfectly resemble ultrasound data of bovine follicles. Implications for the involved but not explicitly modeled hormones are discussed.}, language = {en} } @article{LeenersKruegerGeraedtsetal.2017, author = {Leeners, Brigitte and Kr{\"u}ger, Tillmann H. C. and Geraedts, Kirsten and Tronci, Enrico and Mancini, Toni and Ille, Fabian and Egli, Marcel and R{\"o}blitz, Susanna and Saleh, Lanja and Spanhaus, K. and Schippert, Cordula and Zhang, Y. and Hengartner, M. P.}, title = {Lack of association between female hormone levels and visuospatial working memory, divided attention and cognitive bias across two consecutive menstrual cycles}, journal = {Front. Behav. Neurosci.}, doi = {10.3389/fnbeh.2017.00120}, year = {2017}, language = {en} } @misc{BockmayrSiebertRoeblitzetal.2014, author = {Bockmayr, Alexander and Siebert, Heike and R{\"o}blitz, Susanna and Sch{\"u}tte, Christof and Deuflhard, Peter}, title = {Advanced mathematical modeling in systems biology}, volume = {1}, journal = {MATHEON-Mathematics for Key Technologies}, editor = {Deuflhard, Peter and Gr{\"o}tschel, Martin and H{\"o}mberg, Dietmar and Kramer, J{\"u}rg and Mehrmann, Volker and Polthier, Konrad and Schmidt, Frank and Sch{\"u}tte, Christof and Skutela, Martin and Sprekels, J{\"u}rgen}, publisher = {European Mathematical Society}, pages = {29 -- 44}, year = {2014}, language = {en} } @article{MoualeuNgangueWeiserEhrigetal.2015, author = {Moualeu-Ngangue, Dany Pascal and Weiser, Martin and Ehrig, Rainald and Deuflhard, Peter}, title = {Optimal control for a tuberculosis model with undetected cases in Cameroon}, volume = {20}, journal = {Communications in Nonlinear Science and Numerical Simulation}, number = {3}, doi = {10.1016/j.cnsns.2014.06.037}, pages = {986 -- 1003}, year = {2015}, abstract = {This paper considers the optimal control of tuberculosis through education, diagnosis campaign and chemoprophylaxis of latently infected. A mathematical model which includes important components such as undiagnosed infectious, diagnosed infectious, latently infected and lost-sight infectious is formulated. The model combines a frequency dependent and a density dependent force of infection for TB transmission. Through optimal control theory and numerical simulations, a cost-effective balance of two different intervention methods is obtained. Seeking to minimize the amount of money the government spends when tuberculosis remain endemic in the Cameroonian population, Pontryagin's maximum principle is used to characterize the optimal control. The optimality system is derived and solved numerically using the forward-backward sweep method (FBSM). Results provide a framework for designing cost-effective strategies for diseases with multiple intervention methods. It comes out that combining chemoprophylaxis and education, the burden of TB can be reduced by 80 \% in 10 years.}, language = {en} } @misc{KlebanovSikorskiSchuetteetal.2016, author = {Klebanov, Ilja and Sikorski, Alexander and Sch{\"u}tte, Christof and R{\"o}blitz, Susanna}, title = {Prior estimation and Bayesian inference from large cohort data sets}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-57475}, year = {2016}, abstract = {One of the main goals of mathematical modelling in systems biology related to medical applications is to obtain patient-specific parameterisations and model predictions. In clinical practice, however, the number of available measurements for single patients is usually limited due to time and cost restrictions. This hampers the process of making patient-specific predictions about the outcome of a treatment. On the other hand, data are often available for many patients, in particular if extensive clinical studies have been performed. Using these population data, we propose an iterative algorithm for contructing an informative prior distribution, which then serves as the basis for computing patient-specific posteriors and obtaining individual predictions. We demonsrate the performance of our method by applying it to a low-dimensional parameter estimation problem in a toy model as well as to a high-dimensional ODE model of the human menstrual cycle, which represents a typical example from systems biology modelling.}, language = {en} } @misc{Dierkes2015, author = {Dierkes, Thomas}, title = {Construction of ODE systems from time series data by a highly flexible modelling approach}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-56768}, year = {2015}, abstract = {In this paper, a down-to-earth approach to purely data-based modelling of unknown dynamical systems is presented. Starting from a classical, explicit ODE formulation y=f(t,y) of a dynamical system, a method determining the unknown right-hand side f(t,y) from some trajectory data y_k(t_j), possibly very sparse, is given. As illustrative examples, a semi-standard predator-prey model is reconstructed from a data set describing the population numbers of hares and lynxes over a period of twenty years [1], and a simple damped pendulum system with a highly non-linear right-hand side is recovered from some artificial but very sparse data [2].}, language = {en} } @article{Dierkes2015, author = {Dierkes, Thomas}, title = {Construction of ODE systems from time series data by a highly flexible modelling approach}, volume = {math.NA 1512.03357}, journal = {ArXiv e-prints}, year = {2015}, abstract = {In this paper, a down-to-earth approach to purely data-based modelling of unknown dynamical systems is presented. Starting from a classical, explicit ODE formulation y=f(t,y) of a dynamical system, a method determining the unknown right-hand side f(t,y) from some trajectory data y_k(t_j), possibly very sparse, is given. As illustrative examples, a semi-standard predator-prey model is reconstructed from a data set describing the population numbers of hares and lynxes over a period of twenty years, and a simple damped pendulum system with a highly non-linear right-hand side is recovered from some artificial but very sparse data.