@article{BorongCannistraciConrad2017, author = {Borong, Shao and Cannistraci, Carlo and Conrad, Tim}, title = {Epithelial Mesenchymal Transition Network-based Feature Engineering in Lung Adenocarcinoma Prognosis Prediction Using Multiple Omic Data}, volume = {3}, journal = {Genomics and Computational Biology}, number = {3}, doi = {http://dx.doi.org/10.18547/gcb.2017.vol3.iss3.e57}, pages = {1 -- 13}, year = {2017}, abstract = {Epithelial mesenchymal transition (EMT) process has been shown as highly relevant to cancer prognosis. However, although different biological network-based biomarker identification methods have been proposed to predict cancer prognosis, EMT network has not been directly used for this purpose. In this study, we constructed an EMT regulatory network consisting of 87 molecules and tried to select features that are useful for prognosis prediction in Lung Adenocarcinoma (LUAD). To incorporate multiple molecular profiles, we obtained four types of molecular data including mRNA-Seq, copy number alteration (CNA), DNA methylation, and miRNA-Seq data from The Cancer Genome Atlas. The data were mapped to the EMT network in three alternative ways: mRNA-Seq and miRNA-Seq, DNA methylation, and CNA and miRNA-Seq. Each mapping was employed to extract five different sets of features using discretization and network-based biomarker identification methods. Each feature set was then used to predict prognosis with SVM and logistic regression classifiers. We measured the prediction accuracy with AUC and AUPR values using 10 times 10-fold cross validation. For a more comprehensive evaluation, we also measured the prediction accuracies of clinical features, EMT plus clinical features, randomly picked 87 molecules from each data mapping, and using all molecules from each data type. Counter-intuitively, EMT features do not always outperform randomly selected features and the prediction accuracies of the five feature sets are mostly not significantly different. Clinical features are shown to give the highest prediction accuracies. In addition, the prediction accuracies of both EMT features and random features are comparable as using all features (more than 17,000) from each data type.}, language = {en} } @article{ConradGenzelCvetkovicetal.2017, author = {Conrad, Tim and Genzel, Martin and Cvetkovic, Nada and Wulkow, Niklas and Vybiral, Jan and Kutyniok, Gitta and Sch{\"u}tte, Christof}, title = {Sparse Proteomics Analysis - a compressed sensing-based approach for feature selection and classification of high-dimensional proteomics mass spectrometry data}, volume = {18}, journal = {BMC Bioinformatics}, number = {160}, doi = {10.1186/s12859-017-1565-4}, pages = {1 -- 20}, year = {2017}, abstract = {Motivation: High-throughput proteomics techniques, such as mass spectrometry (MS)-based approaches, produce very high-dimensional data-sets. In a clinical setting one is often interested how MS spectra dier between patients of different classes, for example spectra from healthy patients vs. spectra from patients having a particular disease. Machine learning algorithms are needed to (a) identify these discriminating features and (b) classify unknown spectra based on this feature set. Since the acquired data is usually noisy, the algorithms should be robust to noise and outliers, and the identied feature set should be as small as possible. Results: We present a new algorithm, Sparse Proteomics Analysis (SPA), based on the theory of Compressed Sensing that allows to identify a minimal discriminating set of features from mass spectrometry data-sets. We show how our method performs on artificial and real-world data-sets.}, language = {en} } @article{SeeberConradHoppeetal.2017, author = {Seeber, L. and Conrad, Tim and Hoppe, Christian and Obermeier, Patrick and Chen, X. and Karsch, K. and Muehlhans, S. and Tief, Franziska and Boettcher, Sindy and Diedrich, S. and Schweiger, Brunhilde and Rath, Barbara}, title = {Educating parents about the vaccination status of their children: A user-centered mobile application}, volume = {5}, journal = {Preventive Medicine Reports}, doi = {10.1016/j.pmedr.2017.01.002}, pages = {241 -- 250}, year = {2017}, abstract = {Parents are often uncertain about the vaccination status of their children. In times of vaccine hesitancy, vaccination programs could benefit from active patient participation. The Vaccination App (VAccApp) was developed by the Vienna Vaccine Safety Initiative, enabling parents to learn about the vaccination status of their children, including 25 different routine, special indication and travel vaccines listed in the WHO Immunization Certificate of Vaccination (WHO-ICV). Between 2012 and 2014, the VAccApp was validated in a hospital-based quality management program in Berlin, Germany, in collaboration with the Robert Koch Institute. Parents of 178 children were asked to transfer the immunization data of their children from the WHO-ICV into the VAccApp. The respective WHO-ICV was photocopied for independent, professional data entry (gold standard). Demonstrating the status quo in vaccine information reporting, a Recall Group of 278 parents underwent structured interviews for verbal immunization histories, without the respective WHO-ICV. Only 9\% of the Recall Group were able to provide a complete vaccination status; on average 39\% of the questions were answered correctly. Using the WHO-ICV with the help of the VAccApp resulted in 62\% of parents providing a complete vaccination status; on average 95\% of the questions were answered correctly. After using the VAccApp, parents were more likely to remember key aspects of the vaccination history. User-friendly mobile applications empower parents to take a closer look at the vaccination record, thereby taking an active role in providing accurate vaccination histories. Parents may become motivated to ask informed questions and to keep vaccinations up-to-date.}, language = {en} } @misc{AmbellanLameckervonTycowiczetal.2019, author = {Ambellan, Felix and Lamecker, Hans and von Tycowicz, Christoph and Zachow, Stefan}, title = {Statistical Shape Models - Understanding and Mastering Variation in Anatomy}, issn = {1438-0064}, doi = {10.1007/978-3-030-19385-0_5}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-72699}, year = {2019}, abstract = {In our chapter we are describing how to reconstruct three-dimensional anatomy from medical image data and how to build Statistical 3D Shape Models out of many such reconstructions yielding a new kind of anatomy that not only allows quantitative analysis of anatomical variation but also a visual exploration and educational visualization. Future digital anatomy atlases will not only show a static (average) anatomy but also its normal or pathological variation in three or even four dimensions, hence, illustrating growth and/or disease progression. Statistical Shape Models (SSMs) are geometric models that describe a collection of semantically similar objects in a very compact way. SSMs represent an average shape of many three-dimensional objects as well as their variation in shape. The creation of SSMs requires a correspondence mapping, which can be achieved e.g. by parameterization with a respective sampling. If a corresponding parameterization over all shapes can be established, variation between individual shape characteristics can be mathematically investigated. We will explain what Statistical Shape Models are and how they are constructed. Extensions of Statistical Shape Models will be motivated for articulated coupled structures. In addition to shape also the appearance of objects will be integrated into the concept. Appearance is a visual feature independent of shape that depends on observers or imaging techniques. Typical appearances are for instance the color and intensity of a visual surface of an object under particular lighting conditions, or measurements of material properties with computed tomography (CT) or magnetic resonance imaging (MRI). A combination of (articulated) statistical shape models with statistical models of appearance lead to articulated Statistical Shape and Appearance Models (a-SSAMs).After giving various examples of SSMs for human organs, skeletal structures, faces, and bodies, we will shortly describe clinical applications where such models have been successfully employed. Statistical Shape Models are the foundation for the analysis of anatomical cohort data, where characteristic shapes are correlated to demographic or epidemiologic data. SSMs consisting of several thousands of objects offer, in combination with statistical methods ormachine learning techniques, the possibility to identify characteristic clusters, thus being the foundation for advanced diagnostic disease scoring.}, language = {en} } @misc{AmbellanTackEhlkeetal.2019, author = {Ambellan, Felix and Tack, Alexander and Ehlke, Moritz and Zachow, Stefan}, title = {Automated Segmentation of Knee Bone and Cartilage combining Statistical Shape Knowledge and Convolutional Neural Networks: Data from the Osteoarthritis Initiative}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-72704}, year = {2019}, abstract = {We present a method for the automated segmentation of knee bones and cartilage from magnetic resonance imaging (MRI) that combines a priori knowledge of anatomical shape with Convolutional Neural Networks (CNNs).The proposed approach incorporates 3D Statistical Shape Models (SSMs) as well as 2D and 3D CNNs to achieve a robust and accurate segmentation of even highly pathological knee structures.The shape models and neural networks employed are trained using data from the Osteoarthritis Initiative (OAI) and the MICCAI grand challenge "Segmentation of Knee Images 2010" (SKI10), respectively. We evaluate our method on 40 validation and 50 submission datasets from the SKI10 challenge.For the first time, an accuracy equivalent to the inter-observer variability of human readers is achieved in this challenge.Moreover, the quality of the proposed method is thoroughly assessed using various measures for data from the OAI, i.e. 507 manual segmentations of bone and cartilage, and 88 additional manual segmentations of cartilage. Our method yields sub-voxel accuracy for both OAI datasets. We make the 507 manual segmentations as well as our experimental setup publicly available to further aid research in the field of medical image segmentation.In conclusion, combining localized classification via CNNs with statistical anatomical knowledge via SSMs results in a state-of-the-art segmentation method for knee bones and cartilage from MRI data.