@article{KluweMicheletMuellerSchoelletal.2020, author = {Kluwe, Franziska and Michelet, Robin and M{\"u}ller-Sch{\"o}ll, Anna and Maier, Corinna and Klopp-Schulze, Lena and van Dyk, Madele and Mikus, Gerd and Huisinga, Wilhelm and Kloft, Charlotte}, title = {Perspectives on model-informed precision dosing in the digital health era}, series = {Clinical pharmacology \& therapeutics}, volume = {109}, journal = {Clinical pharmacology \& therapeutics}, number = {1}, publisher = {Wiley}, address = {Hoboken}, issn = {0009-9236}, doi = {10.1002/cpt.2049}, pages = {29 -- 36}, year = {2020}, language = {en} } @article{NassarHohmannMicheletetal.2022, author = {Nassar, Yomna M. and Hohmann, Nicolas and Michelet, Robin and Gottwalt, Katharina and Meid, Andreas D. and Burhenne, J{\"u}rgen and Huisinga, Wilhelm and Haefeli, Walter E. and Mikus, Gerd and Kloft, Charlotte}, title = {Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion}, series = {Clinical Pharmacokinetics}, volume = {61}, journal = {Clinical Pharmacokinetics}, number = {11}, publisher = {Springer}, address = {Northcote}, issn = {0312-5963}, doi = {10.1007/s40262-022-01175-6}, pages = {1595 -- 1607}, year = {2022}, abstract = {Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1\%, +46.7\%, -70.6\%, and -61.1\% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.}, language = {en} } @misc{GrisicHuisingaReinischetal.2017, author = {Grisic, Ana-Marija and Huisinga, Wilhelm and Reinisch, W. and Kloft, Charlotte}, title = {P485 Dosing infliximab in Crohn's disease}, series = {Journal of Crohn's and Colitis}, volume = {11}, journal = {Journal of Crohn's and Colitis}, number = {1}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1873-9946}, doi = {10.1093/ecco-jcc/jjx002.609}, pages = {S325 -- S326}, year = {2017}, abstract = {Background: Infliximab (IFX), an anti-TNF monoclonal antibody approved for the treatment of inflammatory bowel disease, is dosed per kg body weight (BW). However, the rationale for body size adjustment has not been unequivocally demonstrated [1], and first attempts to improve IFX therapy have been undertaken [2]. The aim of our study was to assess the impact of different dosing strategies (i.e. body size-adjusted and fixed dosing) on drug exposure and pharmacokinetic (PK) target attainment. For this purpose, a comprehensive simulation study was performed, using patient characteristics (n=116) from an in-house clinical database. Methods: IFX concentration-time profiles of 1000 virtual, clinically representative patients were generated using a previously published PK model for IFX in patients with Crohn's disease [3]. For each patient 1000 profiles accounting for PK variability were considered. The IFX exposure during maintenance treatment after the following dosing strategies was compared: i) fixed dose, and per ii) BW, iii) lean BW (LBW), iv) body surface area (BSA), v) height (HT), vi) body mass index (BMI) and vii) fat-free mass (FFM)). For each dosing strategy the variability in maximum concentration Cmax, minimum concentration Cmin (= C8weeks) and area under the concentration-time curve (AUC), as well as percent of patients achieving the PK target, Cmin=3 μg/mL [4] were assessed. Results: For all dosing strategies the variability of Cmin (CV ≈110\%) was highest, compared to Cmax and AUC, and was of similar extent regardless of dosing strategy. The proportion of patients reaching the PK target (≈⅓ was approximately equal for all dosing strategies.}, language = {en} } @misc{WeisserStueblerMatheisetal.2017, author = {Weisser, Karin and St{\"u}bler, Sabine and Matheis, Walter and Huisinga, Wilhelm}, title = {Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products}, series = {Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology}, volume = {88}, journal = {Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology}, publisher = {Elsevier}, address = {San Diego}, issn = {0273-2300}, doi = {10.1016/j.yrtph.2017.02.018}, pages = {310 -- 321}, year = {2017}, abstract = {As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved.}, language = {en} } @article{WichaHuisingaKloft2017, author = {Wicha, Sebastian G. and Huisinga, Wilhelm and Kloft, Charlotte}, title = {Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against staphylococcus aureus exploiting in vitro information}, series = {CPT: pharmacometrics \& systems pharmacology}, volume = {6}, journal = {CPT: pharmacometrics \& systems pharmacology}, publisher = {Wiley}, address = {Hoboken}, issn = {2163-8306}, doi = {10.1002/psp4.12197}, pages = {512 -- 522}, year = {2017}, abstract = {Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.}, language = {en} } @article{EdlundGrisicSteenholdtetal.2019, author = {Edlund, Helena and Grisic, Ana-Marija and Steenholdt, Casper and Ainsworth, Mark Andrew and Brynskov, Torn and Huisinga, Wilhelm and Kloft, Charlotte}, title = {Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure}, series = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology}, volume = {41}, journal = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology}, number = {2}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0163-4356}, doi = {10.1097/FTD.0000000000000590}, pages = {235 -- 242}, year = {2019}, abstract = {Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.}, language = {en} } @article{KnoechelKloftHuisinga2018, author = {Kn{\"o}chel, Jane and Kloft, Charlotte and Huisinga, Wilhelm}, title = {Understanding and reducing complex systems pharmacology models based on a novel input-response index}, series = {Journal of pharmacokinetics and pharmacodynamics}, volume = {45}, journal = {Journal of pharmacokinetics and pharmacodynamics}, number = {1}, publisher = {Springer Science + Business Media B.V.}, address = {New York}, issn = {1567-567X}, doi = {10.1007/s10928-017-9561-x}, pages = {139 -- 157}, year = {2018}, abstract = {A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input-response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input-output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable. In this article, we present a novel state- and time-dependent quantity called the input-response index that quantifies the importance of state variables for a given input-response relationship at a particular time. It is based on the concept of time-bounded controllability and observability, and defined with respect to a reference dynamics. In application to the brown snake venom-fibrinogen (Fg) network, the input-response indices give insight into the coordinated action of specific coagulation factors and about those factors that contribute only little to the response. We demonstrate how the indices can be used to reduce large-scale models in a two-step procedure: (i) elimination of states whose dynamics have only minor impact on the input-response relationship, and (ii) proper lumping of the remaining (lower order) model. In application to the brown snake venom-fibrinogen network, this resulted in a reduction from 62 to 8 state variables in the first step, and a further reduction to 5 state variables in the second step. We further illustrate that the sequence, in which a recursive algorithm eliminates and/or lumps state variables, has an impact on the final reduced model. The input-response indices are particularly suited to determine an informed sequence, since they are based on the dynamics of the original system. In summary, the novel measure of importance provides a powerful tool for analysing the complex dynamics of large-scale systems and a means for very efficient model order reduction of nonlinear systems.}, language = {en} } @phdthesis{Knoechel2019, author = {Kn{\"o}chel, Jane}, title = {Model reduction of mechanism-based pharmacodynamic models and its link to classical drug effect models}, doi = {10.25932/publishup-44059}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-440598}, school = {Universit{\"a}t Potsdam}, pages = {vii, 147}, year = {2019}, abstract = {Continuous insight into biological processes has led to the development of large-scale, mechanistic systems biology models of pharmacologically relevant networks. While these models are typically designed to study the impact of diverse stimuli or perturbations on multiple system variables, the focus in pharmacological research is often on a specific input, e.g., the dose of a drug, and a specific output related to the drug effect or response in terms of some surrogate marker. To study a chosen input-output pair, the complexity of the interactions as well as the size of the models hinders easy access and understanding of the details of the input-output relationship. The objective of this thesis is the development of a mathematical approach, in specific a model reduction technique, that allows (i) to quantify the importance of the different state variables for a given input-output relationship, and (ii) to reduce the dynamics to its essential features -- allowing for a physiological interpretation of state variables as well as parameter estimation in the statistical analysis of clinical data. We develop a model reduction technique using a control theoretic setting by first defining a novel type of time-limited controllability and observability gramians for nonlinear systems. We then show the superiority of the time-limited generalised gramians for nonlinear systems in the context of balanced truncation for a benchmark system from control theory. The concept of time-limited controllability and observability gramians is subsequently used to introduce a state and time-dependent quantity called the input-response (ir) index that quantifies the importance of state variables for a given input-response relationship at a particular time. We subsequently link our approach to sensitivity analysis, thus, enabling for the first time the use of sensitivity coefficients for state space reduction. The sensitivity based ir-indices are given as a product of two sensitivity coefficients. This allows not only for a computational more efficient calculation but also for a clear distinction of the extent to which the input impacts a state variable and the extent to which a state variable impacts the output. The ir-indices give insight into the coordinated action of specific state variables for a chosen input-response relationship. Our developed model reduction technique results in reduced models that still allow for a mechanistic interpretation in terms of the quantities/state variables of the original system, which is a key requirement in the field of systems pharmacology and systems biology and distinguished the reduced models from so-called empirical drug effect models. The ir-indices are explicitly defined with respect to a reference trajectory and thereby dependent on the initial state (this is an important feature of the measure). This is demonstrated for an example from the field of systems pharmacology, showing that the reduced models are very informative in their ability to detect (genetic) deficiencies in certain physiological entities. Comparing our novel model reduction technique to the already existing techniques shows its superiority. The novel input-response index as a measure of the importance of state variables provides a powerful tool for understanding the complex dynamics of large-scale systems in the context of a specific drug-response relationship. Furthermore, the indices provide a means for a very efficient model order reduction and, thus, an important step towards translating insight from biological processes incorporated in detailed systems pharmacology models into the population analysis of clinical data.