}, language = {en} } @article{KryvenRoeblitzSchuette2015, author = {Kryven, Ivan and R{\"o}blitz, Susanna and Sch{\"u}tte, Christof}, title = {Solution of the chemical master equation by radial basis functions approximation with interface tracking}, volume = {9}, journal = {BMC Systems Biology}, number = {67}, doi = {10.1186/s12918-015-0210-y}, pages = {1 -- 12}, year = {2015}, abstract = {Background. The chemical master equation is the fundamental equation of stochastic chemical kinetics. This differential-difference equation describes temporal evolution of the probability density function for states of a chemical system. A state of the system, usually encoded as a vector, represents the number of entities or copy numbers of interacting species, which are changing according to a list of possible reactions. It is often the case, especially when the state vector is high-dimensional, that the number of possible states the system may occupy is too large to be handled computationally. One way to get around this problem is to consider only those states that are associated with probabilities that are greater than a certain threshold level. Results. We introduce an algorithm that significantly reduces computational resources and is especially powerful when dealing with multi-modal distributions. The algorithm is built according to two key principles. Firstly, when performing time integration, the algorithm keeps track of the subset of states with significant probabilities (essential support). Secondly, the probability distribution that solves the equation is parametrised with a small number of coefficients using collocation on Gaussian radial basis functions. The system of basis functions is chosen in such a way that the solution is approximated only on the essential support instead of the whole state space. Discussion. In order to demonstrate the effectiveness of the method, we consider four application examples: a) the self-regulating gene model, b) the 2-dimensional bistable toggle switch, c) a generalisation of the bistable switch to a 3-dimensional tristable problem, and d) a 3-dimensional cell differentiation model that, depending on parameter values, may operate in bistable or tristable modes. In all multidimensional examples the manifold containing the system states with significant probabilities undergoes drastic transformations over time. This fact makes the examples especially challenging for numerical methods. Conclusions. The proposed method is a new numerical approach permitting to approximately solve a wide range of problems that have been hard to tackle until now. A full representation of multi-dimensional distributions is recovered. The method is especially attractive when dealing with models that yield solutions of a complex structure, for instance, featuring multi-stability. Electronic version: http://www.biomedcentral.com/1752-0509/9/67}, language = {en} } @inproceedings{BoethDudaHinzmannetal.2015, author = {Boeth, Heide and Duda, Georg and Hinzmann, Daniel and Taylor, William R. and Ehrig, Rainald and Witaschek, Tom and Buttgereit, Frank}, title = {Objektive Quantifizierung der Morgensteifigkeit als Parameter f{\"u}r rheumatoide Arthritis im Metacarpophalangealgelenk}, booktitle = {9. Jahrestagung der Deutschen Gesellschaft f{\"u}r Biomechanik (DGfB), Bonn}, year = {2015}, language = {de} } @misc{EhrigDierkesSchaeferetal.2016, author = {Ehrig, Rainald and Dierkes, Thomas and Sch{\"a}fer, Stefan and R{\"o}blitz, Susanna and Tronci, Enrico and Mancini, Toni and Salvo, Ivano and Alimguzhin, Vadim and Mari, Federico and Melatti, Igor and Massini, Annalisa and Kr{\"u}ger, Tillmann H. C. and Egli, Marcel and Ille, Fabian and Leeners, Brigitte}, title = {An Integrative Approach for Model Driven Computation of Treatments in Reproductive Medicine}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-57103}, year = {2016}, abstract = {We present an overview of the current status of the European collaborative project PAEON. The challenge of PAEON is to provide specialists in reproduc- tive medicine with a computerised model of the menstrual cycle under normal and various pathological conditions, which will allow them to get further in- sight in fertility dynamics. This model also enables the simulation of treatment protocols, which were used within in vitro fertilization. By the definition of virtual patients through biologically admissible parametrizations our approach allows not only the evaluation of a given treatment strategy in silico, but also the design and optimization of such protocols. Once a protocol is formalized in the virtual hospital, the success can be controlled by a treatment execution monitor, which works then as a clinical decision support system. All these tools will be combined in a virtual hospital environment, enabling the access to the PAEON services through the web.}, language = {en} } @misc{PloentzkeBergStoetzeletal.2015, author = {Pl{\"o}ntzke, Julia and Berg, Mascha and St{\"o}tzel, Claudia and R{\"o}blitz, Susanna}, title = {A systems biology approach to bovine fertility and metabolism: Development of a glucose insulin model.}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-56453}, year = {2015}, abstract = {To counteract the antagonistic relationship between milk yield and fertility in dairy cow, a deeper understanding of the underlying biological mechanisms is required. For this purpose, we study physiological networks related to reproduction and metabolism in dairy cows. We interactively develop dynamic, mechanistic models by fitting the models to experimental data and mechanistic knowledge. We have already developed models for potassium balance and hormonal regulation of fertility in the dairy cow, which will briefly be reviewed here. The main focus of this article is a glucose-insulin model currently developed by us. This model links the bovine hormonal cycle and the potassium balance to glucose and thus to energy metabolism. The models can be applied in scientific research, education, experimental planning, drug development and production on farms.}, language = {en} } @article{StoetzelRoeblitzSiebert2015, author = {St{\"o}tzel, Claudia and R{\"o}blitz, Susanna and Siebert, Heike}, title = {Complementing ODE-based System Analysis Using Boolean Networks Derived from an Euler-like Transformation}, journal = {PLOS ONE}, doi = {10.1371/journal.pone.0140954}, year = {2015}, language = {en} }