@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} }