}, language = {en} } @article{ObermeierHeimBiereetal.2018, author = {Obermeier, Patrick and Heim, A. and Biere, Barbara and Hage, E. and Alchikh, Maren and Conrad, Tim and Schweiger, Brunhilde and Rath, Barbara}, title = {Clinical characteristics and disease severity associated with adenovirus infections in infants and children - discovery of a novel adenovirus, HAdV-D80}, journal = {Clinical Infectious Diseases}, year = {2018}, language = {en} } @article{KorkSpiesConradetal.2018, author = {Kork, F. and Spies, Claudia and Conrad, Tim and Weiss, B. and Roenneberg, T. and Wernecke, K.-D. and Balzer, Felix}, title = {Associations of postoperative mortality with the time of day, week and year}, journal = {Anaesthesia}, year = {2018}, language = {en} } @article{GelssKlusEisertetal.2019, author = {Gelß, Patrick and Klus, Stefan and Eisert, Jens and Sch{\"u}tte, Christof}, title = {Multidimensional Approximation of Nonlinear Dynamical Systems}, volume = {14}, journal = {Journal of Computational and Nonlinear Dynamics}, number = {6}, doi = {10.1115/1.4043148}, year = {2019}, abstract = {A key task in the field of modeling and analyzing nonlinear dynamical systems is the recovery of unknown governing equations from measurement data only. There is a wide range of application areas for this important instance of system identification, ranging from industrial engineering and acoustic signal processing to stock market models. In order to find appropriate representations of underlying dynamical systems, various data-driven methods have been proposed by different communities. However, if the given data sets are high-dimensional, then these methods typically suffer from the curse of dimensionality. To significantly reduce the computational costs and storage consumption, we propose the method multidimensional approximation of nonlinear dynamical systems (MANDy) which combines data-driven methods with tensor network decompositions. The efficiency of the introduced approach will be illustrated with the aid of several high-dimensional nonlinear dynamical systems.}, language = {en} } @incollection{AmbellanLameckervonTycowiczetal.2019, author = {Ambellan, Felix and Lamecker, Hans and von Tycowicz, Christoph and Zachow, Stefan}, title = {Statistical Shape Models - Understanding and Mastering Variation in Anatomy}, volume = {3}, booktitle = {Biomedical Visualisation}, number = {1156}, editor = {Rea, Paul M.}, edition = {1}, publisher = {Springer Nature Switzerland AG}, isbn = {978-3-030-19384-3}, doi = {10.1007/978-3-030-19385-0_5}, pages = {67 -- 84}, year = {2019}, abstract = {In our chapter we are describing how to reconstruct three-dimensional anatomy from medical image data and how to build Statistical 3D Shape Models out of many such reconstructions yielding a new kind of anatomy that not only allows quantitative analysis of anatomical variation but also a visual exploration and educational visualization. Future digital anatomy atlases will not only show a static (average) anatomy but also its normal or pathological variation in three or even four dimensions, hence, illustrating growth and/or disease progression. Statistical Shape Models (SSMs) are geometric models that describe a collection of semantically similar objects in a very compact way. SSMs represent an average shape of many three-dimensional objects as well as their variation in shape. The creation of SSMs requires a correspondence mapping, which can be achieved e.g. by parameterization with a respective sampling. If a corresponding parameterization over all shapes can be established, variation between individual shape characteristics can be mathematically investigated. We will explain what Statistical Shape Models are and how they are constructed. Extensions of Statistical Shape Models will be motivated for articulated coupled structures. In addition to shape also the appearance of objects will be integrated into the concept. Appearance is a visual feature independent of shape that depends on observers or imaging techniques. Typical appearances are for instance the color and intensity of a visual surface of an object under particular lighting conditions, or measurements of material properties with computed tomography (CT) or magnetic resonance imaging (MRI). A combination of (articulated) statistical shape models with statistical models of appearance lead to articulated Statistical Shape and Appearance Models (a-SSAMs).After giving various examples of SSMs for human organs, skeletal structures, faces, and bodies, we will shortly describe clinical applications where such models have been successfully employed. Statistical Shape Models are the foundation for the analysis of anatomical cohort data, where characteristic shapes are correlated to demographic or epidemiologic data. SSMs consisting of several thousands of objects offer, in combination with statistical methods ormachine learning techniques, the possibility to identify characteristic clusters, thus being the foundation for advanced diagnostic disease scoring.}, language = {en} } @article{HildebrandtBrueningSchmidtetal.2019, author = {Hildebrandt, Thomas and Bruening, Jan Joris and Schmidt, Nora Laura and Lamecker, Hans and Heppt, Werner and Zachow, Stefan and Goubergrits, Leonid}, title = {The Healthy Nasal Cavity - Characteristics of Morphology and Related Airflow Based on a Statistical Shape Model Viewed from a Surgeon's Perspective}, volume = {35}, journal = {Facial Plastic Surgery}, number = {1}, doi = {10.1055/s-0039-1677721}, pages = {9 -- 13}, year = {2019}, abstract = {Functional surgery on the nasal framework requires referential criteria to objectively assess nasal breathing for indication and follow-up. Thismotivated us to generate amean geometry of the nasal cavity based on a statistical shape model. In this study, the authors could demonstrate that the introduced nasal cavity's mean geometry features characteristics of the inner shape and airflow, which are commonly observed in symptom-free subjects. Therefore, the mean geometry might serve as a reference-like model when one considers qualitative aspects. However, to facilitate quantitative considerations and statistical inference, further research is necessary. Additionally, the authorswere able to obtain details about the importance of the isthmus nasi and the inferior turbinate for the intranasal airstream.}, language = {en} } @article{HildebrandtBrueningLameckeretal.2019, author = {Hildebrandt, Thomas and Bruening, Jan Joris and Lamecker, Hans and Zachow, Stefan and Heppt, Werner and Schmidt, Nora and Goubergrits, Leonid}, title = {Digital Analysis of Nasal Airflow Facilitating Decision Support in Rhinosurgery}, volume = {35}, journal = {Facial Plastic Surgery}, number = {1}, doi = {10.1055/s-0039-1677720}, pages = {1 -- 8}, year = {2019}, abstract = {Successful functional surgery on the nasal framework requires reliable and comprehensive diagnosis. In this regard, the authors introduce a new methodology: Digital Analysis of Nasal Airflow (diANA). It is based on computational fluid dynamics, a statistical shape model of the healthy nasal cavity and rhinologic expertise. diANA necessitates an anonymized tomographic dataset of the paranasal sinuses including the complete nasal cavity and, when available, clinical information. The principle of diANA is to compare the morphology and the respective airflow of an individual nose with those of a reference. This enablesmorphometric aberrations and consecutive flow field anomalies to localize and quantify within a patient's nasal cavity. Finally, an elaborated expert opinion with instructive visualizations is provided. Using diANA might support surgeons in decision-making, avoiding unnecessary surgery, gaining more precision, and target-orientation for indicated operations.}, language = {en} } @article{HettichSchierjottSchillingetal.2018, author = {Hettich, G. and Schierjott, R. A. and Schilling, C. and Maas, A. and Ramm, Heiko and Bindernagel, Matthias and Lamecker, Hans and Grupp, T. M.}, title = {Validation of a Statistical Shape Model for Acetabular Bone Defect Analysis}, journal = {ISTA 2018 London Abstract Book}, year = {2018}, abstract = {Acetabular bone defects are still challenging to quantify. Numerous classification schemes have been proposed to categorize the diverse kinds of defects. However, these classification schemes are mainly descriptive and hence it remains difficult to apply them in pre-clinical testing, implant development and pre-operative planning. By reconstructing the native situation of a defect pelvis using a Statistical Shape Model (SSM), a more quantitative analysis of the bone defects could be performed. The aim of this study is to develop such a SSM and to validate its accuracy using relevant clinical scenarios and parameters.}, language = {en} } @article{MirelesConrad2018, author = {Mireles, Victor and Conrad, Tim}, title = {Reusable building blocks in biological systems}, volume = {15}, journal = {Journal of the Royal Society Interface}, number = {149}, doi = {10.1098/rsif.2018.0595}, pages = {1 -- 10}, year = {2018}, abstract = {One of the most widely recognized features of biological systems is their modularity. The modules that constitute biological systems are said to be redeployed and combined across several conditions, thus acting as building blocks. In this work, we analyse to what extent are these building blocks reusable as compared with those found in randomized versions of a system. We develop a notion of decompositions of systems into phenotypic building blocks, which allows them to overlap while maximizing the number of times a building block is reused across several conditions. Different biological systems present building blocks whose reusability ranges from single use (e.g. condition specific) to constitutive, although their average reusability is not always higher than random equivalents of the system. These decompositions reveal a distinct distribution of building block sizes in real biological systems. This distribution stems, in part, from the peculiar usage pattern of the elements of biological systems, and constitutes a new angle to study the evolution of modularity.