Fakultät für Mathematik, Informatik und Statistik - Digitale Hochschulschriften der LMU - Teil 01/02 Archiv

The goal of bioinformatics is to develop innovative and practical methods and algorithms for bio- logical questions. In many cases, these questions are driven by new biotechnological techniques, especially by genome and cell wide high throughput experiment studies. In principle there are two approaches: 1. Reduction and abstraction of the question to a clearly defined optimization problem, which can be solved with appropriate and efficient algorithms. 2. Development of context based methods, incorporating as much contextual knowledge as possible in the algorithms, and derivation of practical solutions for relevant biological ques- tions on the high-throughput data. These methods can be often supported by appropriate software tools and visualizations, allowing for interactive evaluation of the results by ex- perts. Context based methods are often much more complex and require more involved algorithmic techniques to get practical relevant and efficient solutions for real world problems, as in many cases already the simplified abstraction of problems result in NP-hard problem instances. In many cases, to solve these complex problems, one needs to employ efficient data structures and heuristic search methods to solve clearly defined sub-problems using efficient (polynomial) op- timization (such as dynamic programming, greedy, path- or tree-algorithms). In this thesis, we present new methods and analyses addressing open questions of bioinformatics from different contexts by incorporating the corresponding contextual knowledge. The two main contexts in this thesis are the protein structure similarity context (Part I) and net- work based interpretation of high-throughput data (Part II). For the protein structure similarity context Part I we analyze the consistency of gold standard structure classification systems and derive a consistent benchmark set usable for different ap- plications. We introduce two methods (Vorolign, PPM) for the protein structure similarity recog- nition problem, based on different features of the structures. Derived from the idea and results of Vorolign, we introduce the concept of contact neighbor- hood potential, aiming to improve the results of protein fold recognition and threading. For the re-scoring problem of predicted structure models we introduce the method Vorescore, clearly improving the fold-recognition performance, and enabling the evaluation of the contact neighborhood potential for structure prediction methods in general. We introduce a contact consistent Vorolign variant ccVorolign further improving the structure based fold recognition performance, and enabling direct optimization of the neighborhood po- tential in the future. Due to the enforcement of contact-consistence, the ccVorolign method has much higher computational complexity than the polynomial Vorolign method - the cost of com- puting interpretable and consistent alignments. Finally, we introduce a novel structural alignment method (PPM) enabling the explicit modeling and handling of phenotypic plasticity in protein structures. We employ PPM for the analysis of effects of alternative splicing on protein structures. With the help of PPM we test the hypothesis, whether splice isoforms of the same protein can lead to protein structures with different folds (fold transitions). In Part II of the thesis we present methods generating and using context information for the interpretation of high-throughput experiments. For the generation of context information of molecular regulations we introduce novel textmin- ing approaches extracting relations automatically from scientific publications. In addition to the fast NER (named entity recognition) method (syngrep) we also present a novel, fully ontology-based context-sensitive method (SynTree) allowing for the context-specific dis- ambiguation of ambiguous synonyms and resulting in much better identification performance. This context information is important for the interpretation of high-throughput data, but often missing in current databases. Despite all improvements, the results of automated text-mining methods are error prone. The RelAnn application presented in this thesis helps to curate the automatically extracted regula- tions enabling manual and ontology based curation and annotation. For the usage of high-throughput data one needs additional methods for data processing, for example methods to map the hundreds of millions short DNA/RNA fragments (so called reads) on a reference genome or transcriptome. Such data (RNA-seq reads) are the output of next generation sequencing methods measured by sequencing machines, which are becoming more and more efficient and affordable. Other than current state-of-the-art methods, our novel read-mapping method ContextMap re- solves the occurring ambiguities at the final step of the mapping process, employing thereby the knowledge of the complete set of possible ambiguous mappings. This approach allows for higher precision, even if more nucleotide errors are tolerated in the read mappings in the first step. The consistence between context information of molecular regulations stored in databases and extracted from textmining against measured data can be used to identify and score consistent reg- ulations (GGEA). This method substantially extends the commonly used gene-set based methods such over-representation (ORA) and gene set enrichment analysis (GSEA). Finally we introduce the novel method RelExplain, which uses the extracted contextual knowl- edge and generates network-based and testable hypotheses for the interpretation of high-throughput data.

