From condition-specific interactions towards the differential complexome of proteins

While capturing the transcriptomic state of a cell is a comparably simple effort with modern sequencing techniques, mapping protein interactomes and complexomes in a sample-specific manner is currently not feasible on a large scale. To understand crucial biological processes, however, knowledge on the physical interplay between proteins can be more interesting than just their mere expression. In this thesis, we present and demonstrate four software tools that unlock the cellular wiring in a condition-specific manner and promise a deeper understanding of what happens upon cell fate transitions. PPIXpress allows to exploit the abundance of existing expression data to generate specific interactomes, which can even consider alternative splicing events when protein isoforms can be related to the presence of causative protein domain interactions of an underlying model. As an addition to this work, we developed the convenient differential analysis tool PPICompare to determine rewiring events and their causes within the inferred interaction networks between grouped samples. Furthermore, we present a new implementation of the combinatorial protein complex prediction algorithm DACO that features a significantly reduced runtime. This improvement facilitates an application of the method for a large number of samples and the resulting sample-specific complexes can ultimately be assessed quantitatively with our novel differential protein complex analysis tool CompleXChange.Das Transkriptom einer Zelle ist mit modernen Sequenzierungstechniken vergleichsweise einfach zu erfassen. Die Ermittlung von Proteininteraktionen und -komplexen wiederum ist in großem Maßstab derzeit nicht möglich. Um wichtige biologische Prozesse zu verstehen, kann das Zusammenspiel von Proteinen jedoch erheblich interessanter sein als deren reine Expression. In dieser Arbeit stellen wir vier Software-Tools vor, die es ermöglichen solche Interaktionen zustandsbezogen zu betrachten und damit ein tieferes Verständnis darüber versprechen, was in der Zelle bei Veränderungen passiert. PPIXpress ermöglicht es vorhandene Expressionsdaten zu nutzen, um die aktiven Interaktionen in einem biologischen Kontext zu ermitteln. Wenn Proteinvarianten mit Interaktionen von Proteindomänen in Verbindung gebracht werden können, kann hierbei sogar alternatives Spleißen berücksichtigen werden. Als Ergänzung dazu haben wir das komfortable Differenzialanalyse-Tool PPICompare entwickelt, welches Veränderungen des Interaktoms und deren Ursachen zwischen gruppierten Proben bestimmen kann. Darüber hinaus stellen wir eine neue Implementierung des Proteinkomplex-Vorhersagealgorithmus DACO vor, die eine deutlich reduzierte Laufzeit aufweist. Diese Verbesserung ermöglicht die Anwendung der Methode auf eine große Anzahl von Proben. Die damit bestimmten probenspezifischen Komplexe können schließlich mit unserem neuartigen Differenzialanalyse-Tool CompleXChange quantitativ bewertet werden

Operating system support for warehouse-scale computing

Modern applications are increasingly backed by large-scale data centres. Systems software in these data centre environments, however, faces substantial challenges: the lack of uniform resource abstractions makes sharing and resource management inefficient, infrastructure software lacks end-to-end access control mechanisms, and work placement ignores the effects of hardware heterogeneity and workload interference. In this dissertation, I argue that uniform, clean-slate operating system (OS) abstractions designed to support distributed systems can make data centres more efficient and secure. I present a novel distributed operating system for data centres, focusing on two OS components: the abstractions for resource naming, management and protection, and the scheduling of work to compute resources. First, I introduce a reference model for a decentralised, distributed data centre OS, based on pervasive distributed objects and inspired by concepts in classic 1980s distributed OSes. Translucent abstractions free users from having to understand implementation details, but enable introspection for performance optimisation. Fine-grained access control is supported by combining storable, communicable identifier capabilities, and context-dependent, ephemeral handle capabilities. Finally, multi-phase I/O requests implement optimistically concurrent access to objects while supporting diverse application-level consistency policies. Second, I present the DIOS operating system, an implementation of my model as an extension to Linux. The DIOS system call API is centred around distributed objects, globally resolvable names, and translucent references that carry context-sensitive object meta-data. I illustrate how these concepts support distributed applications, and evaluate the performance of DIOS in microbenchmarks and a data-intensive MapReduce application. I find that it offers improved, finegrained isolation of resources, while permitting flexible sharing. Third, I present the Firmament cluster scheduler, which generalises prior work on scheduling via minimum-cost flow optimisation. Firmament can flexibly express many scheduling policies using pluggable cost models; it makes high-quality placement decisions based on fine-grained information about tasks and resources; and it scales the flow-based scheduling approach to very large clusters. In two case studies, I show that Firmament supports policies that reduce colocation interference between tasks and that it successfully exploits flexibility in the workload to improve the energy efficiency of a heterogeneous cluster. Moreover, my evaluation shows that Firmament scales the minimum-cost flow optimisation to clusters of tens of thousands of machines while still making sub-second placement decisions.St John's College Supplementary Emolument Fund DARP