}, language = {en} } @article{MaConradAlchikhetal.2018, author = {Ma, Xiaolin and Conrad, Tim and Alchikh, Maren and Reiche, J. and Schweiger, Brunhilde and Rath, Barbara}, title = {Can we distinguish respiratory viral infections based on clinical features? A prospective pediatric cohort compared to systematic literature review}, volume = {28}, journal = {Medical Virology}, number = {5}, doi = {10.1002/rmv.1997}, pages = {1 -- 12}, year = {2018}, abstract = {Studies have shown that the predictive value of "clinical diagnoses" of influenza and other respiratory viral infections is low, especially in children. In routine care, pediatricians often resort to clinical diagnoses, even in the absence of robust evidence-based criteria. We used a dual approach to identify clinical characteristics that may help to differentiate infections with common pathogens including influenza, respiratory syncytial virus, adenovirus, metapneumovirus, rhinovirus, bocavirus-1, coronaviruses, or parainfluenza virus: (a) systematic review and meta-analysis of 47 clinical studies published in Medline (June 1996 to March 2017, PROSPERO registration number: CRD42017059557) comprising 49 858 individuals and (b) data-driven analysis of an inception cohort of 6073 children with ILI (aged 0-18 years, 56\% male, December 2009 to March 2015) examined at the point of care in addition to blinded PCR testing. We determined pooled odds ratios for the literature analysis and compared these to odds ratios based on the clinical cohort dataset. This combined analysis suggested significant associations between influenza and fever or headache, as well as between respiratory syncytial virus infection and cough, dyspnea, and wheezing. Similarly, literature and cohort data agreed on significant associations between HMPV infection and cough, as well as adenovirus infection and fever. Importantly, none of the abovementioned features were unique to any particular pathogen but were also observed in association with other respiratory viruses. In summary, our "real-world" dataset confirmed published literature trends, but no individual feature allows any particular type of viral infection to be ruled in or ruled out. For the time being, laboratory confirmation remains essential. More research is needed to develop scientifically validated decision models to inform best practice guidelines and targeted diagnostic algorithms.}, language = {en} } @article{AlchikhConradHoppeetal.2018, author = {Alchikh, Maren and Conrad, Tim and Hoppe, Christian and Ma, Xiaolin and Broberg, Eeva K. and Penttinen, P. and Reiche, J. and Biere, Barbara and Schweiger, Brunhilde and Rath, Barbara}, title = {Are we missing respiratory viral infections in infants and children? Comparison of a hospital-based quality management system with standard of care. Clinical Microbiology and Infection}, journal = {Clinical Microbiology and Infection}, number = {06/18}, doi = {10.1016/j.cmi.2018.05.023}, pages = {1 -- 1}, year = {2018}, language = {en} } @inproceedings{JayrannejadConrad2017, author = {Jayrannejad, Fahrnaz and Conrad, Tim}, title = {Better Interpretable Models for Proteomics Data Analysis Using rule-based Mining}, booktitle = {Springer Lecture Notes in Artificial Intelligence}, pages = {studi}, year = {2017}, abstract = {Recent advances in -omics technology has yielded in large data-sets in many areas of biology, such as mass spectrometry based proteomics. However, analyzing this data is still a challenging task mainly due to the very high dimensionality and high noise content of the data. One of the main objectives of the analysis is the identification of relevant patterns (or features) which can be used for classification of new samples to healthy or diseased. So, a method is required to find easily interpretable models from this data. To gain the above mentioned goal, we have adapted the disjunctive association rule mining algorithm, TitanicOR, to identify emerging patterns from our mass spectrometry proteomics data-sets. Comparison to five state-of-the-art methods shows that our method is advantageous them in terms of identifying the inter-dependency between the features and the TP-rate and precision of the features selected. We further demonstrate the applicability of our algorithm to one previously published clinical data-set.}, language = {en} } @inproceedings{TackZachow2019, author = {Tack, Alexander and Zachow, Stefan}, title = {Accurate Automated Volumetry of Cartilage of the Knee using Convolutional Neural Networks: Data from the Osteoarthritis Initiative}, booktitle = {IEEE 16th International Symposium on Biomedical Imaging (ISBI 2019)}, doi = {10.1109/ISBI.2019.8759201}, pages = {40 -- 43}, year = {2019}, abstract = {Volumetry of cartilage of the knee is needed for knee osteoarthritis (KOA) assessment. It is typically performed manually in a tedious and subjective process. We developed a method for an automated, segmentation-based quantification of cartilage volume by employing 3D Convolutional Neural Networks (CNNs). CNNs were trained in a supervised manner using magnetic resonance imaging data and cartilage volumetry readings performed by clinical experts for 1378 subjects provided by the Osteoarthritis Initiative. It was shown that 3D CNNs are able to achieve volume measures comparable to the magnitude of variation between expert readings and the real in vivo situation. In the future, accurate automated cartilage volumetry might support both, diagnosis of KOA as well as longitudinal analysis of KOA progression.}, language = {en} } @misc{AmbellanTackEhlkeetal.2019, author = {Ambellan, Felix and Tack, Alexander and Ehlke, Moritz and Zachow, Stefan}, title = {Automated Segmentation of Knee Bone and Cartilage combining Statistical Shape Knowledge and Convolutional Neural Networks: Data from the Osteoarthritis Initiative (Supplementary Material)}, volume = {52}, journal = {Medical Image Analysis}, number = {2}, doi = {10.12752/4.ATEZ.1.0}, pages = {109 -- 118}, year = {2019}, abstract = {We present a method for the automated segmentation of knee bones and cartilage from magnetic resonance imaging that combines a priori knowledge of anatomical shape with Convolutional Neural Networks (CNNs). The proposed approach incorporates 3D Statistical Shape Models (SSMs) as well as 2D and 3D CNNs to achieve a robust and accurate segmentation of even highly pathological knee structures. The shape models and neural networks employed are trained using data of the Osteoarthritis Initiative (OAI) and the MICCAI grand challenge "Segmentation of Knee Images 2010" (SKI10), respectively. We evaluate our method on 40 validation and 50 submission datasets of the SKI10 challenge. For the first time, an accuracy equivalent to the inter-observer variability of human readers has been achieved in this challenge. Moreover, the quality of the proposed method is thoroughly assessed using various measures for data from the OAI, i.e. 507 manual segmentations of bone and cartilage, and 88 additional manual segmentations of cartilage. Our method yields sub-voxel accuracy for both OAI datasets. We made the 507 manual segmentations as well as our experimental setup publicly available to further aid research in the field of medical image segmentation. In conclusion, combining statistical anatomical knowledge via SSMs with the localized classification via CNNs results in a state-of-the-art segmentation method for knee bones and cartilage from MRI data.}, language = {en} } @article{KoltaiSchuette2018, author = {Koltai, P{\´e}ter and Sch{\"u}tte, Christof}, title = {A multiscale perturbation expansion approach for Markov state modeling of non-stationary molecular dynamics}, volume = {16}, journal = {SIAM J. Multiscale Model. Simul.}, number = {4}, publisher = {SIAM}, doi = {10.1137/17M1146403}, pages = {1455 -- 1485}, year = {2018}, abstract = {We investigate metastable dynamical systems subject to non-stationary forcing as they appear in molecular dynamics for systems driven by external fields. We show, that if the strength of the forcing is inversely proportional to the length of the slow metastable time scales of the unforced system, then the effective behavior of the forced system on slow time scales can be described by a low-dimensional reduced master equation. Our construction is explicit and uses the multiscale perturbation expansion method called two-timing, or method of multiple scales. The reduced master equation—a Markov state model—can be assembled by constructing two equilibrium Markov state models; one for the unforced system, and one for a slightly perturbed one.}, language = {en} } @article{AmbellanTackEhlkeetal.2019, author = {Ambellan, Felix and Tack, Alexander and Ehlke, Moritz and Zachow, Stefan}, title = {Automated Segmentation of Knee Bone and Cartilage combining Statistical Shape Knowledge and Convolutional Neural Networks: Data from the Osteoarthritis Initiative}, volume = {52}, journal = {Medical Image Analysis}, number = {2}, doi = {10.1016/j.media.2018.11.009}, pages = {109 -- 118}, year = {2019}, abstract = {We present a method for the automated segmentation of knee bones and cartilage from magnetic resonance imaging that combines a priori knowledge of anatomical shape with Convolutional Neural Networks (CNNs). The proposed approach incorporates 3D Statistical Shape Models (SSMs) as well as 2D and 3D CNNs to achieve a robust and accurate segmentation of even highly pathological knee structures. The shape models and neural networks employed are trained using data of the Osteoarthritis Initiative (OAI) and the MICCAI grand challenge "Segmentation of Knee Images 2010" (SKI10), respectively. We evaluate our method on 40 validation and 50 submission datasets of the SKI10 challenge. For the first time, an accuracy equivalent to the inter-observer variability of human readers has been achieved in this challenge. Moreover, the quality of the proposed method is thoroughly assessed using various measures for data from the OAI, i.e. 507 manual segmentations of bone and cartilage, and 88 additional manual segmentations of cartilage. Our method yields sub-voxel accuracy for both OAI datasets. We made the 507 manual segmentations as well as our experimental setup publicly available to further aid research in the field of medical image segmentation. In conclusion, combining statistical anatomical knowledge via SSMs with the localized classification via CNNs results in a state-of-the-art segmentation method for knee bones and cartilage from MRI data.