Dynamic imaging series acquired in medical and biological research are often analyzed with the help of compartment models. Compartment models provide a parametric, nonlinear function of interpretable, kinetic parameters describing how some concentration of interest evolves over time. Aiming to estimate the kinetic parameters, this leads to a nonlinear regression problem. In many applications, the number of compartments needed in the model is not known from biological considerations but should be inferred from the data along with the kinetic parameters. As data from medical and biological experiments are often available in the form of images, the spatial data structure of the images has to be taken into account. This thesis addresses the problem of parameter estimation and model selection in compartment models. Besides a penalized maximum likelihood based approach, several Bayesian approaches-including a hierarchical model with Gaussian Markov random field priors and a model state approach with flexible model dimension-are proposed and evaluated to accomplish this task. Existing methods are extended for parameter estimation and model selection in more complex compartment models. However, in nonlinear regression and, in particular, for more complex compartment models, redundancy issues may arise. This thesis analyzes difficulties arising due to redundancy issues and proposes several approaches to alleviate those redundancy issues by regularizing the parameter space. The potential of the proposed estimation and model selection approaches is evaluated in simulation studies as well as for two in vivo imaging applications: a dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) study on breast cancer and a study on the binding behavior of molecules in living cell nuclei observed in a fluorescence recovery after photobleaching (FRAP) experiment.

Direct touch input on interactive surfaces has become a predominating standard for the manipulation of digital information in our everyday lives. However, compared to our rich interchange with the physical world, the interaction with touch-based systems is limited in terms of flexibility of input and expressiveness of output. Particularly, the lack of tactile feedback greatly reduces the general usability of a touch-based system and hinders from a productive entanglement of the virtual information with the physical world. This thesis proposes remote tactile feedback as a novel method to provide programmed tactile stimuli supporting direct touch interactions. The overall principle is to spatially decouple the location of touch input (e.g. fingertip or hand) and the location of the tactile sensation on the user's body (e.g. forearm or back). Remote tactile feedback is an alternative concept which avoids particular challenges of existing approaches. Moreover, the principle provides inherent characteristics which can accommodate for the requirements of current and future touch interfaces. To define the design space, the thesis provides a structured overview of current forms of touch surfaces and identifies trends towards non-planar and non-rigid forms with more versatile input mechanisms. Furthermore, a classification highlights limitations of the current methods to generate tactile feedback on touch-based systems. The proposed notion of tactile sensory relocation is a form of sensory substitution. Underlying neurological and psychological principles corroborate the approach. Thus, characteristics of the human sense of touch and principles from sensory substitution help to create a technical and conceptual framework for remote tactile feedback. Three consecutive user studies measure and compare the effects of both direct and remote tactile feedback on the performance and the subjective ratings of the user. Furthermore, the experiments investigate different body locations for the application of tactile stimuli. The results show high subjective preferences for tactile feedback, regardless of its type of application. Additionally, the data reveals no significant differences between the effects of direct and remote stimuli. The results back the feasibility of the approach and provide parameters for the design of stimuli and the effective use of the concept. The main part of the thesis describes the systematical exploration and analysis of the inherent characteristics of remote tactile feedback. Four specific features of the principle are identified: (1) the simplification of the integration of cutaneous stimuli, (2) the transmission of proactive, reactive and detached feedback, (3) the increased expressiveness of tactile sensations and (4) the provision of tactile feedback during multi-touch. In each class, several prototypical remote tactile interfaces are used in evaluations to analyze the concept. For example, the PhantomStation utilizes psychophysical phenomena to reduce the number of single tactile actuators. An evaluation with the prototype compares standard actuator technologies with each other in order to enable simple and scalable implementations. The ThermalTouch prototype creates remote thermal stimuli to reproduce material characteristics on standard touchscreens. The results show a stable rate of virtual object discrimination based on remotely applied temperature profiles. The AutmotiveRTF system is implemented in a vehicle and supports the driver's input on the in-vehicle-infotainment system. A field study with the system focuses on evaluating the effects of proactive and reactive feedback on the user's performance. The main contributions of the dissertation are: First, the thesis introduces the principle of remote tactile feedback and defines a design space for this approach as an alternative method to provide non-visual cues on interactive surfaces. Second, the thesis describes technical examples to rapidly prototype remote tactile feedback systems. Third, these prototypes are deployed in several evaluations which highlight the beneficial subjective and objective effects of the approach. Finally, the thesis presents features and inherent characteristics of remote tactile feedback as a means to support the interaction on today's touchscreens and future interactive surfaces.