}, language = {en} } @phdthesis{Solms2017, author = {Solms, Alexander Maximilian}, title = {Integrating nonlinear mixed effects and physiologically-based modeling approaches for the analysis of repeated measurement studies}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-397070}, school = {Universit{\"a}t Potsdam}, pages = {x, 141}, year = {2017}, abstract = {During the drug discovery \& development process, several phases encompassing a number of preclinical and clinical studies have to be successfully passed to demonstrate safety and efficacy of a new drug candidate. As part of these studies, the characterization of the drug's pharmacokinetics (PK) is an important aspect, since the PK is assumed to strongly impact safety and efficacy. To this end, drug concentrations are measured repeatedly over time in a study population. The objectives of such studies are to describe the typical PK time-course and the associated variability between subjects. Furthermore, underlying sources significantly contributing to this variability, e.g. the use of comedication, should be identified. The most commonly used statistical framework to analyse repeated measurement data is the nonlinear mixed effect (NLME) approach. At the same time, ample knowledge about the drug's properties already exists and has been accumulating during the discovery \& development process: Before any drug is tested in humans, detailed knowledge about the PK in different animal species has to be collected. This drug-specific knowledge and general knowledge about the species' physiology is exploited in mechanistic physiological based PK (PBPK) modeling approaches -it is, however, ignored in the classical NLME modeling approach. Mechanistic physiological based models aim to incorporate relevant and known physiological processes which contribute to the overlying process of interest. In comparison to data--driven models they are usually more complex from a mathematical perspective. For example, in many situations, the number of model parameters outrange the number of measurements and thus reliable parameter estimation becomes more complex and partly impossible. As a consequence, the integration of powerful mathematical estimation approaches like the NLME modeling approach -which is widely used in data-driven modeling -and the mechanistic modeling approach is not well established; the observed data is rather used as a confirming instead of a model informing and building input. Another aggravating circumstance of an integrated approach is the inaccessibility to the details of the NLME methodology so that these approaches can be adapted to the specifics and needs of mechanistic modeling. Despite the fact that the NLME modeling approach exists for several decades, details of the mathematical methodology is scattered around a wide range of literature and a comprehensive, rigorous derivation is lacking. Available literature usually only covers selected parts of the mathematical methodology. Sometimes, important steps are not described or are only heuristically motivated, e.g. the iterative algorithm to finally determine the parameter estimates. Thus, in the present thesis the mathematical methodology of NLME modeling is systemically described and complemented to a comprehensive description, comprising the common theme from ideas and motivation to the final parameter estimation. Therein, new insights for the interpretation of different approximation methods used in the context of the NLME modeling approach are given and illustrated; furthermore, similarities and differences between them are outlined. Based on these findings, an expectation-maximization (EM) algorithm to determine estimates of a NLME model is described. Using the EM algorithm and the lumping methodology by Pilari2010, a new approach on how PBPK and NLME modeling can be combined is presented and exemplified for the antibiotic levofloxacin. Therein, the lumping identifies which processes are informed by the available data and the respective model reduction improves the robustness in parameter estimation. Furthermore, it is shown how apriori known factors influencing the variability and apriori known unexplained variability is incorporated to further mechanistically drive the model development. Concludingly, correlation between parameters and between covariates is automatically accounted for due to the mechanistic derivation of the lumping and the covariate relationships. A useful feature of PBPK models compared to classical data-driven PK models is in the possibility to predict drug concentration within all organs and tissue in the body. Thus, the resulting PBPK model for levofloxacin is used to predict drug concentrations and their variability within soft tissues which are the site of action for levofloxacin. These predictions are compared with data of muscle and adipose tissue obtained by microdialysis, which is an invasive technique to measure a proportion of drug in the tissue, allowing to approximate the concentrations in the interstitial fluid of tissues. Because, so far, comparing human in vivo tissue PK and PBPK predictions are not established, a new conceptual framework is derived. The comparison of PBPK model predictions and microdialysis measurements shows an adequate agreement and reveals further strengths of the presented new approach. We demonstrated how mechanistic PBPK models, which are usually developed in the early stage of drug development, can be used as basis for model building in the analysis of later stages, i.e. in clinical studies. As a consequence, the extensively collected and accumulated knowledge about species and drug are utilized and updated with specific volunteer or patient data. The NLME approach combined with mechanistic modeling reveals new insights for the mechanistic model, for example identification and quantification of variability in mechanistic processes. This represents a further contribution to the learn \& confirm paradigm across different stages of drug development. Finally, the applicability of mechanism--driven model development is demonstrated on an example from the field of Quantitative Psycholinguistics to analyse repeated eye movement data. Our approach gives new insight into the interpretation of these experiments and the processes behind.}, language = {en} } @phdthesis{Gopalakrishnan2016, author = {Gopalakrishnan, Sathej}, title = {Mathematical modelling of host-disease-drug interactions in HIV disease}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-100100}, school = {Universit{\"a}t Potsdam}, pages = {121}, year = {2016}, abstract = {The human immunodeficiency virus (HIV) has resisted nearly three decades of efforts targeting a cure. Sustained suppression of the virus has remained a challenge, mainly due to the remarkable evolutionary adaptation that the virus exhibits by the accumulation of drug-resistant mutations in its genome. Current therapeutic strategies aim at achieving and maintaining a low viral burden and typically involve multiple drugs. The choice of optimal combinations of these drugs is crucial, particularly in the background of treatment failure having occurred previously with certain other drugs. An understanding of the dynamics of viral mutant genotypes aids in the assessment of treatment failure with a certain drug combination, and exploring potential salvage treatment regimens. Mathematical models of viral dynamics have proved invaluable in understanding the viral life cycle and the impact of antiretroviral drugs. However, such models typically use simplified and coarse-grained mutation schemes, that curbs the extent of their application to drug-specific clinical mutation data, in order to assess potential next-line therapies. Statistical models of mutation accumulation have served well in dissecting mechanisms of resistance evolution by reconstructing mutation pathways under different drug-environments. While these models perform well in predicting treatment outcomes by statistical learning, they do not incorporate drug effect mechanistically. Additionally, due to an inherent lack of temporal features in such models, they are less informative on aspects such as predicting mutational abundance at treatment failure. This limits their application in analyzing the pharmacology of antiretroviral drugs, in particular, time-dependent characteristics of HIV therapy such as pharmacokinetics and pharmacodynamics, and also in understanding the impact of drug efficacy on mutation dynamics. In this thesis, we develop an integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data. Our combined modelling approach enables us to study the dynamics of different mutant genotypes and assess mutational abundance at virological failure. As an application of our model, we estimate in vivo fitness characteristics of viral mutants under different drug environments. Our approach also extends naturally to multiple-drug therapies. Further, we demonstrate the versatility of our model by showing how it can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors. Additionally, we address another important aspect in the clinical management of HIV disease, namely drug pharmacokinetics. It is clear that time-dependent changes in in vivo drug concentration could have an impact on the antiviral effect, and also influence decisions on dosing intervals. We present a framework that provides an integrated understanding of key characteristics of multiple-dosing regimens including drug accumulation ratios and half-lifes, and then explore the impact of drug pharmacokinetics on viral suppression. Finally, parameter identifiability in such nonlinear models of viral dynamics is always a concern, and we investigate techniques that alleviate this issue in our setting.