}, language = {en} } @article{ShaoBjaanaesHellandetal.2019, author = {Shao, Borong and Bjaanaes, Maria and Helland, Aslaug and Sch{\"u}tte, Christof and Conrad, Tim}, title = {EMT network-based feature selection improves prognosis prediction in lung adenocarcinoma}, volume = {14}, journal = {PLOS ONE}, number = {1}, doi = {10.1371/journal.pone.0204186}, year = {2019}, abstract = {Various feature selection algorithms have been proposed to identify cancer prognostic biomarkers. In recent years, however, their reproducibility is criticized. The performance of feature selection algorithms is shown to be affected by the datasets, underlying networks and evaluation metrics. One of the causes is the curse of dimensionality, which makes it hard to select the features that generalize well on independent data. Even the integration of biological networks does not mitigate this issue because the networks are large and many of their components are not relevant for the phenotype of interest. With the availability of multi-omics data, integrative approaches are being developed to build more robust predictive models. In this scenario, the higher data dimensions create greater challenges. We proposed a phenotype relevant network-based feature selection (PRNFS) framework and demonstrated its advantages in lung cancer prognosis prediction. We constructed cancer prognosis relevant networks based on epithelial mesenchymal transition (EMT) and integrated them with different types of omics data for feature selection. With less than 2.5\% of the total dimensionality, we obtained EMT prognostic signatures that achieved remarkable prediction performance (average AUC values above 0.8), very significant sample stratifications, and meaningful biological interpretations. In addition to finding EMT signatures from different omics data levels, we combined these single-omics signatures into multi-omics signatures, which improved sample stratifications significantly. Both single- and multi-omics EMT signatures were tested on independent multi-omics lung cancer datasets and significant sample stratifications were obtained.}, language = {en} } @article{GuptaPeterJungetal.2019, author = {Gupta, Pooja and Peter, Sarah and Jung, Markus and Lewin, Astrid and Hemmrich-Stanisak, Georg and Franke, Andre and von Kleist, Max and Sch{\"u}tte, Christof and Einspanier, Ralf and Sharbati, Soroush and zur Bruegge, Jennifer}, title = {Analysis of long non-coding RNA and mRNA expression in bovine macrophages brings up novel 2 aspects of Mycobacterium avium subspecies paratuberculosis infections}, volume = {9}, journal = {Scientific Reports in Nature}, doi = {10.1038/s41598-018-38141-x}, year = {2019}, abstract = {Paratuberculosis is a major disease in cattle that severely affects animal welfare and causes huge economic losses worldwide. Development of alternative diagnostic methods is of urgent need to control the disease. Recent studies suggest that long non-coding RNAs (lncRNAs) play a crucial role in regulating immune function and may confer valuable information about the disease. However, their role has not yet been investigated in cattle with respect to infection towards Paratuberculosis. Therefore, we investigated the alteration in genomic expression profiles of mRNA and lncRNA in bovine macrophages in response to Paratuberculosis infection using RNA-Seq. We identified 397 potentially novel lncRNA candidates in macrophages of which 38 were differentially regulated by the infection. A total of 820 coding genes were also significantly altered by the infection. Co-expression analysis of lncRNAs and their neighbouring coding genes suggest regulatory functions of lncRNAs in pathways related to immune response. For example, this included protein coding genes such as TNIP3, TNFAIP3 and NF-κB2 that play a role in NF-κB2 signalling, a pathway associated with immune response. This study advances our understanding of lncRNA roles during Paratuberculosis infection.}, language = {en} } @article{BernardSalamancaThunbergetal.2017, author = {Bernard, Florian and Salamanca, Luis and Thunberg, Johan and Tack, Alexander and Jentsch, Dennis and Lamecker, Hans and Zachow, Stefan and Hertel, Frank and Goncalves, Jorge and Gemmar, Peter}, title = {Shape-aware Surface Reconstruction from Sparse 3D Point-Clouds}, volume = {38}, journal = {Medical Image Analysis}, doi = {10.1016/j.media.2017.02.005}, pages = {77 -- 89}, year = {2017}, abstract = {The reconstruction of an object's shape or surface from a set of 3D points plays an important role in medical image analysis, e.g. in anatomy reconstruction from tomographic measurements or in the process of aligning intra-operative navigation and preoperative planning data. In such scenarios, one usually has to deal with sparse data, which significantly aggravates the problem of reconstruction. However, medical applications often provide contextual information about the 3D point data that allow to incorporate prior knowledge about the shape that is to be reconstructed. To this end, we propose the use of a statistical shape model (SSM) as a prior for surface reconstruction. The SSM is represented by a point distribution model (PDM), which is associated with a surface mesh. Using the shape distribution that is modelled by the PDM, we formulate the problem of surface reconstruction from a probabilistic perspective based on a Gaussian Mixture Model (GMM). In order to do so, the given points are interpreted as samples of the GMM. By using mixture components with anisotropic covariances that are "oriented" according to the surface normals at the PDM points, a surface-based fitting is accomplished. Estimating the parameters of the GMM in a maximum a posteriori manner yields the reconstruction of the surface from the given data points. We compare our method to the extensively used Iterative Closest Points method on several different anatomical datasets/SSMs (brain, femur, tibia, hip, liver) and demonstrate superior accuracy and robustness on sparse data.}, language = {en} } @article{WinkelmannSchuette2016, author = {Winkelmann, Stefanie and Sch{\"u}tte, Christof}, title = {The Spatiotemporal Master Equation: Approximation of Reaction-Diffusion Dynamics via Markov State Modeling}, volume = {145}, journal = {Journal of Chemical Physics}, number = {21}, doi = {10.1063/1.4971163}, year = {2016}, abstract = {Accurate modeling and numerical simulation of reaction kinetics is a topic of steady interest.We consider the spatiotemporal chemical master equation (ST-CME) as a model for stochastic reaction-diffusion systems that exhibit properties of metastability. The space of motion is decomposed into metastable compartments and diffusive motion is approximated by jumps between these compartments. Treating these jumps as first-order reactions, simulation of the resulting stochastic system is possible by the Gillespie method. We present the theory of Markov state models (MSM) as a theoretical foundation of this intuitive approach. By means of Markov state modeling, both the number and shape of compartments and the transition rates between them can be determined. We consider the ST-CME for two reaction-diffusion systems and compare it to more detailed models. Moreover, a rigorous formal justification of the ST-CME by Galerkin projection methods is presented.}, language = {en} } @article{DuwalWinkelmannSchuetteetal.2015, author = {Duwal, Sulav and Winkelmann, Stefanie and Sch{\"u}tte, Christof and von Kleist, Max}, title = {Optimal Treatment Strategies in the Context of 'Treatment for Prevention' against HIV/1 in Resource-Poor Settings}, volume = {11}, journal = {PloS Computational Biology}, number = {4}, doi = {10.1371/journal.pcbi.1004200}, year = {2015}, abstract = {An estimated 2.7 million new HIV-1 infections occurred in 2010. `Treatment-for-prevention' may strongly prevent HIV-1 transmission. The basic idea is that immediate treatment initiation rapidly decreases virus burden, which reduces the number of transmittable viruses and thereby the probability of infection. However, HIV inevitably develops drug resistance, which leads to virus rebound and nullifies the effect of `treatment-for-prevention' for the time it remains unrecognized. While timely conducted treatment changes may avert periods of viral rebound, necessary treatment options and diagnostics may be lacking in resource-constrained settings. Within this work, we provide a mathematical platform for comparing different treatment paradigms that can be applied to many medical phenomena. We use this platform to optimize two distinct approaches for the treatment of HIV-1: (i) a diagnostic-guided treatment strategy, based on infrequent and patient-specific diagnostic schedules and (ii) a pro-active strategy that allows treatment adaptation prior to diagnostic ascertainment. Both strategies are compared to current clinical protocols (standard of care and the HPTN052 protocol) in terms of patient health, economic means and reduction in HIV-1 onward transmission exemplarily for South Africa. All therapeutic strategies are assessed using a coarse-grained stochastic model of within-host HIV dynamics and pseudo-codes for solving the respective optimal control problems are provided. Our mathematical model suggests that both optimal strategies (i)-(ii) perform better than the current clinical protocols and no treatment in terms of economic means, life prolongation and reduction of HIV-transmission. The optimal diagnostic-guided strategy suggests rare diagnostics and performs similar to the optimal pro-active strategy. Our results suggest that 'treatment-for-prevention' may be further improved using either of the two analyzed treatment paradigms.