Aktuelle Methoden zur dynamischen Modellierung von biologischen Systemen sind für Benutzer ohne mathematische Ausbildung oft wenig verständlich. Des Weiteren fehlen sehr oft genaue Daten und detailliertes Wissen über Konzentrationen, Reaktionskinetiken oder regulatorische Effekte. Daher erfordert eine computergestützte Modellierung eines biologischen Systems, mit Unsicherheiten und grober Information umzugehen, die durch qualitatives Wissen und natürlichsprachliche Beschreibungen zur Verfügung gestellt wird. Der Autor schlägt einen neuen Ansatz vor, mit dem solche Beschränkungen überwunden werden können. Dazu wird eine Petri-Netz-basierte graphische Darstellung von Systemen mit einer leistungsstarken und dennoch intuitiven Fuzzy-Logik-basierten Modellierung verknüpft. Der Petri Netz und Fuzzy Logik (PNFL) Ansatz erlaubt eine natürlichsprachlich-basierte Beschreibung von biologischen Entitäten sowie eine Wenn-Dann-Regel-basierte Definition von Reaktionen. Beides kann einfach und direkt aus qualitativem Wissen abgeleitet werden. PNFL verbindet damit qualitatives Wissen und quantitative Modellierung.

Fahrrelevante und unterhaltungsbezogene Informationen werden, historisch betrachtet, räumlich getrennt im Fahrzeuginnenraum angeordnet: Für die Fahraufgabe notwendige Anzeigen befinden sich direkt vor dem Fahrer (Kombiinstrument und Head-Up Display) und Inhalte des Fahrerinformationssystems in der Mittelkonsole (zentrales Informationsdisplay). Aktuell ist eine Auflösung dieser strikten Trennung zu beobachten. Beispielsweise werden im Kombiinstrument Teilumfänge der Infotainmentinhalte abgerufen und bedient. Um dem Fahrer einen sicheren Umgang mit den zunehmenden Infotainmentinhalten zu ermöglichen, die Komplexität des Fahrerinteraktionsraumes zu reduzieren und den Kundennutzen zu steigern, betrachtet die vorliegende Arbeit die derzeit isolierten Displays ganzheitlich und lotet die Grenzen der momentan strikten Informationsverteilung neu aus. Es werden Grundlagen für die verkehrsgerechte Bedienung und Darstellung verteilter Informationen abhängig von deren Anzeigefläche gelegt, Konzepte zur nutzerinitiierten Individualisierung entwickelt und das Zusammenspiel von unterschiedlichen Anzeigeflächen evaluiert. Die in dieser Arbeit durchgeführten Studien zeigen, dass der räumlich verteilte Fahrerinteraktionsraum die Bedienung des Fahrerinformationssystems für den Nutzer sicherer und attraktiver gestaltet.

I introduced among other things the notion of generalized pseudoholomorphic curves and pairs. Furthermore, I studied their properties and their role in topological string theory.

