New Statistical Algorithms for the Analysis of Mass Spectrometry Time-Of-Flight Mass Data with Applications in Clinical Diagnostics

Mass spectrometry (MS) based techniques have emerged as a standard forlarge-scale protein analysis. The ongoing progress in terms of more sensitive machines and improved data analysis algorithms led to a constant expansion of its fields of applications. Recently, MS was introduced into clinical proteomics with the prospect of early disease detection using proteomic pattern matching. Analyzing biological samples (e.g. blood) by mass spectrometry generates mass spectra that represent the components (molecules) contained in a sample as masses and their respective relative concentrations. In this work, we are interested in those components that are constant within a group of individuals but differ much between individuals of two distinct groups. These distinguishing components that dependent on a particular medical condition are generally called biomarkers. Since not all biomarkers found by the algorithms are of equal (discriminating) quality we are only interested in a small biomarker subset that - as a combination - can be used as a fingerprint for a disease. Once a fingerprint for a particular disease (or medical condition) is identified, it can be used in clinical diagnostics to classify unknown spectra. In this thesis we have developed new algorithms for automatic extraction of disease specific fingerprints from mass spectrometry data. Special emphasis has been put on designing highly sensitive methods with respect to signal detection. Thanks to our statistically based approach our methods are able to detect signals even below the noise level inherent in data acquired by common MS machines, such as hormones. To provide access to these new classes of algorithms to collaborating groups we have created a web-based analysis platform that provides all necessary interfaces for data transfer, data analysis and result inspection. To prove the platform's practical relevance it has been utilized in several clinical studies two of which are presented in this thesis. In these studies it could be shown that our platform is superior to commercial systems with respect to fingerprint identification. As an outcome of these studies several fingerprints for different cancer types (bladder, kidney, testicle, pancreas, colon and thyroid) have been detected and validated. The clinical partners in fact emphasize that these results would be impossible with a less sensitive analysis tool (such as the currently available systems). In addition to the issue of reliably finding and handling signals in noise we faced the problem to handle very large amounts of data, since an average dataset of an individual is about 2.5 Gigabytes in size and we have data of hundreds to thousands of persons. To cope with these large datasets, we developed a new framework for a heterogeneous (quasi) ad-hoc Grid - an infrastructure that allows to integrate thousands of computing resources (e.g. Desktop Computers, Computing Clusters or specialized hardware, such as IBM's Cell Processor in a Playstation 3)

A Scalable Workflow for a Configurable Neuromorphic Platform

This thesis establishes a scalable multi-user workflow for the operation of a highly configurable, large-scale neuromorphic hardware platform. The resulting software framework provides unified low-level as well as parallel high-level access. The latter is realized by an efficient abstract neural network description library, an automated translation of networks into hardware specific configurations and an experiment server infrastructure responsible for scheduling and executing experiments. Scalability, manual guidance and a broad support for handling hardware imper- fections render the model translation process suitable for large networks as well as large-scale neuromorphic systems. Networks with local connectivity, random networks and cortical column models are explored to study the topological aptitude of the neuromorphic platform and to benchmark the workflow. Depending on the model, performance improvements of more than two orders of magnitude have been achieved over a previous implementation. Additionally, an automated defect assessment for hardware synapses is introduced, indicating that most synapses are available for model emulation. In a second study, a tempotron-based hardware liquid state machine has been developed and applied to different tasks, including a memory challenge and digit recognition. The trained tempotron inherently compensates for fixed pattern variations making the setup suitable for analog neuromorphic hardware. The achieved performance is comparable to reference software simulations