}, language = {en} } @article{SarichDjurdjevacConradBruckneretal.2014, author = {Sarich, Marco and Djurdjevac Conrad, Natasa and Bruckner, Sharon and Conrad, Tim and Sch{\"u}tte, Christof}, title = {Modularity revisited: A novel dynamics-based concept for decomposing complex networks}, volume = {1}, journal = {Journal of Computational Dynamics}, number = {1}, doi = {10.3934/jcd.2014.1.191}, pages = {191 -- 212}, year = {2014}, language = {en} } @article{AkbariShandizBoulosSavarssonetal.2018, author = {Akbari Shandiz, Mohsen and Boulos, Paul and S{\ae}varsson, Stefan and Ramm, Heiko and Fu, Chun Kit and Miller, Stephen and Zachow, Stefan and Anglin, Carolyn}, title = {Changes in Knee Shape and Geometry Resulting from Total Knee Arthroplasty}, volume = {232}, journal = {Journal of Engineering in Medicine}, number = {1}, doi = {10.1177/0954411917743274}, pages = {67 -- 79}, year = {2018}, abstract = {Changes in knee shape and geometry resulting from total knee arthroplasty can affect patients in numerous important ways: pain, function, stability, range of motion, and kinematics. Quantitative data concerning these changes have not been previously available, to our knowledge, yet are essential to understand individual experiences of total knee arthroplasty and thereby improve outcomes for all patients. The limiting factor has been the challenge of accurately measuring these changes. Our study objective was to develop a conceptual framework and analysis method to investigate changes in knee shape and geometry, and prospectively apply it to a sample total knee arthroplasty population. Using clinically available computed tomography and radiography imaging systems, the three-dimensional knee shape and geometry of nine patients (eight varus and one valgus) were compared before and after total knee arthroplasty. All patients had largely good outcomes after their total knee arthroplasty. Knee shape changed both visually and numerically. On average, the distal condyles were slightly higher medially and lower laterally (range: +4.5 mm to -4.4 mm), the posterior condyles extended farther out medially but not laterally (range: +1.8 to -6.4 mm), patellofemoral distance increased throughout flexion by 1.8-3.5 mm, and patellar thickness alone increased by 2.9 mm (range: 0.7-5.2 mm). External femoral rotation differed preop and postop. Joint line distance, taking cartilage into account, changed by +0.7 to -1.5 mm on average throughout flexion. Important differences in shape and geometry were seen between pre-total knee arthroplasty and post-total knee arthroplasty knees. While this is qualitatively known, this is the first study to report it quantitatively, an important precursor to identifying the reasons for the poor outcome of some patients. Using the developed protocol and visualization techniques to compare patients with good versus poor clinical outcomes could lead to changes in implant design, implant selection, component positioning, and surgical technique. Recommendations based on this sample population are provided. Intraoperative and postoperative feedback could ultimately improve patient satisfaction.}, language = {en} } @article{DibakJdelRazoDeSanchoetal.2018, author = {Dibak, Manuel and J. del Razo, Mauricio and De Sancho, David and Sch{\"u}tte, Christof and No{\´e}, Frank}, title = {MSM/RD: Coupling Markov state models of molecular kinetics with reaction-diffusion simulations}, volume = {148}, journal = {Journal of Chemical Physics}, number = {214107}, doi = {10.1063/1.5020294}, year = {2018}, abstract = {Molecular dynamics (MD) simulations can model the interactions between macromolecules with high spatiotemporal resolution but at a high computational cost. By combining high-throughput MD with Markov state models (MSMs), it is now possible to obtain long-timescale behavior of small to intermediate biomolecules and complexes. To model the interactions of many molecules at large lengthscales, particle-based reaction-diffusion (RD) simulations are more suitable but lack molecular detail. Thus, coupling MSMs and RD simulations (MSM/RD) would be highly desirable, as they could efficiently produce simulations at large time- and lengthscales, while still conserving the characteristic features of the interactions observed at atomic detail. While such a coupling seems straightforward, fundamental questions are still open: Which definition of MSM states is suitable? Which protocol to merge and split RD particles in an association/dissociation reaction will conserve the correct bimolecular kinetics and thermodynamics? In this paper, we make the first step towards MSM/RD by laying out a general theory of coupling and proposing a first implementation for association/dissociation of a protein with a small ligand (A + B <--> C). Applications on a toy model and CO diffusion into the heme cavity of myoglobin are reported.}, language = {en} } @article{TackMukhopadhyayZachow2018, author = {Tack, Alexander and Mukhopadhyay, Anirban and Zachow, Stefan}, title = {Knee Menisci Segmentation using Convolutional Neural Networks: Data from the Osteoarthritis Initiative}, volume = {26}, journal = {Osteoarthritis and Cartilage}, number = {5}, doi = {10.1016/j.joca.2018.02.907}, pages = {680 -- 688}, year = {2018}, abstract = {Abstract: Objective: To present a novel method for automated segmentation of knee menisci from MRIs. To evaluate quantitative meniscal biomarkers for osteoarthritis (OA) estimated thereof. Method: A segmentation method employing convolutional neural networks in combination with statistical shape models was developed. Accuracy was evaluated on 88 manual segmentations. Meniscal volume, tibial coverage, and meniscal extrusion were computed and tested for differences between groups of OA, joint space narrowing (JSN), and WOMAC pain. Correlation between computed meniscal extrusion and MOAKS experts' readings was evaluated for 600 subjects. Suitability of biomarkers for predicting incident radiographic OA from baseline to 24 months was tested on a group of 552 patients (184 incident OA, 386 controls) by performing conditional logistic regression. Results: Segmentation accuracy measured as Dice Similarity Coefficient was 83.8\% for medial menisci (MM) and 88.9\% for lateral menisci (LM) at baseline, and 83.1\% and 88.3\% at 12-month follow-up. Medial tibial coverage was significantly lower for arthritic cases compared to non-arthritic ones. Medial meniscal extrusion was significantly higher for arthritic knees. A moderate correlation between automatically computed medial meniscal extrusion and experts' readings was found (ρ=0.44). Mean medial meniscal extrusion was significantly greater for incident OA cases compared to controls (1.16±0.93 mm vs. 0.83±0.92 mm; p<0.05). Conclusion: Especially for medial menisci an excellent segmentation accuracy was achieved. Our meniscal biomarkers were validated by comparison to experts' readings as well as analysis of differences w.r.t groups of OA, JSN, and WOMAC pain. It was confirmed that medial meniscal extrusion is a predictor for incident OA.}, language = {en} } @inproceedings{AmbellanTackEhlkeetal.2018, author = {Ambellan, Felix and Tack, Alexander and Ehlke, Moritz and Zachow, Stefan}, title = {Automated Segmentation of Knee Bone and Cartilage combining Statistical Shape Knowledge and Convolutional Neural Networks: Data from the Osteoarthritis Initiative}, booktitle = {Medical Imaging with Deep Learning}, year = {2018}, abstract = {We present a method for the automated segmentation of knee bones and cartilage from magnetic resonance imaging, that combines a priori knowledge of anatomical shape with Convolutional Neural Networks (CNNs). The proposed approach incorporates 3D Statistical Shape Models (SSMs) as well as 2D and 3D CNNs to achieve a robust and accurate segmentation of even highly pathological knee structures. The method is evaluated on data of the MICCAI grand challenge "Segmentation of Knee Images 2010". For the first time an accuracy equivalent to the inter-observer variability of human readers has been achieved in this challenge. Moreover, the quality of the proposed method is thoroughly assessed using various measures for 507 manual segmentations of bone and cartilage, and 88 additional manual segmentations of cartilage. Our method yields sub-voxel accuracy. In conclusion, combining of anatomical knowledge using SSMs with localized classification via CNNs results in a state-of-the-art segmentation method.}, language = {en} } @article{KlusNueskePeitzetal.2020, author = {Klus, Stefan and N{\"u}ske, Feliks and Peitz, Sebastian and Niemann, Jan-Hendrik and Clementi, Cecilia and Sch{\"u}tte, Christof}, title = {Data-driven approximation of the Koopman generator: Model reduction, system identification, and control}, volume = {406}, journal = {Physica D: Nonlinear Phenomena}, doi = {10.1016/j.physd.2020.132416}, year = {2020}, language = {en} } @article{ChaumelSchotteBizzarroetal.2020, author = {Chaumel, J{\´u}lia and Schotte, Merlind and Bizzarro, Joseph J. and Zaslansky, Paul and Fratzl, Peter and Baum, Daniel and Dean, Mason N.}, title = {Co-aligned chondrocytes: Zonal morphological variation and structured arrangement of cell lacunae in tessellated cartilage}, volume = {134}, journal = {Bone}, doi = {10.1016/j.bone.2020.115264}, pages = {115264}, year = {2020}, abstract = {In most vertebrates the embryonic cartilaginous skeleton is replaced by bone during development. During this process, cartilage cells (chondrocytes) mineralize the extracellular matrix and undergo apoptosis, giving way to bone cells (osteocytes). In contrast, sharks and rays (elasmobranchs) have cartilaginous skeletons throughout life, where only the surface mineralizes, forming a layer of tiles (tesserae). Elasmobranch chondrocytes, unlike those of other vertebrates, survive cartilage mineralization and are maintained alive in spaces (lacunae) within tesserae. However, the function(s) of the chondrocytes in the mineralized tissue remain unknown. Applying a custom analysis workflow to high-resolution synchrotron microCT scans of tesserae, we characterize the morphologies and arrangements of stingray chondrocyte lacunae, using lacunar morphology as a proxy for chondrocyte morphology. We show that the cell density is comparable in unmineralized and mineralized tissue from our study species and that cells maintain the similar volume even when they have been incorporated into tesserae. This discovery supports previous hypotheses that elasmobranch chondrocytes, unlike those of other taxa, do not proliferate, hypertrophy or undergo apoptosis during mineralization. Tessera lacunae show zonal variation in their shapes—being flatter further from and more spherical closer to the unmineralized cartilage matrix and larger in the center of tesserae— and show pronounced organization into parallel layers and strong orientation toward neighboring tesserae. Tesserae also exhibit local variation in lacunar density, with the density considerably higher near pores passing through the tesseral layer, suggesting pores and cells interact (e.g. that pores contain a nutrient source). We hypothesize that the different lacunar types reflect the stages of the tesserae formation process, while also representing local variation in tissue architecture and cell function. Lacunae are linked by small passages (canaliculi) in the matrix to form elongate series at the tesseral periphery and tight clusters in the center of tesserae, creating a rich connectivity among cells. The network arrangement and the shape variation of chondrocytes in tesserae indicate that cells may interact within and between tesserae and manage mineralization differently from chondrocytes in other vertebrates, perhaps performing analogous roles to osteocytes in bone.