Boosting is an iterative algorithm for functional approximation and numerical optimization which can be applied to solve statistical regression-type problems. By design, boosting can mimic the solutions of many conventional statistical models, such as the linear model, the generalized linear model, and the generalized additive model, but its strength is to enhance these models or even go beyond. It enjoys increasing attention since a) it is a generic algorithm, easily extensible to exciting new problems, and b) it can cope with``difficult'' data where conventional statistical models fail. In this dissertation, we design autoregressive time series models based on boosting which capture nonlinearity in the mean and in the variance, and propose new models for multi-step forecasting of both. We use a special version of boosting, called componentwise gradient boosting, which is innovative in the estimation of the conditional variance of asset returns by sorting out irrelevant (lagged) predictors. We propose a model which enables us not only to identify the factors which drive market volatility, but also to assess the specific nature of their impact. Therefore, we gain a deeper insight into the nature of the volatility processes. We analyze four broad asset classes, namely, stocks, commodities, bonds, and foreign exchange, and use a wide range of potential macro and financial drivers. The proposed model for volatility forecasting performs very favorably for stocks and commodities relative to the common GARCH(1,1) benchmark model. The advantages are particularly convincing for longer forecasting horizons. To our knowledge, the application of boosting to multi-step forecasting of either the mean or the variance has not been done before. In a separate study, we focus on the conditional mean of German industrial production. With boosting, we improve the forecasting accuracy when compared to several competing models including the benchmark in this field, the linear autoregressive model. In an exhaustive simulation study we show that boosting of high-order nonlinear autoregressive time series can be very competitive in terms of goodness-of-fit when compared to alternative nonparametric models. Finally, we apply boosting in a spatio-temporal context to data coming from outside the econometric field. We estimate the browsing pressure on young beech trees caused by the game species within the borders of the Bavarian Forest National Park ``Bayerischer Wald,'' Germany. We found that using the geographic coordinates of the browsing cases contributes considerably to the fit. Furthermore, this bivariate geographic predictor is better suited for prediction if it allows for abrupt changes in the browsing pressure.

Many real-world application domains such as sensor-monitoring systems for environmental research or medical diagnostic systems are dealing with data that is represented by multiple observations. In contrast to single-observation data, where each object is assigned to exactly one occurrence, multi-observation data is based on several occurrences that are subject to two key properties: temporal variability and uncertainty. When defining similarity between data objects, these properties play a significant role. In general, methods designed for single-observation data hardly apply for multi-observation data, as they are either not supported by the data models or do not provide sufficiently efficient or effective solutions. Prominent directions incorporating the key properties are the fields of time series, where data is created by temporally successive observations, and uncertain data, where observations are mutually exclusive. This thesis provides research contributions for similarity processing - similarity search and data mining - on time series and uncertain data. The first part of this thesis focuses on similarity processing in time series databases. A variety of similarity measures have recently been proposed that support similarity processing w.r.t. various aspects. In particular, this part deals with time series that consist of periodic occurrences of patterns. Examining an application scenario from the medical domain, a solution for activity recognition is presented. Finally, the extraction of feature vectors allows the application of spatial index structures, which support the acceleration of search and mining tasks resulting in a significant efficiency gain. As feature vectors are potentially of high dimensionality, this part introduces indexing approaches for the high-dimensional space for the full-dimensional case as well as for arbitrary subspaces. The second part of this thesis focuses on similarity processing in probabilistic databases. The presence of uncertainty is inherent in many applications dealing with data collected by sensing devices. Often, the collected information is noisy or incomplete due to measurement or transmission errors. Furthermore, data may be rendered uncertain due to privacy-preserving issues with the presence of confidential information. This creates a number of challenges in terms of effectively and efficiently querying and mining uncertain data. Existing work in this field either neglects the presence of dependencies or provides only approximate results while applying methods designed for certain data. Other approaches dealing with uncertain data are not able to provide efficient solutions. This part presents query processing approaches that outperform existing solutions of probabilistic similarity ranking. This part finally leads to the application of the introduced techniques to data mining tasks, such as the prominent problem of probabilistic frequent itemset mining.

The main goal of this thesis is to explore a new general construction of orbifoldizing Hopf- and Nicholsalgebras, describe the growth of the automorphism group and compare the behaviour of certain associated categories to Kirillov's orbifoldizing. Together with outlooks towards vertex algebras these aspects form the 5-fold subdivision of this thesis. The main applications of this theory is the construction of new finite-dimensional Nichols algebras with sometimes large rank. In the process, the associated group is centrally extended and the root system is folded, as shown e.g. for E6->F4 on the title page. Thus, in some sense, orbifoldizing constructs new finite-dimensional quantum groups with nonabelian Cartan-algebra.