SoS: self-organizing substrates

Large-scale networked systems often, both by design or chance exhibit self-organizing properties. Understanding self-organization using tools from cybernetics, particularly modeling them as Markov processes is a first step towards a formal framework which can be used in (decentralized) systems research and design.Interesting aspects to look for include the time evolution of a system and to investigate if and when a system converges to some absorbing states or stabilizes into a dynamic (and stable) equilibrium and how it performs under such an equilibrium state. Such a formal framework brings in objectivity in systems research, helping discern facts from artefacts as well as providing tools for quantitative evaluation of such systems. This thesis introduces such formalism in analyzing and evaluating peer-to-peer (P2P) systems in order to better understand the dynamics of such systems which in turn helps in better designs. In particular this thesis develops and studies the fundamental building blocks for a P2P storage system. In the process the design and evaluation methodology we pursue illustrate the typical methodological approaches in studying and designing self-organizing systems, and how the analysis methodology influences the design of the algorithms themselves to meet system design goals (preferably with quantifiable guarantees). These goals include efficiency, availability and durability, load-balance, high fault-tolerance and self-maintenance even in adversarial conditions like arbitrarily skewed and dynamic load and high membership dynamics (churn), apart of-course the specific functionalities that the system is supposed to provide. The functionalities we study here are some of the fundamental building blocks for various P2P applications and systems including P2P storage systems, and hence we call them substrates or base infrastructure. These elemental functionalities include: (i) Reliable and efficient discovery of resources distributed over the network in a decentralized manner; (ii) Communication among participants in an address independent manner, i.e., even when peers change their physical addresses; (iii) Availability and persistence of stored objects in the network, irrespective of availability or departure of individual participants from the system at any time; and (iv) Freshness of the objects/resources' (up-to-date replicas). Internet-scale distributed index structures (often termed as structured overlays) are used for discovery and access of resources in a decentralized setting. We propose a rapid construction from scratch and maintenance of the P-Grid overlay network in a self-organized manner so as to provide efficient search of both individual keys as well as a whole range of keys, doing so providing good load-balancing characteristics for diverse kind of arbitrarily skewed loads - storage and replication, query forwarding and query answering loads. For fast overlay construction we employ recursive partitioning of the key-space so that the resulting partitions are balanced with respect to storage load and replication. The proper algorithmic parameters for such partitioning is derived from a transient analysis of the partitioning process which has Markov property. Preservation of ordering information in P-Grid such that queries other than exact queries, like range queries can be efficiently and rather trivially handled makes P-Grid suitable for data-oriented applications. Fast overlay construction is analogous to building an index on a new set of keys making P-Grid suitable as the underlying indexing mechanism for peer-to-peer information retrieval applications among other potential applications which may require frequent indexing of new attributes apart regular updates to an existing index. In order to deal with membership dynamics, in particular changing physical address of peers across sessions, the overlay itself is used as a (self-referential) directory service for maintaining the participating peers' physical addresses across sessions. Exploiting this self-referential directory, a family of overlay maintenance scheme has been designed with lower communication overhead than other overlay maintenance strategies. The notion of dynamic equilibrium study for overlays under continuous churn and repairs, modeled as a Markov process, was introduced in order to evaluate and compare the overlay maintenance schemes. While the self-referential directory was originally invented to realize overlay maintenance schemes with lower overheads than existing overlay maintenance schemes, the self-referential directory is generic in nature and can be used for various other purposes, e.g., as a decentralized public key infrastructure. Persistence of peer identity across sessions, in spite of changes in physical address, provides a logical independence of the overlay network from the underlying physical network. This has many other potential usages, for example, efficient maintenance mechanisms for P2P storage systems and P2P trust and reputation management. We specifically look into the dynamics of maintaining redundancy for storage systems and design a novel lazy maintenance strategy. This strategy is algorithmically a simple variant of existing maintenance strategies which adapts to the system dynamics. This randomized lazy maintenance strategy thus explores the cost-performance trade-offs of the storage maintenance operations in a self-organizing manner. We model the storage system (redundancy), under churn and maintenance, as a Markov process. We perform an equilibrium study to show that the system operates in a more stable dynamic equilibrium with our strategy than for the existing maintenance scheme for comparable overheads. Particularly, we show that our maintenance scheme provides substantial performance gains in terms of maintenance overhead and system's resilience in presence of churn and correlated failures. Finally, we propose a gossip mechanism which works with lower communication overhead than existing approaches for communication among a relatively large set of unreliable peers without assuming any specific structure for their mutual connectivity. We use such a communication primitive for propagating replica updates in P2P systems, facilitating management of mutable content in P2P systems. The peer population affected by a gossip can be modeled as a Markov process. Studying the transient spread of gossips help in choosing proper algorithm parameters to reduce communication overhead while guaranteeing coverage of online peers. Each of these substrates in themselves were developed to find practical solutions for real problems. Put together, these can be used in other applications, including a P2P storage system with support for efficient lookup and inserts, membership dynamics, content mutation and updates, persistence and availability. Many of the ideas have already been implemented in real systems and several others are in the way to be integrated into the implementations. There are two principal contributions of this dissertation. It provides design of the P2P systems which are useful for end-users as well as other application developers who can build upon these existing systems. Secondly, it adapts and introduces the methodology of analysis of a system's time-evolution (tools typically used in diverse domains including physics and cybernetics) to study the long run behavior of P2P systems, and uses this methodology to (re-)design appropriate algorithms and evaluate them. We observed that studying P2P systems from the perspective of complex systems reveals their inner dynamics and hence ways to exploit such dynamics for suitable or better algorithms. In other words, the analysis methodology in itself strongly influences and inspires the way we design such systems. We believe that such an approach of orchestrating self-organization in internet-scale systems, where the algorithms and the analysis methodology have strong mutual influence will significantly change the way future such systems are developed and evaluated. We envision that such an approach will particularly serve as an important tool for the nascent but fast moving P2P systems research and development community