}, language = {en} } @article{MelinParraGuillenHartungetal.2018, author = {Melin, Johanna and Parra-Guillen, Zinnia Patricia and Hartung, Niklas and Huisinga, Wilhelm and Ross, Richard J. and Whitaker, Martin J. and Kloft, Charlotte}, title = {Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults}, series = {Clinical Pharmacokinetics}, volume = {57}, journal = {Clinical Pharmacokinetics}, number = {4}, publisher = {Springer}, address = {Northcote}, issn = {0312-5963}, doi = {10.1007/s40262-017-0575-8}, pages = {515 -- 527}, year = {2018}, abstract = {Background and objective Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort (R) oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Methods Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort (R) or 20 mg of Infacort (R)/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Results Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline (cort),15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing < 20 kg. Conclusions Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing < 20 kg.}, language = {en} } @article{JiaAnslanChenetal.2022, author = {Jia, Weihan and Anslan, Sten and Chen, Fahu and Cao, Xianyong and Dong, Hailiang and Dulias, Katharina and Gu, Zhengquan and Heinecke, Liv and Jiang, Hongchen and Kruse, Stefan and Kang, Wengang and Li, Kai and Liu, Sisi and Liu, Xingqi and Liu, Ying and Ni, Jian and Schwalb, Antje and Stoof-Leichsenring, Kathleen R. and Shen, Wei and Tian, Fang and Wang, Jing and Wang, Yongbo and Wang, Yucheng and Xu, Hai and Yang, Xiaoyan and Zhang, Dongju and Herzschuh, Ulrike}, title = {Sedimentary ancient DNA reveals past ecosystem and biodiversity changes on the Tibetan Plateau: overview and prospects}, series = {Quaternary science reviews : the international multidisciplinary research and review journal}, volume = {293}, journal = {Quaternary science reviews : the international multidisciplinary research and review journal}, publisher = {Elsevier}, address = {Oxford}, issn = {0277-3791}, doi = {10.1016/j.quascirev.2022.107703}, pages = {14}, year = {2022}, abstract = {Alpine ecosystems on the Tibetan Plateau are being threatened by ongoing climate warming and intensified human activities. Ecological time-series obtained from sedimentary ancient DNA (sedaDNA) are essential for understanding past ecosystem and biodiversity dynamics on the Tibetan Plateau and their responses to climate change at a high taxonomic resolution. Hitherto only few but promising studies have been published on this topic. The potential and limitations of using sedaDNA on the Tibetan Plateau are not fully understood. Here, we (i) provide updated knowledge of and a brief introduction to the suitable archives, region-specific taphonomy, state-of-the-art methodologies, and research questions of sedaDNA on the Tibetan Plateau; (ii) review published and ongoing sedaDNA studies from the Tibetan Plateau; and (iii) give some recommendations for future sedaDNA study designs. Based on the current knowledge of taphonomy, we infer that deep glacial lakes with freshwater and high clay sediment input, such as those from the southern and southeastern Tibetan Plateau, may have a high potential for sedaDNA studies. Metabarcoding (for microorganisms and plants), metagenomics (for ecosystems), and hybridization capture (for prehistoric humans) are three primary sedaDNA approaches which have been successfully applied on the Tibetan Plateau, but their power is still limited by several technical issues, such as PCR bias and incompleteness of taxonomic reference databases. Setting up high-quality and open-access regional taxonomic reference databases for the Tibetan Plateau should be given priority in the future. To conclude, the archival, taphonomic, and methodological conditions of the Tibetan Plateau are favorable for performing sedaDNA studies. More research should be encouraged to address questions about long-term ecological dynamics at ecosystem scale and to bring the paleoecology of the Tibetan Plateau into a new era.}, language = {en} } @article{BusseSimonPetroffetal.2022, author = {Busse, David and Simon, Philipp and Petroff, David and El-Najjar, Nahed and Schmitt, Lisa and Bindellini, Davide and Dietrich, Arne and Zeitlinger, Markus and Huisinga, Wilhelm and Michelet, Robin and Wrigge, Hermann and Kloft, Charlotte}, title = {High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients}, series = {Antimicrobial agents and chemotherapy}, volume = {66}, journal = {Antimicrobial agents and chemotherapy}, number = {6}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0066-4804}, doi = {10.1128/aac.02302-21}, pages = {12}, year = {2022}, abstract = {The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an \%fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0\% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3\% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status.}, language = {en} } @article{WeineltStegemannTheloeetal.2022, author = {Weinelt, Ferdinand Anton and Stegemann, Miriam Songa and Theloe, Anja and Pf{\"a}fflin, Frieder and Achterberg, Stephan and Weber, Franz and D{\"u}bel, Lucas and Mikolajewska, Agata and Uhrig, Alexander and Kiessling, Peggy and Huisinga, Wilhelm and Michelet, Robin and Hennig, Stefanie and Kloft, Charlotte}, title = {Evaluation of a meropenem and piperacillin monitoring program in intensive care unit patients calls for the regular assessment of empirical targets and easy-to-use dosing decision tools}, series = {Antibiotics : open access journal}, volume = {11}, journal = {Antibiotics : open access journal}, number = {6}, publisher = {MDPI}, address = {Basel}, issn = {2079-6382}, doi = {10.3390/antibiotics11060758}, pages = {17}, year = {2022}, abstract = {The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1-5 x MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8-40 mg/L and 16-80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0\%, piperacillin: 93.9\%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7\%, piperacillin 50.5\%) with the lowest TA for severely impaired renal function (meropenem: 13.9\%, piperacillin: 29.2\%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13\%, piperacillin: 4.78\%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing.}, language = {en} } @inproceedings{DemarisGrišićHuisingaetal.2020, author = {D{\´e}maris, Alise and Grišić, Ana-Marija and Huisinga, Wilhelm and Walter, Reinisch and Kloft, Charlotte}, title = {Evaluation of dosing strategies of anti-TNF alpha monoclonal antibodies using pharmacokinetic modelling and simulation}, series = {Journal of Crohn's and Colitis}, volume = {14}, booktitle = {Journal of Crohn's and Colitis}, number = {Supp. 1}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1873-9946}, doi = {10.1093/ecco-jcc/jjz203.201}, pages = {S171 -- S172}, year = {2020}, abstract = {Background: Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn's disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods: A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration-time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results: For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110\% and CV ≈80\%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15\%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52-71\%), being the highest for LBW-adjusted dosing. Conclusion: By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66\% vs. 71\%, respectively).}, language = {en} } @article{HetheyHartungWangorschetal.2021, author = {Hethey, Christoph Philipp and Hartung, Niklas and Wangorsch, Gaby and Weisser, Karin and Huisinga, Wilhelm}, title = {Physiology-based toxicokinetic modelling of aluminium in rat and man}, series = {Archives of toxicology : official journal of EUROTOX}, volume = {95}, journal = {Archives of toxicology : official journal of EUROTOX}, number = {9}, publisher = {Springer}, address = {Berlin ; Heidelberg}, issn = {0340-5761}, doi = {10.1007/s00204-021-03107-y}, pages = {2977 -- 3000}, year = {2021}, abstract = {A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope Al-27, both in animals and man. These limitations are absent in studies with Al-26 as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans-especially in toxicological relevant tissues like bone and brain-is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of Al-26 tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated Al-26 dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous Al-26 data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans.}, language = {en} } @article{StachanowNeumannBlankensteinetal.2022, author = {Stachanow, Viktoria and Neumann, Uta and Blankenstein, Oliver and Bindellini, Davide and Melin, Johanna and Ross, Richard and Whitaker, Martin J. J. and Huisinga, Wilhelm and Michelet, Robin and Kloft, Charlotte}, title = {Exploring dried blood spot cortisol concentrations as an alternative for monitoring pediatric adrenal insufficiency patients}, series = {Frontiers in pharmacology}, volume = {13}, journal = {Frontiers in pharmacology}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {1663-9812}, doi = {10.3389/fphar.2022.819590}, pages = {8}, year = {2022}, abstract = {Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.