}, language = {en} } @article{SchotteChaumelDeanetal.2020, author = {Schotte, Merlind and Chaumel, J{\´u}lia and Dean, Mason N. and Baum, Daniel}, title = {Image analysis pipeline for segmentation of a biological porosity network, the lacuno-canalicular system in stingray tesserae}, volume = {7}, journal = {MethodsX}, doi = {10.1016/j.mex.2020.100905}, pages = {100905}, year = {2020}, abstract = {A prerequisite for many analysis tasks in modern comparative biology is the segmentation of 3-dimensional (3D) images of the specimens being investigated (e.g. from microCT data). Depending on the specific imaging technique that was used to acquire the images and on the image resolution, different segmentation tools will be required. While some standard tools exist that can often be applied for specific subtasks, building whole processing pipelines solely from standard tools is often difficult. Some tasks may even necessitate the implementation of manual interaction tools to achieve a quality that is sufficient for the subsequent analysis. In this work, we present a pipeline of segmentation tools that can be used for the semi-automatic segmentation and quantitative analysis of voids in tissue (i.e. internal structural porosity). We use this pipeline to analyze lacuno-canalicular networks in stingray tesserae from 3D images acquired with synchrotron microCT. * The first step of this processing pipeline, the segmentation of the tesserae, was performed using standard marker-based watershed segmentation. The efficient processing of the next two steps, that is, the segmentation of all lacunae spaces belonging to a specific tessera and the separation of these spaces into individual lacunae required modern, recently developed tools. * For proofreading, we developed a graph-based interactive method that allowed us to quickly split lacunae that were accidentally merged, and to merge lacunae that were wrongly split. * Finally, the tesserae and their corresponding lacunae were subdivided into anatomical regions of interest (structural wedges) using a semi- manual approach.}, language = {en} } @misc{MollenhauerSchusterKlusetal.2020, author = {Mollenhauer, Mattes and Schuster, Ingmar and Klus, Stefan and Sch{\"u}tte, Christof}, title = {Singular Value Decomposition of Operators on Reproducing Kernel Hilbert Spaces}, volume = {304}, journal = {Advances om Dynamics, Optimization and Computation. Series: Studies in Systems, Decision and Control. A volume dedicated to Michael Dellnitz on his 60th birthday}, editor = {Junge, Oliver and Sch{\"u}tze, O. and Froyland, Gary and Ober-Blobaum, S. and Padberg-Gehle, K.}, publisher = {Springer International}, isbn = {978-3-030-51264-4}, doi = {10.1007/978-3-030-51264-4_5}, pages = {109 -- 131}, year = {2020}, language = {en} } @article{AlchikhConradMaetal.2019, author = {Alchikh, Maren and Conrad, Tim and Ma, Xiaolin and Broberg, Eeva K. and Penttinen, P. and Reiche, J. and Biere, Barbara and Schweiger, Brunhilde and Rath, Barbara and Hoppe, Christian}, title = {Are we missing respiratory viral infections in infants and children? Comparison of a hospital-based quality management system with standard of care}, volume = {25}, journal = {Clinical Microbiology and Infection}, number = {3}, issn = {1469-0691}, doi = {10.1016/j.cmi.2018.05.023}, pages = {380.e9 -- 380.e16}, year = {2019}, language = {en} } @article{HaaseSunkaraKohletal.2019, author = {Haase, Tobias and Sunkara, Vikram and Kohl, Benjamin and Meier, Carola and Bußmann, Patricia and Becker, Jessica and Jagielski, Michal and von Kleist, Max and Ertel, Wolfgang}, title = {Discerning the spatio-temporal disease patterns of surgically induced OA mouse models}, volume = {14}, journal = {PLOS One}, number = {4}, publisher = {PLOS One}, doi = {10.1371/journal.pone.0213734}, year = {2019}, abstract = {Osteoarthritis (OA) is the most common cause of disability in ageing societies, with no effective therapies available to date. Two preclinical models are widely used to validate novel OA interventions (MCL-MM and DMM). Our aim is to discern disease dynamics in these models to provide a clear timeline in which various pathological changes occur. OA was surgically induced in mice by destabilisation of the medial meniscus. Analysis of OA progression revealed that the intensity and duration of chondrocyte loss and cartilage lesion formation were significantly different in MCL-MM vs DMM. Firstly, apoptosis was seen prior to week two and was narrowly restricted to the weight bearing area. Four weeks post injury the magnitude of apoptosis led to a 40-60\% reduction of chondrocytes in the non-calcified zone. Secondly, the progression of cell loss preceded the structural changes of the cartilage spatio-temporally. Lastly, while proteoglycan loss was similar in both models, collagen type II degradation only occurred more prominently in MCL-MM. Dynamics of chondrocyte loss and lesion formation in preclinical models has important implications for validating new therapeutic strategies. Our work could be helpful in assessing the feasibility and expected response of the DMM- and the MCL-MM models to chondrocyte mediated therapies.}, language = {en} } @article{RamsConrad2020, author = {Rams, Mona and Conrad, Tim}, title = {Dictionary Learning for transcriptomics data reveals type-specific gene modules in a multi-class setting}, volume = {62}, journal = {it - Information Technology}, number = {3-4}, publisher = {De Gruyter}, address = {Oldenbourg}, issn = {2196-7032}, doi = {https://doi.org/10.1515/itit-2019-0048}, year = {2020}, language = {en} } @article{RaySunkaraSchuetteetal.2020, author = {Ray, Sourav and Sunkara, Vikram and Sch{\"u}tte, Christof and Weber, Marcus}, title = {How to calculate pH-dependent binding rates for receptor-ligand systems based on thermodynamic simulations with different binding motifs}, volume = {46}, journal = {Molecular Simulation}, number = {18}, publisher = {Taylor and Francis}, doi = {10.1080/08927022.2020.1839660}, pages = {1443 -- 1452}, year = {2020}, abstract = {Molecular simulations of ligand-receptor interactions are a computational challenge, especially when their association- ('on'-rate) and dissociation- ('off'-rate) mechanisms are working on vastly differing timescales. One way of tackling this multiscale problem is to compute the free-energy landscapes, where molecular dynamics (MD) trajectories are used to only produce certain statistical ensembles. The approach allows for deriving the transition rates between energy states as a function of the height of the activation-energy barriers. In this article, we derive the association rates of the opioids fentanyl and N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenyl propionamide (NFEPP) in a μ-opioid receptor by combining the free-energy landscape approach with the square-root-approximation method (SQRA), which is a particularly robust version of Markov modelling. The novelty of this work is that we derive the association rates as a function of the pH level using only an ensemble of MD simulations. We also verify our MD-derived insights by reproducing the in vitro study performed by the Stein Lab.}, language = {en} } @article{LindowBruenigDercksenetal.2020, author = {Lindow, Norbert and Br{\"u}nig, Florian and Dercksen, Vincent J. and Fabig, Gunar and Kiewisz, Robert and Redemann, Stefanie and M{\"u}ller-Reichert, Thomas and Prohaska, Steffen and Baum, Daniel}, title = {Semi-automatic stitching of filamentous structures in image stacks from serial-section electron tomography}, journal = {bioRxiv}, doi = {10.1101/2020.05.28.120899}, year = {2020}, abstract = {We present a software-assisted workflow for the alignment and matching of filamentous structures across a 3D stack of serial images. This is achieved by combining automatic methods, visual validation, and interactive correction. After an initial alignment, the user can continuously improve the result by interactively correcting landmarks or matches of filaments. Supported by a visual quality assessment of regions that have been already inspected, this allows a trade-off between quality and manual labor. The software tool was developed to investigate cell division by quantitative 3D analysis of microtubules (MTs) in both mitotic and meiotic spindles. For this, each spindle is cut into a series of semi-thick physical sections, of which electron tomograms are acquired. The serial tomograms are then stitched and non-rigidly aligned to allow tracing and connecting of MTs across tomogram boundaries. In practice, automatic stitching alone provides only an incomplete solution, because large physical distortions and a low signal-to-noise ratio often cause experimental difficulties. To derive 3D models of spindles despite the problems related to sample preparation and subsequent data collection, semi-automatic validation and correction is required to remove stitching mistakes. However, due to the large number of MTs in spindles (up to 30k) and their resulting dense spatial arrangement, a naive inspection of each MT is too time consuming. Furthermore, an interactive visualization of the full image stack is hampered by the size of the data (up to 100 GB). Here, we present a specialized, interactive, semi-automatic solution that considers all requirements for large-scale stitching of filamentous structures in serial-section image stacks. The key to our solution is a careful design of the visualization and interaction tools for each processing step to guarantee real-time response, and an optimized workflow that efficiently guides the user through datasets.