@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}
}
@misc{MaierHartungdeWiljesetal.2020,
  author    = {Maier, Corinna and Hartung, Niklas and de Wiljes, Jana and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe},
  number    = {827},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-44550},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-445500},
  pages     = {14},
  year      = {2020},
  abstract  = {An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas.},
  language  = {en}
}
@article{MaierHartungdeWiljesetal.2020,
  author    = {Maier, Corinna and Hartung, Niklas and de Wiljes, Jana and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy},
  series = {CPT: Pharmacometrics \& Systems Pharmacology},
  volume    = {XX},
  journal   = {CPT: Pharmacometrics \& Systems Pharmacology},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12492},
  pages     = {12},
  year      = {2020},
  abstract  = {An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas.},
  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}
}