}, language = {en} } @phdthesis{Schindler2023, author = {Schindler, Daniel}, title = {Mathematical modeling and simulation of protrusion-driven cell dynamics}, doi = {10.25932/publishup-61327}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-613275}, school = {Universit{\"a}t Potsdam}, pages = {VI, 161}, year = {2023}, abstract = {Amoeboid cell motility takes place in a variety of biomedical processes such as cancer metastasis, embryonic morphogenesis, and wound healing. In contrast to other forms of cell motility, it is mainly driven by substantial cell shape changes. Based on the interplay of explorative membrane protrusions at the front and a slower-acting membrane retraction at the rear, the cell moves in a crawling kind of way. Underlying these protrusions and retractions are multiple physiological processes resulting in changes of the cytoskeleton, a meshwork of different multi-functional proteins. The complexity and versatility of amoeboid cell motility raise the need for novel computational models based on a profound theoretical framework to analyze and simulate the dynamics of the cell shape. The objective of this thesis is the development of (i) a mathematical framework to describe contour dynamics in time and space, (ii) a computational model to infer expansion and retraction characteristics of individual cell tracks and to produce realistic contour dynamics, (iii) and a complementing Open Science approach to make the above methods fully accessible and easy to use. In this work, we mainly used single-cell recordings of the model organism Dictyostelium discoideum. Based on stacks of segmented microscopy images, we apply a Bayesian approach to obtain smooth representations of the cell membrane, so-called cell contours. We introduce a one-parameter family of regularized contour flows to track reference points on the contour (virtual markers) in time and space. This way, we define a coordinate system to visualize local geometric and dynamic quantities of individual contour dynamics in so-called kymograph plots. In particular, we introduce the local marker dispersion as a measure to identify membrane protrusions and retractions in a fully automated way. This mathematical framework is the basis of a novel contour dynamics model, which consists of three biophysiologically motivated components: one stochastic term, accounting for membrane protrusions, and two deterministic terms to control the shape and area of the contour, which account for membrane retractions. Our model provides a fully automated approach to infer protrusion and retraction characteristics from experimental cell tracks while being also capable of simulating realistic and qualitatively different contour dynamics. Furthermore, the model is used to classify two different locomotion types: the amoeboid and a so-called fan-shaped type. With the complementing Open Science approach, we ensure a high standard regarding the usability of our methods and the reproducibility of our research. In this context, we introduce our software publication named AmoePy, an open-source Python package to segment, analyze, and simulate amoeboid cell motility. Furthermore, we describe measures to improve its usability and extensibility, e.g., by detailed run instructions and an automatically generated source code documentation, and to ensure its functionality and stability, e.g., by automatic software tests, data validation, and a hierarchical package structure. The mathematical approaches of this work provide substantial improvements regarding the modeling and analysis of amoeboid cell motility. We deem the above methods, due to their generalized nature, to be of greater value for other scientific applications, e.g., varying organisms and experimental setups or the transition from unicellular to multicellular movement. Furthermore, we enable other researchers from different fields, i.e., mathematics, biophysics, and medicine, to apply our mathematical methods. By following Open Science standards, this work is of greater value for the cell migration community and a potential role model for other Open Science contributions.}, language = {en} } @phdthesis{Perera2021, author = {Perera, Upeksha}, title = {Solutions of direct and inverse Sturm-Liouville problems}, doi = {10.25932/publishup-53006}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-530064}, school = {Universit{\"a}t Potsdam}, pages = {x, 109}, year = {2021}, abstract = {Lie group method in combination with Magnus expansion is utilized to develop a universal method applicable to solving a Sturm-Liouville Problem (SLP) of any order with arbitrary boundary conditions. It is shown that the method has ability to solve direct regular and some singular SLPs of even orders (tested up to order eight), with a mix of boundary conditions (including non-separable and finite singular endpoints), accurately and efficiently. The present technique is successfully applied to overcome the difficulties in finding suitable sets of eigenvalues so that the inverse SLP problem can be effectively solved. Next, a concrete implementation to the inverse Sturm-Liouville problem algorithm proposed by Barcilon (1974) is provided. Furthermore, computational feasibility and applicability of this algorithm to solve inverse Sturm-Liouville problems of order n=2,4 is verified successfully. It is observed that the method is successful even in the presence of significant noise, provided that the assumptions of the algorithm are satisfied. In conclusion, this work provides methods that can be adapted successfully for solving a direct (regular/singular) or inverse SLP of an arbitrary order with arbitrary boundary conditions.}, language = {en} } @article{HijaziFreitagLandwehr2023, author = {Hijazi, Saddam and Freitag, Melina A. and Landwehr, Niels}, title = {POD-Galerkin reduced order models and physics-informed neural networks for solving inverse problems for the Navier-Stokes equations}, series = {Advanced modeling and simulation in engineering sciences : AMSES}, volume = {10}, journal = {Advanced modeling and simulation in engineering sciences : AMSES}, number = {1}, publisher = {SpringerOpen}, address = {Berlin}, issn = {2213-7467}, doi = {10.1186/s40323-023-00242-2}, pages = {38}, year = {2023}, abstract = {We present a Reduced Order Model (ROM) which exploits recent developments in Physics Informed Neural Networks (PINNs) for solving inverse problems for the Navier-Stokes equations (NSE). In the proposed approach, the presence of simulated data for the fluid dynamics fields is assumed. A POD-Galerkin ROM is then constructed by applying POD on the snapshots matrices of the fluid fields and performing a Galerkin projection of the NSE (or the modified equations in case of turbulence modeling) onto the POD reduced basis. A POD-Galerkin PINN ROM is then derived by introducing deep neural networks which approximate the reduced outputs with the input being time and/or parameters of the model. The neural networks incorporate the physical equations (the POD-Galerkin reduced equations) into their structure as part of the loss function. Using this approach, the reduced model is able to approximate unknown parameters such as physical constants or the boundary conditions. A demonstration of the applicability of the proposed ROM is illustrated by three cases which are the steady flow around a backward step, the flow around a circular cylinder and the unsteady turbulent flow around a surface mounted cubic obstacle.}, language = {en} } @article{MolkenthinDonnerReichetal.2022, author = {Molkenthin, Christian and Donner, Christian and Reich, Sebastian and Z{\"o}ller, Gert and Hainzl, Sebastian and Holschneider, Matthias and Opper, Manfred}, title = {GP-ETAS: semiparametric Bayesian inference for the spatio-temporal epidemic type aftershock sequence model}, series = {Statistics and Computing}, volume = {32}, journal = {Statistics and Computing}, number = {2}, publisher = {Springer}, address = {Dordrecht}, issn = {0960-3174}, doi = {10.1007/s11222-022-10085-3}, pages = {25}, year = {2022}, abstract = {The spatio-temporal epidemic type aftershock sequence (ETAS) model is widely used to describe the self-exciting nature of earthquake occurrences. While traditional inference methods provide only point estimates of the model parameters, we aim at a fully Bayesian treatment of model inference, allowing naturally to incorporate prior knowledge and uncertainty quantification of the resulting estimates. Therefore, we introduce a highly flexible, non-parametric representation for the spatially varying ETAS background intensity through a Gaussian process (GP) prior. Combined with classical triggering functions this results in a new model formulation, namely the GP-ETAS model. We enable tractable and efficient Gibbs sampling by deriving an augmented form of the GP-ETAS inference problem. This novel sampling approach allows us to assess the posterior model variables conditioned on observed earthquake catalogues, i.e., the spatial background intensity and the parameters of the triggering function. Empirical results on two synthetic data sets indicate that GP-ETAS outperforms standard models and thus demonstrate the predictive power for observed earthquake catalogues including uncertainty quantification for the estimated parameters. Finally, a case study for the l'Aquila region, Italy, with the devastating event on 6 April 2009, is presented.