}, language = {en} } @article{PimentelSzengelEhlkeetal.2020, author = {Pimentel, Pedro and Szengel, Angelika and Ehlke, Moritz and Lamecker, Hans and Zachow, Stefan and Estacio, Laura and Doenitz, Christian and Ramm, Heiko}, title = {Automated Virtual Reconstruction of Large Skull Defects using Statistical Shape Models and Generative Adversarial Networks}, volume = {12439}, journal = {Towards the Automatization of Cranial Implant Design in Cranioplasty}, editor = {Li, Jianning and Egger, Jan}, edition = {1}, publisher = {Springer International Publishing}, doi = {10.1007/978-3-030-64327-0_3}, pages = {16 -- 27}, year = {2020}, abstract = {We present an automated method for extrapolating missing regions in label data of the skull in an anatomically plausible manner. The ultimate goal is to design patient-speci� c cranial implants for correcting large, arbitrarily shaped defects of the skull that can, for example, result from trauma of the head. Our approach utilizes a 3D statistical shape model (SSM) of the skull and a 2D generative adversarial network (GAN) that is trained in an unsupervised fashion from samples of healthy patients alone. By � tting the SSM to given input labels containing the skull defect, a First approximation of the healthy state of the patient is obtained. The GAN is then applied to further correct and smooth the output of the SSM in an anatomically plausible manner. Finally, the defect region is extracted using morphological operations and subtraction between the extrapolated healthy state of the patient and the defective input labels. The method is trained and evaluated based on data from the MICCAI 2020 AutoImplant challenge. It produces state-of-the art results on regularly shaped cut-outs that were present in the training and testing data of the challenge. Furthermore, due to unsupervised nature of the approach, the method generalizes well to previously unseen defects of varying shapes that were only present in the hidden test dataset.}, language = {en} } @article{OeltzeJaffraMeuschkeNeugebaueretal.2019, author = {Oeltze-Jaffra, Steffen and Meuschke, Monique and Neugebauer, Mathias and Saalfeld, Sylvia and Lawonn, Kai and Janiga, Gabor and Hege, Hans-Christian and Zachow, Stefan and Preim, Bernhard}, title = {Generation and Visual Exploration of Medical Flow Data: Survey, Research Trends, and Future Challenges}, volume = {38}, journal = {Computer Graphics Forum}, number = {1}, publisher = {Wiley}, doi = {10.1111/cgf.13394}, pages = {87 -- 125}, year = {2019}, abstract = {Simulations and measurements of blood and air flow inside the human circulatory and respiratory system play an increasingly important role in personalized medicine for prevention, diagnosis, and treatment of diseases. This survey focuses on three main application areas. (1) Computational Fluid Dynamics (CFD) simulations of blood flow in cerebral aneurysms assist in predicting the outcome of this pathologic process and of therapeutic interventions. (2) CFD simulations of nasal airflow allow for investigating the effects of obstructions and deformities and provide therapy decision support. (3) 4D Phase-Contrast (4D PC) Magnetic Resonance Imaging (MRI) of aortic hemodynamics supports the diagnosis of various vascular and valve pathologies as well as their treatment. An investigation of the complex and often dynamic simulation and measurement data requires the coupling of sophisticated visualization, interaction, and data analysis techniques. In this paper, we survey the large body of work that has been conducted within this realm. We extend previous surveys by incorporating nasal airflow, addressing the joint investigation of blood flow and vessel wall properties, and providing a more fine-granular taxonomy of the existing techniques. From the survey, we extract major research trends and identify open problems and future challenges. The survey is intended for researchers interested in medical flow but also more general, in the combined visualization of physiology and anatomy, the extraction of features from flow field data and feature-based visualization, the visual comparison of different simulation results, and the interactive visual analysis of the flow field and derived characteristics.}, language = {en} } @article{RathConradMylesetal.2017, author = {Rath, Barbara and Conrad, Tim and Myles, Puja and Alchikh, Maren and Ma, Xiaolin and Hoppe, Christian and Tief, Franziska and Chen, Xi and Obermeier, Patrick and Kisler, Bron and Schweiger, Brunhilde}, title = {Influenza and other respiratory viruses: standardizing disease severity in surveillance and clinical trials}, volume = {15}, journal = {Expert Review of Anti-infective Therapy}, number = {6}, doi = {10.1080/14787210.2017.1295847}, pages = {545 -- 568}, year = {2017}, abstract = {Introduction: Influenza-Like Illness is a leading cause of hospitalization in children. Disease burden due to influenza and other respiratory viral infections is reported on a population level, but clinical scores measuring individual changes in disease severity are urgently needed. Areas covered: We present a composite clinical score allowing individual patient data analyses of disease severity based on systematic literature review and WHO-criteria for uncomplicated and complicated disease. The 22-item ViVI Disease Severity Score showed a normal distribution in a pediatric cohort of 6073 children aged 0-18 years (mean age 3.13; S.D. 3.89; range: 0 to 18.79). Expert commentary: The ViVI Score was correlated with risk of antibiotic use as well as need for hospitalization and intensive care. The ViVI Score was used to track children with influenza, respiratory syncytial virus, human metapneumovirus, human rhinovirus, and adenovirus infections and is fully compliant with regulatory data standards. The ViVI Disease Severity Score mobile application allows physicians to measure disease severity at the point-of care thereby taking clinical trials to the next level.}, language = {en} } @article{MarzbanConradMarbanetal.2018, author = {Marzban, Forough and Conrad, Tim and Marban, Pouria and Sodoudi, Sahar}, title = {Estimation of the Near-Surface Air Temperature during the Day and Nighttime from MODIS in Berlin, Germany}, volume = {7}, journal = {International Journal of Advanced Remote Sensing and GIS}, number = {1}, doi = {10.23953/cloud.ijarsg.337}, pages = {2478 -- 2517}, year = {2018}, abstract = {Air temperature (Tair or T2m) is an important climatological variable for forest biosphere processes and climate change research. Due to the low density and the uneven distribution of weather stations, traditional ground-based observations cannot accurately capture the spatial distribution of Tair. In this study, Tair in Berlin is estimated during the day and night time over six land cover/land use (LC/LU) types by satellite remote sensing data over a large domain and a relatively long period (7 years). Aqua and Terra MODIS (Moderate Resolution Imaging Spectroradiometer) data and meteorological data for the period from 2007 to 2013 were collected to estimate Tair. Twelve environmental variables (land surface temperature (LST), normalized difference vegetation index (NDVI), Julian day, latitude, longitude, Emissivity31, Emissivity32, altitude, albedo, wind speed, wind direction and air pressure) were selected as predictors. Moreover, a comparison between LST from MODIS Terra and Aqua with daytime and night time air temperatures (Tday, Tnight) was done respectively and in addition, the spatial variability of LST and Tair relationship by applying a varying window size on the MODIS LST grid was examined. An analysis of the relationship between the observed Tair and the spatially averaged remotely sensed LST, indicated that 3 × 3 and 1 × 1 pixel size was the optimal window size for the statistical model estimating Tair from MODIS data during the day and night time, respectively. Three supervised learning methods (Adaptive Neuro Fuzzy Inference system (ANFIS), Artificial Neural Network (ANN) and Support vector machine (SVR)) were used to estimate Tair during the day and night time, and their performances were validated by cross-validation for each LC/LU. Moreover, tuning the hyper parameters of some models like SVR and ANN were investigated. For tuning the hyper parameters of SVR, Simulated Annealing (SA) was applied (SA-SVR model) and a multiple-layer feed-forward (MLF) neural networks with three layers and different nodes in hidden layers are used with Levenber-Marquardt back-propagation (LM-BP), in order to achieve higher accuracy in the estimation of Tair. Results indicated that the ANN model achieved better accuracy (RMSE= 2.16°C, MAE = 1.69°C, R2 = 0.95) than SA_SVR model (RMSE= 2.50°C, MAE = 1.92°C, R2 = 0.91) and ANFIS model (RMSE= 2.88°C, MAE= 2.2°C, R2 = 0.89) over six LC/LU during the day and night time. The Q-Q diagram of SA-SVR, ANFIS and NN show that all three models slightly tended to underestimate and overestimate the extreme and low temperatures for all LC/LU classes during the day and night time. The weak performance in the extreme and low temperatures are a consequence of the small number of data in these temperatures. These satisfactory results indicate that this approach is proper for estimating air temperature and spatial window size is an important factor that should be considered in the estimation of air temperature.}, language = {en} } @article{KoltaiWuNoeetal.2018, author = {Koltai, Peter and Wu, Hao and No{\´e}, Frank and Sch{\"u}tte, Christof}, title = {Optimal data-driven estimation of generalized Markov state models for non-equilibrium dynamics}, volume = {6}, journal = {Computation}, number = {1}, publisher = {MDPI}, address = {Basel, Switzerland}, doi = {10.3390/computation6010022}, pages = {22}, year = {2018}, language = {en} } @article{DibakdelRazodeSanchoetal.2018, author = {Dibak, Manuel and del Razo, Mauricio J. and de Sancho, David and Sch{\"u}tte, Christof and No{\´e}, Frank}, title = {MSM/RD: Coupling Markov state models of molecular kinetics with reaction-diffusion simulations}, volume = {148}, journal = {Journal of Chemical Physics}, number = {21}, doi = {10.1063/1.5020294}, year = {2018}, abstract = {Molecular dynamics (MD) simulations can model the interactions between macromolecules with high spatiotemporal resolution but at a high computational cost. By combining high-throughput MD with Markov state models (MSMs), it is now possible to obtain long time-scale behavior of small to intermediate biomolecules and complexes. To model the interactions of many molecules at large length scales, particle-based reaction-diffusion (RD) simulations are more suitable but lack molecular detail. Thus, coupling MSMs and RD simulations (MSM/RD) would be highly desirable, as they could efficiently produce simulations at large time and length scales, while still conserving the characteristic features of the interactions observed at atomic detail. While such a coupling seems straightforward, fundamental questions are still open: Which definition of MSM states is suitable? Which protocol to merge and split RD particles in an association/dissociation reaction will conserve the correct bimolecular kinetics and thermodynamics? In this paper, we make the first step toward MSM/RD by laying out a general theory of coupling and proposing a first implementation for association/dissociation of a protein with a small ligand (A + B ⇌ C). Applications on a toy model and CO diffusion into the heme cavity of myoglobin are reported.