Large-scale inference in the focally damaged human brain

Clinical outcomes in focal brain injury reflect the interactions between two distinct anatomically distributed patterns: the functional organisation of the brain and the structural distribution of injury. The challenge of understanding the functional architecture of the brain is familiar; that of understanding the lesion architecture is barely acknowledged. Yet, models of the functional consequences of focal injury are critically dependent on our knowledge of both. The studies described in this thesis seek to show how machine learning-enabled high-dimensional multivariate analysis powered by large-scale data can enhance our ability to model the relation between focal brain injury and clinical outcomes across an array of modelling applications. All studies are conducted on internationally the largest available set of MR imaging data of focal brain injury in the context of acute stroke (N=1333) and employ kernel machines at the principal modelling architecture. First, I examine lesion-deficit prediction, quantifying the ceiling on achievable predictive fidelity for high-dimensional and low-dimensional models, demonstrating the former to be substantially higher than the latter. Second, I determine the marginal value of adding unlabelled imaging data to predictive models within a semi-supervised framework, quantifying the benefit of assembling unlabelled collections of clinical imaging. Third, I compare high- and low-dimensional approaches to modelling response to therapy in two contexts: quantifying the effect of treatment at the population level (therapeutic inference) and predicting the optimal treatment in an individual patient (prescriptive inference). I demonstrate the superiority of the high-dimensional approach in both settings

New Fundamental Technologies in Data Mining

The progress of data mining technology and large public popularity establish a need for a comprehensive text on the subject. The series of books entitled by "Data Mining" address the need by presenting in-depth description of novel mining algorithms and many useful applications. In addition to understanding each section deeply, the two books present useful hints and strategies to solving problems in the following chapters. The contributing authors have highlighted many future research directions that will foster multi-disciplinary collaborations and hence will lead to significant development in the field of data mining

A Statistical Approach to the Alignment of fMRI Data

Multi-subject functional Magnetic Resonance Image studies are critical. The anatomical and functional structure varies across subjects, so the image alignment is necessary. We define a probabilistic model to describe functional alignment. Imposing a prior distribution, as the matrix Fisher Von Mises distribution, of the orthogonal transformation parameter, the anatomical information is embedded in the estimation of the parameters, i.e., penalizing the combination of spatially distant voxels. Real applications show an improvement in the classification and interpretability of the results compared to various functional alignment methods

A comparison of the CAR and DAGAR spatial random effects models with an application to diabetics rate estimation in Belgium

When hierarchically modelling an epidemiological phenomenon on a finite collection of sites in space, one must always take a latent spatial effect into account in order to capture the correlation structure that links the phenomenon to the territory. In this work, we compare two autoregressive spatial models that can be used for this purpose: the classical CAR model and the more recent DAGAR model. Differently from the former, the latter has a desirable property: its ρ parameter can be naturally interpreted as the average neighbor pair correlation and, in addition, this parameter can be directly estimated when the effect is modelled using a DAGAR rather than a CAR structure. As an application, we model the diabetics rate in Belgium in 2014 and show the adequacy of these models in predicting the response variable when no covariates are available

Markovian-based clustering of internet addiction trajectories

A hidden Markov clustering procedure is applied to a sample of n=185 longitudinal Internet Addiction Test trajectories collected in Switzerland. The best solution has 4 groups. This solution is related to the level of emotional wellbeing of the subjects, but no relation is observed with age, gender and BMI

Advances in knowledge discovery and data mining Part II

19th Pacific-Asia Conference, PAKDD 2015, Ho Chi Minh City, Vietnam, May 19-22, 2015, Proceedings, Part II</p

A discussion on hidden Markov models for life course data

This is an introduction on discrete-time Hidden Markov models (HMM) for longitudinal data analysis in population and life course studies. In the Markovian perspective, life trajectories are considered as the result of a stochastic process in which the probability of occurrence of a particular state or event depends on the sequence of states observed so far. Markovian models are used to analyze the transition process between successive states. Starting from the traditional formulation of a first-order discrete-time Markov chain where each state is liked to the next one, we present the hidden Markov models where the current response is driven by a latent variable that follows a Markov process. The paper presents also a simple way of handling categorical covariates to capture the effect of external factors on the transition probabilities and existing software are briefly overviewed. Empirical illustrations using data on self reported health demonstrate the relevance of the different extensions for life course analysis