}, language = {en} } @article{KucharskiErgintavAhmadetal.2019, author = {Kucharski, Maciej and Ergintav, Arzu and Ahmad, Wael Abdullah and Krstić, Miloš and Ng, Herman Jalli and Kissinger, Dietmar}, title = {A Scalable 79-GHz Radar Platform Based on Single-Channel Transceivers}, series = {IEEE Transactions on Microwave Theory and Techniques}, volume = {67}, journal = {IEEE Transactions on Microwave Theory and Techniques}, number = {9}, publisher = {Inst. of Electr. and Electronics Engineers}, address = {Piscataway}, issn = {0018-9480}, doi = {10.1109/TMTT.2019.2914104}, pages = {3882 -- 3896}, year = {2019}, abstract = {This paper presents a scalable E-band radar platform based on single-channel fully integrated transceivers (TRX) manufactured using 130-nm silicon-germanium (SiGe) BiCMOS technology. The TRX is suitable for flexible radar systems exploiting massive multiple-input-multipleoutput (MIMO) techniques for multidimensional sensing. A fully integrated fractional-N phase-locked loop (PLL) comprising a 39.5-GHz voltage-controlled oscillator is used to generate wideband frequency-modulated continuous-wave (FMCW) chirp for E-band radar front ends. The TRX is equipped with a vector modulator (VM) for high-speed carrier modulation and beam-forming techniques. A single TRX achieves 19.2-dBm maximum output power and 27.5-dB total conversion gain with input-referred 1-dB compression point of -10 dBm. It consumes 220 mA from 3.3-V supply and occupies 3.96 mm(2) silicon area. A two-channel radar platform based on full-custom TRXs and PLL was fabricated to demonstrate high-precision and high-resolution FMCW sensing. The radar enables up to 10-GHz frequency ramp generation in 74-84-GHz range, which results in 1.5-cm spatial resolution. Due to high output power, thus high signal-to-noise ratio (SNR), a ranging precision of 7.5 mu m for a target at 2 m was achieved. The proposed architecture supports scalable multichannel applications for automotive FMCW using a single local oscillator (LO).}, language = {en} } @article{SharmaHainzlZoelleretal.2020, author = {Sharma, Shubham and Hainzl, Sebastian and Z{\"o}ller, Gert and Holschneider, Matthias}, title = {Is Coulomb stress the best choice for aftershock forecasting?}, series = {Journal of geophysical research : Solid earth}, volume = {125}, journal = {Journal of geophysical research : Solid earth}, number = {9}, publisher = {American Geophysical Union}, address = {Washington}, issn = {2169-9313}, doi = {10.1029/2020JB019553}, pages = {12}, year = {2020}, abstract = {The Coulomb failure stress (CFS) criterion is the most commonly used method for predicting spatial distributions of aftershocks following large earthquakes. However, large uncertainties are always associated with the calculation of Coulomb stress change. The uncertainties mainly arise due to nonunique slip inversions and unknown receiver faults; especially for the latter, results are highly dependent on the choice of the assumed receiver mechanism. Based on binary tests (aftershocks yes/no), recent studies suggest that alternative stress quantities, a distance-slip probabilistic model as well as deep neural network (DNN) approaches, all are superior to CFS with predefined receiver mechanism. To challenge this conclusion, which might have large implications, we use 289 slip inversions from SRCMOD database to calculate more realistic CFS values for a layered half-space and variable receiver mechanisms. We also analyze the effect of the magnitude cutoff, grid size variation, and aftershock duration to verify the use of receiver operating characteristic (ROC) analysis for the ranking of stress metrics. The observations suggest that introducing a layered half-space does not improve the stress maps and ROC curves. However, results significantly improve for larger aftershocks and shorter time periods but without changing the ranking. We also go beyond binary testing and apply alternative statistics to test the ability to estimate aftershock numbers, which confirm that simple stress metrics perform better than the classic Coulomb failure stress calculations and are also better than the distance-slip probabilistic model.}, language = {en} } @phdthesis{Maier2021, author = {Maier, Corinna}, title = {Bayesian data assimilation and reinforcement learning for model-informed precision dosing in oncology}, doi = {10.25932/publishup-51587}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-515870}, school = {Universit{\"a}t Potsdam}, pages = {x, 138}, year = {2021}, abstract = {While patients are known to respond differently to drug therapies, current clinical practice often still follows a standardized dosage regimen for all patients. For drugs with a narrow range of both effective and safe concentrations, this approach may lead to a high incidence of adverse events or subtherapeutic dosing in the presence of high patient variability. Model-informedprecision dosing (MIPD) is a quantitative approach towards dose individualization based on mathematical modeling of dose-response relationships integrating therapeutic drug/biomarker monitoring (TDM) data. MIPD may considerably improve the efficacy and safety of many drug therapies. Current MIPD approaches, however, rely either on pre-calculated dosing tables or on simple point predictions of the therapy outcome. These approaches lack a quantification of uncertainties and the ability to account for effects that are delayed. In addition, the underlying models are not improved while applied to patient data. Therefore, current approaches are not well suited for informed clinical decision-making based on a differentiated understanding of the individually predicted therapy outcome. The objective of this thesis is to develop mathematical approaches for MIPD, which (i) provide efficient fully Bayesian forecasting of the individual therapy outcome including associated uncertainties, (ii) integrate Markov decision processes via reinforcement learning (RL) for a comprehensive decision framework for dose individualization, (iii) allow for continuous learning across patients and hospitals. Cytotoxic anticancer chemotherapy with its major dose-limiting toxicity, neutropenia, serves as a therapeutically relevant application example. For more comprehensive therapy forecasting, we apply Bayesian data assimilation (DA) approaches, integrating patient-specific TDM data into mathematical models of chemotherapy-induced neutropenia that build on prior population analyses. The value of uncertainty quantification is demonstrated as it allows reliable computation of the patient-specific probabilities of relevant clinical quantities, e.g., the neutropenia grade. In view of novel home monitoring devices that increase the amount of TDM data available, the data processing of sequential DA methods proves to be more efficient and facilitates handling of the variability between dosing events. By transferring concepts from DA and RL we develop novel approaches for MIPD. While DA-guided dosing integrates individualized uncertainties into dose selection, RL-guided dosing provides a framework to consider delayed effects of dose selections. The combined DA-RL approach takes into account both aspects simultaneously and thus represents a holistic approach towards MIPD. Additionally, we show that RL can be used to gain insights into important patient characteristics for dose selection. The novel dosing strategies substantially reduce the occurrence of both subtherapeutic and life-threatening neutropenia grades in a simulation study based on a recent clinical study (CEPAC-TDM trial) compared to currently used MIPD approaches. If MIPD is to be implemented in routine clinical practice, a certain model bias with respect to the underlying model is inevitable, as the models are typically based on data from comparably small clinical trials that reflect only to a limited extent the diversity in real-world patient populations. We propose a sequential hierarchical Bayesian inference framework that enables continuous cross-patient learning to learn the underlying model parameters of the target patient population. It is important to note that the approach only requires summary information of the individual patient data to update the model. This separation of the individual inference from population inference enables implementation across different centers of care. The proposed approaches substantially improve current MIPD approaches, taking into account new trends in health care and aspects of practical applicability. They enable progress towards more informed clinical decision-making, ultimately increasing patient benefits beyond the current practice.}, language = {en} } @article{MicheletBindelliniMelinetal.2023, author = {Michelet, Robin and Bindellini, Davide and Melin, Johanna and Neumann, Uta and Blankenstein, Oliver and Huisinga, Wilhelm and Johnson, Trevor N. and Whitaker, Martin J. and Ross, Richard and Kloft, Charlotte}, title = {Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach}, series = {Frontiers in Pharmacology}, volume = {13}, journal = {Frontiers in Pharmacology}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {1663-9812}, doi = {10.3389/fphar.2022.1090554}, pages = {14}, year = {2023}, abstract = {Introduction: Hydrocortisone is the standard of care in cortisol replacement therapy for congenital adrenal hyperplasia patients. Challenges in mimicking cortisol circadian rhythm and dosing individualization can be overcome by the support of mathematical modelling. Previously, a non-linear mixed-effects (NLME) model was developed based on clinical hydrocortisone pharmacokinetic (PK) pediatric and adult data. Additionally, a physiologically-based pharmacokinetic (PBPK) model was developed for adults and a pediatric model was obtained using maturation functions for relevant processes. In this work, a middle-out approach was applied. The aim was to investigate whether PBPK-derived maturation functions could provide a better description of hydrocortisone PK inter-individual variability when implemented in the NLME framework, with the goal of providing better individual predictions towards precision dosing at the patient level. Methods: Hydrocortisone PK data from 24 adrenal insufficiency pediatric patients and 30 adult healthy volunteers were used for NLME model development, while the PBPK model and maturation functions of clearance and cortisol binding globulin (CBG) were developed based on previous studies published in the literature. Results: Clearance (CL) estimates from both approaches were similar for children older than 1 year (CL/F increasing from around 150 L/h to 500 L/h), while CBG concentrations differed across the whole age range (CBG(NLME) stable around 0.5 mu M vs. steady increase from 0.35 to 0.8 mu M for CBG (PBPK)). PBPK-derived maturation functions were subsequently included in the NLME model. After inclusion of the maturation functions, none, a part of, or all parameters were re-estimated. However, the inclusion of CL and/or CBG maturation functions in the NLME model did not result in improved model performance for the CL maturation function (\& UDelta;OFV > -15.36) and the re-estimation of parameters using the CBG maturation function most often led to unstable models or individual CL prediction bias. Discussion: Three explanations for the observed discrepancies could be postulated, i) non-considered maturation of processes such as absorption or first-pass effect, ii) lack of patients between 1 and 12 months, iii) lack of correction of PBPK CL maturation functions derived from urinary concentration ratio data for the renal function relative to adults. These should be investigated in the future to determine how NLME and PBPK methods can work towards deriving insights into pediatric hydrocortisone PK.