}, language = {en} } @inproceedings{EstacioEhlkeTacketal.2021, author = {Estacio, Laura and Ehlke, Moritz and Tack, Alexander and Castro-Gutierrez, Eveling and Lamecker, Hans and Mora, Rensso and Zachow, Stefan}, title = {Unsupervised Detection of Disturbances in 2D Radiographs}, booktitle = {2021 IEEE 18th International Symposium on Biomedical Imaging (ISBI)}, doi = {10.1109/ISBI48211.2021.9434091}, pages = {367 -- 370}, year = {2021}, abstract = {We present a method based on a generative model for detection of disturbances such as prosthesis, screws, zippers, and metals in 2D radiographs. The generative model is trained in an unsupervised fashion using clinical radiographs as well as simulated data, none of which contain disturbances. Our approach employs a latent space consistency loss which has the benefit of identifying similarities, and is enforced to reconstruct X-rays without disturbances. In order to detect images with disturbances, an anomaly score is computed also employing the Frechet distance between the input X-ray and the reconstructed one using our generative model. Validation was performed using clinical pelvis radiographs. We achieved an AUC of 0.77 and 0.83 with clinical and synthetic data, respectively. The results demonstrated a good accuracy of our method for detecting outliers as well as the advantage of utilizing synthetic data.}, language = {en} } @article{SekuboyinaBayatHusseinietal.2020, author = {Sekuboyina, Anjany and Bayat, Amirhossein and Husseini, Malek E. and L{\"o}ffler, Maximilian and Li, Hongwei and Tetteh, Giles and Kukačka, Jan and Payer, Christian and Štern, Darko and Urschler, Martin and Chen, Maodong and Cheng, Dalong and Lessmann, Nikolas and Hu, Yujin and Wang, Tianfu and Yang, Dong and Xu, Daguang and Ambellan, Felix and Amiranashvili, Tamaz and Ehlke, Moritz and Lamecker, Hans and Lehnert, Sebastian and Lirio, Marilia and de Olaguer, Nicol{\´a}s P{\´e}rez and Ramm, Heiko and Sahu, Manish and Tack, Alexander and Zachow, Stefan and Jiang, Tao and Ma, Xinjun and Angerman, Christoph and Wang, Xin and Wei, Qingyue and Brown, Kevin and Wolf, Matthias and Kirszenberg, Alexandre and Puybareau, {\´E}lodie and Valentinitsch, Alexander and Rempfler, Markus and Menze, Bj{\"o}rn H. and Kirschke, Jan S.}, title = {VerSe: A Vertebrae Labelling and Segmentation Benchmark for Multi-detector CT Images}, journal = {arXiv}, arxiv = {http://arxiv.org/abs/2001.09193}, year = {2020}, language = {en} } @article{WulkowConradDjurdjevacConradetal.2021, author = {Wulkow, Hanna and Conrad, Tim and Djurdjevac Conrad, Natasa and M{\"u}ller, Sebastian A. and Nagel, Kai and Sch{\"u}tte, Christof}, title = {Prediction of Covid-19 spreading and optimal coordination of counter-measures: From microscopic to macroscopic models to Pareto fronts}, volume = {16}, journal = {PLOS One}, number = {4}, publisher = {Public Library of Science}, doi = {10.1371/journal.pone.0249676}, year = {2021}, language = {en} } @article{BanischDjurdjevacConradSchuette2015, author = {Banisch, Ralf and Djurdjevac Conrad, Natasa and Sch{\"u}tte, Christof}, title = {Reactive flows and unproductive cycles for random walks on complex networks}, journal = {The European Physical Journal Special Topics, vol. 224, iss. 12 (2015) pp. 2369-2387}, doi = {10.1140/epjst/e2015-02417-8}, year = {2015}, language = {en} } @misc{BanischDjurdjevacConradSchuette2015, author = {Banisch, Ralf and Djurdjevac Conrad, Natasa and Sch{\"u}tte, Christof}, title = {Reactive flows and unproductive cycles for random walks on complex networks}, issn = {1438-0064}, doi = {10.1140/epjst/e2015-02417-8}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-54239}, year = {2015}, abstract = {We present a comprehensive theory for analysis and understanding of transition events between an initial set A and a target set B for general ergodic finite-state space Markov chains or jump processes, including random walks on networks as they occur, e.g., in Markov State Modelling in molecular dynamics. The theory allows us to decompose the probability flow generated by transition events between the sets A and B into the productive part that directly flows from A to B through reaction pathways and the unproductive part that runs in loops and is supported on cycles of the underlying network. It applies to random walks on directed networks and nonreversible Markov processes and can be seen as an extension of Transition Path Theory. Information on reaction pathways and unproductive cycles results from the stochastic cycle decomposition of the underlying network which also allows to compute their corresponding weight, thus characterizing completely which structure is used how often in transition events. The new theory is illustrated by an application to a Markov State Model resulting from weakly damped Langevin dynamics where the unproductive cycles are associated with periodic orbits of the underlying Hamiltonian dynamics.}, language = {en} } @article{WinkelmannSchuettevonKleist2014, author = {Winkelmann, Stefanie and Sch{\"u}tte, Christof and von Kleist, Max}, title = {Markov Control Processes with Rare State Observation: Theory and Application to Treatment Scheduling in HIV-1}, volume = {12}, journal = {Communications in Mathematical Sciences}, number = {5}, doi = {10.4310/CMS.2014.v12.n5.a4}, pages = {859 -- 877}, year = {2014}, abstract = {Markov Decision Processes (MDP) or Partially Observable MDPs (POMDP) are used for modelling situations in which the evolution of a process is partly random and partly controllable. These MDP theories allow for computing the optimal control policy for processes that can continuously or frequently be observed, even if only partially. However, they cannot be applied if state observation is very costly and therefore rare (in time). We present a novel MDP theory for rare, costly observations and derive the corresponding Bellman equation. In the new theory, state information can be derived for a particular cost after certain, rather long time intervals. The resulting information costs enter into the total cost and thus into the optimization criterion. This approach applies to many real world problems, particularly in the medical context, where the medical condition is examined rather rarely because examination costs are high. At the same time, the approach allows for efficient numerical realization. We demonstrate the usefulness of the novel theory by determining, from the national economic perspective, optimal therapeutic policies for the treatment of the human immunodeficiency virus (HIV) in resource-rich and resource-poor settings. Based on the developed theory and models, we discover that available drugs may not be utilized efficiently in resource-poor settings due to exorbitant diagnostic costs.}, language = {en} } @article{DjurdjevacConradBanischSchuette2015, author = {Djurdjevac Conrad, Natasa and Banisch, Ralf and Sch{\"u}tte, Christof}, title = {Modularity of Directed Networks: Cycle Decomposition Approach}, journal = {Journal of Computational Dynamics 2 (2015) pp. 1-24}, doi = {10.3934/jcd.2015.2.1}, year = {2015}, abstract = {The problem of decomposing networks into modules (or clusters) has gained much attention in recent years, as it can account for a coarsegrained description of complex systems, often revealing functional subunits of these systems. A variety of module detection algorithms have been proposed, mostly oriented towards finding hard partitionings of undirected networks. Despite the increasing number of fuzzy clustering methods for directed networks, many of these approaches tend to neglect important directional information. In this paper, we present a novel random walk based approach for finding fuzzy partitions of directed, weighted networks, where edge directions play a crucial role in defining how well nodes in a module are interconnected. We will show that cycle decomposition of a random walk process connects the notion of network modules and information transport in a network, leading to a new, symmetric measure of node communication. Finally, we will use this measure to introduce a communication graph, for which we will show that although being undirected it inherits all necessary information about modular structures from the original network.}, language = {en} } @misc{WangSchuette2014, author = {Wang, Han and Sch{\"u}tte, Christof}, title = {Building Markov State Models for Periodically Driven Non-Equilibrium Systems}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-53167}, year = {2014}, abstract = {Recent years have seen an increased interest in non-equilibrium molecular dynamics (NEMD) simulations, especially for molecular systems with periodic forcing by external fields, e.g., in the context of studying effects of electromagnetic radiation on the human body tissue. Lately, an NEMD methods with local thermostating has been proposed that allows for studying non-equilibrium processes in a statistically reliable and thermodynamically consistent way. In this article, we demonstrate how to construct Markov State Models (MSMs) for such NEMD simulations. MSM building has been well-established for systems in equilibrium where MSMs with just a few (macro-)states allow for accurate reproduction of the essential kinetics of the molecular system under consideration. Non-equilibrium MSMs have been lacking so far. The article presents how to construct such MSMs and illustrates their validity and usefulness for the case of conformation dynamics of alanine dipeptide in an external electric field.}, language = {en} }