In using the term 'hybrid interactions', we refer to interaction forms that comprise both tangible and intangible interactions as well as a close coupling of the physical or embodied representation with digital output. Until now, there has been no description of a formal design process for this emerging research domain, no description that can be followed during the creation of these types of interactions. As a result, designers face limitations in prototyping these systems. In this thesis, we share our systematic approach to envisioning, prototyping, and iteratively developing these interaction forms by following an extended interaction design process. We share our experiences with process extensions in the form of toolkits, which we built for this research and utilized to aid designers in the development of hybrid interactive systems. The proposed tools incorporate different characteristics and are intended to be used at different points in the design process. In Sketching with Objects, we describe a low-fdelity toolkit that is intended to be used in the very early phases of the process, such as ideation and user research. By introducing Paperbox, we present an implementation to be used in the mid-process phases for fnding the appropriate mapping between physical representation and digital content during the creation of tangible user interfaces (TUI) atop interactive surfaces. In a follow-up project, we extended this toolkit to also be used in conjunction with capacitive sensing devices. To do this, we implemented Sketch-a-TUI. This approach allows designers to create TUIs on capacitive sensing devices rapidly and at low cost. To lower the barriers for designers using the toolkit, we created the Sketch-a-TUIApp, an application that allows even novice users (users without previous coding experience) to create early instantiations of TUIs. In order to prototype intangible interactions, we used open soft- and hardware components and proposed an approach of investigating interactivity in correlation with intangible interaction forms on a higher fdelity. With our fnal design process extension, Lightbox, we assisted a design team in systematically developing a remote interaction system connected to a media façade covering a building. All of the above-mentioned toolkits were explored both in real-life contexts and in projects with industrial partners. The evaluation was therefore mainly performed in the wild, which led to the adaptation of metrics suitable to the individual cases and contexts.

The framework for simultaneous inference by Hothorn, Bretz, and Westfall (2008) allows for a unified treatment of multiple comparisons in general parametric models where the study questions are specified as linear combinations of elemental model parameters. However, due to the asymptotic nature of the reference distribution the procedure controls the error rate across all comparisons only for sufficiently large samples. This thesis evaluates the small samples properties of simultaneous inference in complex parametric designs. These designs are necessary to address questions from applied research and include nonstandard parametric models or data in which the assumptions of classical procedures for multiple comparisons are not met. This thesis first treats multiple comparisons of samples with heterogeneous variances. Usage of a heteroscedastic consistent covariance estimation prevents an increase in the probability of false positive findings for reasonable sample sizes whereas the classical procedures show liberal or conservative behavior which persists even with increasing sample size. The focus of the second part are multiple comparisons in survival models. Multiple comparisons to a control can be performed in correlated survival data modeled by a frailty Cox model under control of the familywise error rate in sample sizes applicable for clinical trials. As a further application, multiple comparisons in survival models can be performed to investigate trends. The procedure achieves good power to detect different dose-response shapes and controls the error probability to falsely detect any trend. The third part addresses multiple comparisons in semiparametric mixed models. Simultaneous inference in the linear mixed model representation of these models yields an approach for multiple comparisons of curves of arbitrary shape. The sections on which curves differ can also be identified. For reasonably large samples the overall error rate to detect any non-existent difference is controlled. An extension allows for multiple comparisons of areas under the curve. However the resulting procedure achieves an overall error control only for sample sizes considerably larger than available in studies in which multiple AUC comparisons are usually performed. The usage of the evaluated procedures is illustrated by examples from applied research including comparisons of fatty acid contents between Bacillus simplex lineages, comparisons of experimental drugs with a control for prolongation in survival of chronic myelogeneous leukemia patients, and comparisons of curves describing a morphological structure along the spinal cord between variants of the EphA4 gene in mice.