}, language = {en} } @article{KrippendorffOyarzunHuisinga2012, author = {Krippendorff, Ben-Fillippo and Oyarz{\´u}n, Diego A. and Huisinga, Wilhelm}, title = {Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling}, series = {Journal of pharmacokinetics and pharmacodynamics}, volume = {39}, journal = {Journal of pharmacokinetics and pharmacodynamics}, number = {2}, publisher = {Springer}, address = {New York}, issn = {1567-567X}, doi = {10.1007/s10928-012-9243-7}, pages = {125 -- 139}, year = {2012}, abstract = {Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.}, language = {en} } @article{WeissHuisinga2011, author = {Weiss, Andrea Y. and Huisinga, Wilhelm}, title = {Error-controlled global sensitivity analysis of ordinary differential equations}, series = {Journal of computational physics}, volume = {230}, journal = {Journal of computational physics}, number = {17}, publisher = {Elsevier}, address = {San Diego}, issn = {0021-9991}, doi = {10.1016/j.jcp.2011.05.011}, pages = {6824 -- 6842}, year = {2011}, abstract = {We propose a novel strategy for global sensitivity analysis of ordinary differential equations. It is based on an error-controlled solution of the partial differential equation (PDE) that describes the evolution of the probability density function associated with the input uncertainty/variability. The density yields a more accurate estimate of the output uncertainty/variability, where not only some observables (such as mean and variance) but also structural properties (e.g., skewness, heavy tails, bi-modality) can be resolved up to a selected accuracy. For the adaptive solution of the PDE Cauchy problem we use the Rothe method with multiplicative error correction, which was originally developed for the solution of parabolic PDEs. We show that, unlike in parabolic problems, conservation properties necessitate a coupling of temporal and spatial accuracy to avoid accumulation of spatial approximation errors over time. We provide convergence conditions for the numerical scheme and suggest an implementation using approximate approximations for spatial discretization to efficiently resolve the coupling of temporal and spatial accuracy. The performance of the method is studied by means of low-dimensional case studies. The favorable properties of the spatial discretization technique suggest that this may be the starting point for an error-controlled sensitivity analysis in higher dimensions.}, language = {en} } @article{WeisseMiddletonHuisinga2010, author = {Weiße, Andrea Y. and Middleton, Richard H. and Huisinga, Wilhelm}, title = {Quantifying uncertainty, variability and likelihood for ordinary differential equation models}, issn = {1752-0509}, doi = {10.1186/1752-0509-4-144}, year = {2010}, abstract = {Background: In many applications, ordinary differential equation (ODE) models are subject to uncertainty or variability in initial conditions and parameters. Both, uncertainty and variability can be quantified in terms of a probability density function on the state and parameter space. Results: The partial differential equation that describes the evolution of this probability density function has a form that is particularly amenable to application of the well- known method of characteristics. The value of the density at some point in time is directly accessible by the solution of the original ODE extended by a single extra dimension (for the value of the density). This leads to simple methods for studying uncertainty, variability and likelihood, with significant advantages over more traditional Monte Carlo and related approaches especially when studying regions with low probability. Conclusions: While such approaches based on the method of characteristics are common practice in other disciplines, their advantages for the study of biological systems have so far remained unrecognized. Several examples illustrate performance and accuracy of the approach and its limitations.}, language = {en} } @article{PilariPreusseHuisinga2011, author = {Pilari, Sabine and Preusse, Cornelia and Huisinga, Wilhelm}, title = {Gestational influences on the pharmacokinetics of gestagenic drugs a combined in silico, in vitro and in vivo analysis}, series = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS}, volume = {42}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS}, number = {4}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0928-0987}, doi = {10.1016/j.ejps.2010.12.003}, pages = {318 -- 331}, year = {2011}, abstract = {During preclinical development of a gestagenic drug, a significant increase of the total plasma concentration was observed after multiple dosing in pregnant rabbits, but not in (non-pregnant) rats or monkeys. We used a PBPK modeling approach in combination with in vitro and in vivo data to address the question to what extent the pharmacologically active free drug concentration is affected by pregnancy induced processes. In human, a significant increase in sex hormone binding globulin (SHBG), and an induction of hepatic CYP3A4 as well as plasma esterases is observed during pregnancy. We find that the observed increase in total plasma trough levels in rabbits can be explained as a combined result of (i) drug accumulation due to multiple dosing, (ii) increase of the binding protein SHBG, and (iii) clearance induction. For human, we predict that free drug concentrations in plasma would not increase during pregnancy above the steady state trough level for non-pregnant women.}, language = {en} } @article{vonKleistMenzStockeretal.2011, author = {von Kleist, Max and Menz, Stephan and Stocker, Hartmut and Arasteh, Keikawus and Schuette, Christof and Huisinga, Wilhelm}, title = {HIV quasispecies dynamics during pro-active treatment switching impact on multi-drug resistance and resistance archiving in latent reservoirs}, series = {PLoS one}, volume = {6}, journal = {PLoS one}, number = {3}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0018204}, pages = {12}, year = {2011}, abstract = {The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at \& 80 days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after a single pro-active treatment switch. The clinical validity of this finding, however, remains to be shown by a corresponding trial.}, language = {en} } @inproceedings{SteenholdtEdlundAinsworthetal.2015, author = {Steenholdt, Casper and Edlund, Helena and Ainsworth, Mark A. and Brynskov, Jorn and Thomsen, Ole Ostergaard and Huisinga, Wilhelm and Kloft, Charlotte}, title = {Relationship between measures of infliximab exposure and clinical outcome of infliximab intensification at therapeutic failure in Crohn's disease}, series = {JOURNAL OF CROHNS \& COLITIS}, volume = {9}, booktitle = {JOURNAL OF CROHNS \& COLITIS}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1873-9946}, pages = {S330 -- S330}, year = {2015}, language = {en} } @article{MenzLatorreSchuetteetal.2012, author = {Menz, Stephan and Latorre, Juan C. and Sch{\"u}tte, Christof and Huisinga, Wilhelm}, title = {Hybrid stochastic-deterministic solution of the chemical master equation}, series = {Multiscale modeling \& simulation : a SIAM interdisciplinary journal}, volume = {10}, journal = {Multiscale modeling \& simulation : a SIAM interdisciplinary journal}, number = {4}, publisher = {Society for Industrial and Applied Mathematics}, address = {Philadelphia}, issn = {1540-3459}, doi = {10.1137/110825716}, pages = {1232 -- 1262}, year = {2012}, abstract = {The chemical master equation (CME) is the fundamental evolution equation of the stochastic description of biochemical reaction kinetics. In most applications it is impossible to solve the CME directly due to its high dimensionality. Instead, indirect approaches based on realizations of the underlying Markov jump process are used, such as the stochastic simulation algorithm (SSA). In the SSA, however, every reaction event has to be resolved explicitly such that it becomes numerically inefficient when the system's dynamics include fast reaction processes or species with high population levels. In many hybrid approaches, such fast reactions are approximated as continuous processes or replaced by quasi-stationary distributions in either a stochastic or a deterministic context. Current hybrid approaches, however, almost exclusively rely on the computation of ensembles of stochastic realizations. We present a novel hybrid stochastic-deterministic approach to solve the CME directly. Our starting point is a partitioning of the molecular species into discrete and continuous species that induces a partitioning of the reactions into discrete-stochastic and continuous-deterministic processes. The approach is based on a WKB (Wentzel-Kramers-Brillouin) ansatz for the conditional probability distribution function (PDF) of the continuous species (given a discrete state) in combination with Laplace's method of integral approximation. The resulting hybrid stochastic-deterministic evolution equations comprise a CME with averaged propensities for the PDF of the discrete species that is coupled to an evolution equation of the related expected levels of the continuous species for each discrete state. In contrast to indirect hybrid methods, the impact of the evolution of discrete species on the dynamics of the continuous species has to be taken into account explicitly. The proposed approach is efficient whenever the number of discrete molecular species is small. We illustrate the performance of the new hybrid stochastic-deterministic approach in an application to model systems of biological interest.}, language = {en} } @inproceedings{AnderssonKeuneckeEseretal.2014, author = {Andersson, H. and Keunecke, A. and Eser, A. and Huisinga, Wilhelm and Reinisch, W. and Kloft, Charlotte}, title = {Pharmacokinetic considerations for optimising dosing regimens of a potsdam univ infliximab in patients with Crohn's disease}, series = {JOURNAL OF CROHNS \& COLITIS}, volume = {8}, booktitle = {JOURNAL OF CROHNS \& COLITIS}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1873-9946}, doi = {10.1016/S1873-9946(14)60086-6}, pages = {S44 -- S44}, year = {2014}, language = {en} } @article{EngbertRabeKliegletal.2021, author = {Engbert, Ralf and Rabe, Maximilian Michael and Kliegl, Reinhold and Reich, Sebastian}, title = {Sequential data assimilation of the stochastic SEIR epidemic model for regional COVID-19 dynamics}, series = {Bulletin of mathematical biology : official journal of the Society for Mathematical Biology}, volume = {83}, journal = {Bulletin of mathematical biology : official journal of the Society for Mathematical Biology}, number = {1}, publisher = {Springer}, address = {New York}, issn = {0092-8240}, doi = {10.1007/s11538-020-00834-8}, pages = {16}, year = {2021}, abstract = {Newly emerging pandemics like COVID-19 call for predictive models to implement precisely tuned responses to limit their deep impact on society. Standard epidemic models provide a theoretically well-founded dynamical description of disease incidence. For COVID-19 with infectiousness peaking before and at symptom onset, the SEIR model explains the hidden build-up of exposed individuals which creates challenges for containment strategies. However, spatial heterogeneity raises questions about the adequacy of modeling epidemic outbreaks on the level of a whole country. Here, we show that by applying sequential data assimilation to the stochastic SEIR epidemic model, we can capture the dynamic behavior of outbreaks on a regional level. Regional modeling, with relatively low numbers of infected and demographic noise, accounts for both spatial heterogeneity and stochasticity. Based on adapted models, short-term predictions can be achieved. Thus, with the help of these sequential data assimilation methods, more realistic epidemic models are within reach.}, language = {en} } @article{KaminskiSchlagenhaufRappetal.2018, author = {Kaminski, Jakob A. and Schlagenhauf, Florian and Rapp, Michael A. and Awasthi, Swapnil and Ruggeri, Barbara and Deserno, Lorenz and Banaschewski, Tobias and Bokde, Arun L. W. and Bromberg, Uli and B{\"u}chel, Christian and Quinlan, Erin Burke and Desrivieres, Sylvane and Flor, Herta and Frouin, Vincent and Garavan, Hugh and Gowland, Penny and Ittermann, Bernd and Martinot, Jean-Luc and Martinot, Marie-Laure Paillere and Nees, Frauke and Orfanos, Dimitri Papadopoulos and Paus, Tomas and Poustka, Luise and Smolka, Michael N. and Fr{\"o}hner, Juliane H. and Walter, Henrik and Whelan, Robert and Ripke, Stephan and Schumann, Gunter and Heinz, Andreas}, title = {Epigenetic variance in dopamine D2 receptor}, series = {Translational Psychiatry}, volume = {8}, journal = {Translational Psychiatry}, publisher = {Nature Publ. Group}, address = {New York}, organization = {IMAGEN Consortium}, issn = {2158-3188}, doi = {10.1038/s41398-018-0222-7}, pages = {11}, year = {2018}, abstract = {Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the "missing heritability" between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.}, language = {en} } @article{GerlachGlueckKunze2023, author = {Gerlach, Moritz and Gl{\"u}ck, Jochen and Kunze, Markus}, title = {Stability of transition semigroups and applications to parabolic equations}, series = {Transactions of the American Mathematical Society}, volume = {376}, journal = {Transactions of the American Mathematical Society}, number = {1}, publisher = {American Mathematical Soc.}, address = {Providence}, issn = {0002-9947}, doi = {10.1090/tran/8620}, pages = {153 -- 180}, year = {2023}, abstract = {This paper deals with the long-term behavior of positive operator semigroups on spaces of bounded functions and of signed measures, which have applications to parabolic equations with unbounded coefficients and to stochas-tic analysis. The main results are a Tauberian type theorem characterizing the convergence to equilibrium of strongly Feller semigroups and a generalization of a classical convergence theorem of Doob. None of these results requires any kind of time regularity of the semigroup.}, language = {en} } @article{DimitrovaKoppitz2022, author = {Dimitrova, Ilinka and Koppitz, J{\"o}rg}, title = {On relative ranks of the semigroup of orientation-preserving transformations on infinite chain with restricted range}, series = {Communications in algebra}, volume = {50}, journal = {Communications in algebra}, number = {5}, publisher = {Taylor \& Francis Group}, address = {Philadelphia}, issn = {0092-7872}, doi = {10.1080/00927872.2021.2000998}, pages = {2157 -- 2168}, year = {2022}, abstract = {Let X be an infinite linearly ordered set and let Y be a nonempty subset of X. We calculate the relative rank of the semigroup OP(X,Y) of all orientation-preserving transformations on X with restricted range Y modulo the semigroup O(X,Y) of all order-preserving transformations on X with restricted range Y. For Y = X, we characterize the relative generating sets of minimal size.}, language = {en} } @article{DimitrovaKoppitz2020, author = {Dimitrova, Ilinka and Koppitz, J{\"o}rg}, title = {On relative ranks of the semigroup of orientation-preserving transformations on infinite chains}, series = {Asian-European journal of mathematics}, volume = {14}, journal = {Asian-European journal of mathematics}, number = {08}, publisher = {World Scientific}, address = {Singapore}, issn = {1793-5571}, doi = {10.1142/S1793557121501461}, pages = {15}, year = {2020}, abstract = {In this paper, we determine the relative rank of the semigroup OP(X) of all orientation-preserving transformations on infinite chains modulo the semigroup O(X) of all order-preserving transformations.}, language = {en} } @article{SharmaHainzlZoeller2023, author = {Sharma, Shubham and Hainzl, Sebastian and Z{\"o}ller, Gert}, title = {Seismicity parameters dependence on main shock-induced co-seismic stress}, series = {Geophysical journal international}, volume = {235}, journal = {Geophysical journal international}, number = {1}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0956-540X}, doi = {10.1093/gji/ggad201}, pages = {509 -- 517}, year = {2023}, abstract = {The Gutenberg-Richter (GR) and the Omori-Utsu (OU) law describe the earthquakes' energy release and temporal clustering and are thus of great importance for seismic hazard assessment. Motivated by experimental results, which indicate stress-dependent parameters, we consider a combined global data set of 127 main shock-aftershock sequences and perform a systematic study of the relationship between main shock-induced stress changes and associated seismicity patterns. For this purpose, we calculate space-dependent Coulomb Stress (\& UDelta;CFS) and alternative receiver-independent stress metrics in the surrounding of the main shocks. Our results indicate a clear positive correlation between the GR b-value and the induced stress, contrasting expectations from laboratory experiments and suggesting a crucial role of structural heterogeneity and strength variations. Furthermore, we demonstrate that the aftershock productivity increases nonlinearly with stress, while the OU parameters c and p systematically decrease for increasing stress changes. Our partly unexpected findings can have an important impact on future estimations of the aftershock hazard.}, language = {en} } @phdthesis{Sareeto2024, author = {Sareeto, Apatsara}, title = {Algebraic properties of a subsemigroup of the symmetric inverse semigroup}, school = {Universit{\"a}t Potsdam}, pages = {92}, year = {2024}, language = {en} } @article{GerlachGlueck2017, author = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen}, title = {On a convergence theorem for semigroups of positive integral operators}, series = {Comptes Rendus Mathematique}, volume = {355}, journal = {Comptes Rendus Mathematique}, publisher = {Elsevier}, address = {Paris}, issn = {1631-073X}, doi = {10.1016/j.crma.2017.07.017}, pages = {973 -- 976}, year = {2017}, abstract = {We give a new and very short proof of a theorem of Greiner asserting that a positive and contractive -semigroup on an -space is strongly convergent in case it has a strictly positive fixed point and contains an integral operator. Our proof is a streamlined version of a much more general approach to the asymptotic theory of positive semigroups developed recently by the authors. Under the assumptions of Greiner's theorem, this approach becomes particularly elegant and simple. We also give an outlook on several generalisations of this result.}, language = {en} } @article{Gerlach2018, author = {Gerlach, Moritz Reinhardt}, title = {Convergence of dynamics and the Perron-Frobenius operator}, series = {Israel Journal of Mathematics}, volume = {225}, journal = {Israel Journal of Mathematics}, number = {1}, publisher = {Hebrew univ magnes press}, address = {Jerusalem}, issn = {0021-2172}, doi = {10.1007/s11856-018-1671-7}, pages = {451 -- 463}, year = {2018}, abstract = {We complete the picture how the asymptotic behavior of a dynamical system is reflected by properties of the associated Perron-Frobenius operator. Our main result states that strong convergence of the powers of the Perron-Frobenius operator is equivalent to setwise convergence of the underlying dynamic in the measure algebra. This situation is furthermore characterized by uniform mixing-like properties of the system.}, language = {en} } @article{GerlachGlueck2019, author = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen}, title = {Convergence of positive operator semigroups}, series = {Transactions of the American Mathematical Society}, volume = {372}, journal = {Transactions of the American Mathematical Society}, number = {9}, publisher = {American Mathematical Soc.}, address = {Providence}, issn = {0002-9947}, doi = {10.1090/tran/7836}, pages = {6603 -- 6627}, year = {2019}, abstract = {We present new conditions for semigroups of positive operators to converge strongly as time tends to infinity. Our proofs are based on a novel approach combining the well-known splitting theorem by Jacobs, de Leeuw, and Glicksberg with a purely algebraic result about positive group representations. Thus, we obtain convergence theorems not only for one-parameter semigroups but also for a much larger class of semigroup representations. Our results allow for a unified treatment of various theorems from the literature that, under technical assumptions, a bounded positive C-0-semigroup containing or dominating a kernel operator converges strongly as t ->infinity. We gain new insights into the structure theoretical background of those theorems and generalize them in several respects; especially we drop any kind of continuity or regularity assumption with respect to the time parameter.}, language = {en} } @article{EdekoGerlachKuehner2019, author = {Edeko, Nikolai and Gerlach, Moritz Reinhardt and K{\"u}hner, Viktoria}, title = {Measure-preserving semiflows and one-parameter Koopman semigroups}, series = {Semigroup forum}, volume = {98}, journal = {Semigroup forum}, number = {1}, publisher = {Springer}, address = {New York}, issn = {0037-1912}, doi = {10.1007/s00233-018-9960-3}, pages = {48 -- 63}, year = {2019}, abstract = {For a finite measure space X, we characterize strongly continuous Markov lattice semigroups on Lp(X) by showing that their generator A acts as a derivation on the dense subspace D(A)L(X). We then use this to characterize Koopman semigroups on Lp(X) if X is a standard probability space. In addition, we show that every measurable and measure-preserving flow on a standard probability space is isomorphic to a continuous flow on a compact Borel probability space.}, language = {en} } @article{GerlachGlueck2018, author = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen}, title = {Lower bounds and the asymptotic behaviour of positive operator semigroups}, series = {Ergodic theory and dynamical systems}, volume = {38}, journal = {Ergodic theory and dynamical systems}, publisher = {Cambridge Univ. Press}, address = {New York}, issn = {0143-3857}, doi = {10.1017/etds.2017.9}, pages = {3012 -- 3041}, year = {2018}, abstract = {If (T-t) is a semigroup of Markov operators on an L-1-space that admits a nontrivial lower bound, then a well-known theorem of Lasota and Yorke asserts that the semigroup is strongly convergent as t -> infinity. In this article we generalize and improve this result in several respects. First, we give a new and very simple proof for the fact that the same conclusion also holds if the semigroup is merely assumed to be bounded instead of Markov. As a main result, we then prove a version of this theorem for semigroups which only admit certain individual lower bounds. Moreover, we generalize a theorem of Ding on semigroups of Frobenius-Perron operators. We also demonstrate how our results can be adapted to the setting of general Banach lattices and we give some counterexamples to show optimality of our results. Our methods combine some rather concrete estimates and approximation arguments with abstract functional analytical tools. One of these tools is a theorem which relates the convergence of a time-continuous operator semigroup to the convergence of embedded discrete semigroups.}, language = {en} } @article{GerlachGlueck2019, author = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen}, title = {Mean ergodicity vs weak almost periodicity}, series = {Studia mathematica}, volume = {248}, journal = {Studia mathematica}, number = {1}, publisher = {Polska Akademia Nauk, Instytut Matematyczny}, address = {Warszawa}, issn = {0039-3223}, doi = {10.4064/sm170918-20-3}, pages = {45 -- 56}, year = {2019}, abstract = {We provide explicit examples of positive and power-bounded operators on c(0) and l(infinity) which are mean ergodic but not weakly almost periodic. As a consequence we prove that a countably order complete Banach lattice on which every positive and power-bounded mean ergodic operator is weakly almost periodic is necessarily a KB-space. This answers several open questions from the literature. Finally, we prove that if T is a positive mean ergodic operator with zero fixed space on an arbitrary Banach lattice, then so is every power of T .}, language = {en} } @article{FalkenhagenKnoechelKloftetal.2023, author = {Falkenhagen, Undine and Kn{\"o}chel, Jane and Kloft, Charlotte and Huisinga, Wilhelm}, title = {Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models}, series = {CPT: Pharmacometrics \& Systems Pharmacology}, volume = {12}, journal = {CPT: Pharmacometrics \& Systems Pharmacology}, number = {4}, publisher = {Wiley}, address = {Hoboken}, issn = {2163-8306}, doi = {10.1002/psp4.12903}, pages = {432 -- 443}, year = {2023}, abstract = {Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analysis of clinical data. Here, we extend the approach beyond state reduction to also include the simplification of reaction rates, elimination of reactions, and analytic solutions. We additionally ensure that the reduced model maintains a prespecified approximation quality not only for a reference individual but also for a diverse virtual population. We illustrate the extended approach for the warfarin effect on blood coagulation. Using the model-reduction approach, we derive a novel small-scale warfarin/international normalized ratio model and demonstrate its suitability for biomarker identification. Due to the systematic nature of the approach in comparison with empirical model building, the proposed model-reduction algorithm provides an improved rationale to build PD models also from QSP models in other applications.}, language = {en} } @article{StueblerKloftHuisinga2023, author = {St{\"u}bler, Sabine and Kloft, Charlotte and Huisinga, Wilhelm}, title = {Cell-level systems biology model to study inflammatory bowel diseases and their treatment options}, series = {CPT: pharmacometrics \& systems pharmacology}, volume = {12}, journal = {CPT: pharmacometrics \& systems pharmacology}, number = {5}, publisher = {Nature Publ. Group}, address = {London}, issn = {2163-8306}, doi = {10.1002/psp4.12932}, pages = {690 -- 705}, year = {2023}, abstract = {To help understand the complex and therapeutically challenging inflammatory bowel diseases (IBDs), we developed a systems biology model of the intestinal immune system that is able to describe main aspects of IBD and different treatment modalities thereof. The model, including key cell types and processes of the mucosal immune response, compiles a large amount of isolated experimental findings from literature into a larger context and allows for simulations of different inflammation scenarios based on the underlying data and assumptions. In the context of a large and diverse virtual IBD population, we characterized the patients based on their phenotype (in contrast to healthy individuals, they developed persistent inflammation after a trigger event) rather than on a priori assumptions on parameter differences to a healthy individual. This allowed to reproduce the enormous diversity of predispositions known to lead to IBD. Analyzing different treatment effects, the model provides insight into characteristics of individual drug therapy. We illustrate for anti-TNF-alpha therapy, how the model can be used (i) to decide for alternative treatments with best prospects in the case of nonresponse, and (ii) to identify promising combination therapies with other available treatment options.}, language = {en} } @article{BomansonJanhunenSchaubetal.2016, author = {Bomanson, Jori and Janhunen, Tomi and Schaub, Torsten and Gebser, Martin and Kaufmann, Benjamin}, title = {Answer Set Programming Modulo Acyclicity}, series = {Fundamenta informaticae}, volume = {147}, journal = {Fundamenta informaticae}, publisher = {IOS Press}, address = {Amsterdam}, issn = {0169-2968}, doi = {10.3233/FI-2016-1398}, pages = {63 -- 91}, year = {2016}, abstract = {Acyclicity constraints are prevalent in knowledge representation and applications where acyclic data structures such as DAGs and trees play a role. Recently, such constraints have been considered in the satisfiability modulo theories (SMT) framework, and in this paper we carry out an analogous extension to the answer set programming (ASP) paradigm. The resulting formalism, ASP modulo acyclicity, offers a rich set of primitives to express constraints related to recursive structures. In the technical results of the paper, we relate the new generalization with standard ASP by showing (i) how acyclicity extensions translate into normal rules, (ii) how weight constraint programs can be instrumented by acyclicity extensions to capture stability in analogy to unfounded set checking, and (iii) how the gap between supported and stable models is effectively closed in the presence of such an extension. Moreover, we present an efficient implementation of acyclicity constraints by incorporating a respective propagator into the state-of-the-art ASP solver CLASP. The implementation provides a unique combination of traditional unfounded set checking with acyclicity propagation. In the experimental part, we evaluate the interplay of these orthogonal checks by equipping logic programs with supplementary acyclicity constraints. The performance results show that native support for acyclicity constraints is a worthwhile addition, furnishing a complementary modeling construct in ASP itself as well as effective means for translation-based ASP solving.}, language = {en} } @article{LinkeSchaub1999, author = {Linke, Thomas and Schaub, Torsten}, title = {Default reasoning via blocking sets}, year = {1999}, language = {en} }