Extracting the Structure and Conformations of Biological Entities from Large Datasets

In biology, structure determines function, which often proceeds via changes in conformation. Efficient means for determining structure exist, but mapping conformations continue to present a serious challenge. Single-particles approaches, such as cryogenic electron microscopy (cryo-EM) and emerging diffract & destroy X-ray techniques are, in principle, ideally positioned to overcome these challenges. But the algorithmic ability to extract information from large heterogeneous datasets consisting of unsorted snapshots - each emanating from an unknown orientation of an object in an unknown conformation - remains elusive. It is the objective of this thesis to describe and validate a powerful suite of manifold-based algorithms able to extract structural and conformational information from large datasets. These computationally efficient algorithms offer a new approach to determining the structure and conformations of viruses and macromolecules. After an introduction, we demonstrate a distributed, exact k-Nearest Neighbor Graph (k-NNG) construction method, in order to establish a firm algorithmic basis for manifold-based analysis. The proposed algorithm uses Graphics Processing Units (GPUs) and exploits multiple levels of parallelism in distributed computational environment and it is scalable for different cluster sizes, with each compute node in the cluster containing multiple GPUs. Next, we present applications of manifold-based analysis in determining structure and conformational variability. Using the Diffusion Map algorithm, a new approach is presented, which is capable of determining structure of symmetric objects, such as viruses, to 1/100th of the object diameter, using low-signal diffraction snapshots. This is demonstrated by means of a successful 3D reconstruction of the Satellite Tobacco Necrosis Virus (STNV) to atomic resolution from simulated diffraction snapshots with and without noise. We next present a new approach for determining discrete conformational changes of the enzyme Adenylate kinase (ADK) from very large datasets of up to 20 million snapshots, each with ~104 pixels. This exceeds by an order of magnitude the largest dataset previously analyzed. Finally, we present a theoretical framework and an algorithmic pipeline for capturing continuous conformational changes of the ribosome from ultralow-signal (-12dB) experimental cryo-EM. Our analysis shows a smooth, concerted change in molecular structure in two-dimensional projection, which might be indicative of the way the ribosome functions as a molecular machine. The thesis ends with a summary and future prospects

Enhanced clustering analysis pipeline for performance analysis of parallel applications

Clustering analysis is widely used to stratify data in the same cluster when they are similar according to the specific metrics. We can use the cluster analysis to group the CPU burst of a parallel application, and the regions on each process in-between communication calls or calls to the parallel runtime. The resulting clusters obtained are the different computational trends or phases that appear in the application. These clusters are useful to understand the behavior of the computation part of the application and focus the analyses on those that present performance issues. Although density-based clustering algorithms are a powerful and efficient tool to summarize this type of information, their traditional user-guided clustering methodology has many shortcomings and deficiencies in dealing with the complexity of data, the diversity of data structures, high-dimensionality of data, and the dramatic increase in the amount of data. Consequently, the majority of DBSCAN-like algorithms have weaknesses to handle high-dimensionality and/or Multi-density data, and they are sensitive to their hyper-parameter configuration. Furthermore, extracting insight from the obtained clusters is an intuitive and manual task. To mitigate these weaknesses, we have proposed a new unified approach to replace the user-guided clustering with an automated clustering analysis pipeline, called Enhanced Cluster Identification and Interpretation (ECII) pipeline. To build the pipeline, we propose novel techniques including Robust Independent Feature Selection, Feature Space Curvature Map, Organization Component Analysis, and hyper-parameters tuning to feature selection, density homogenization, cluster interpretation, and model selection which are the main components of our machine learning pipeline. This thesis contributes four new techniques to the Machine Learning field with a particular use case in Performance Analytics field. The first contribution is a novel unsupervised approach for feature selection on noisy data, called Robust Independent Feature Selection (RIFS). Specifically, we choose a feature subset that contains most of the underlying information, using the same criteria as the Independent component analysis. Simultaneously, the noise is separated as an independent component. The second contribution of the thesis is a parametric multilinear transformation method to homogenize cluster densities while preserving the topological structure of the dataset, called Feature Space Curvature Map (FSCM). We present a new Gravitational Self-organizing Map to model the feature space curvature by plugging the concepts of gravity and fabric of space into the Self-organizing Map algorithm to mathematically describe the density structure of the data. To homogenize the cluster density, we introduce a novel mapping mechanism to project the data from the non-Euclidean curved space to a new Euclidean flat space. The third contribution is a novel topological-based method to study potentially complex high-dimensional categorized data by quantifying their shapes and extracting fine-grain insights from them to interpret the clustering result. We introduce our Organization Component Analysis (OCA) method for the automatic arbitrary cluster-shape study without an assumption about the data distribution. Finally, to tune the DBSCAN hyper-parameters, we propose a new tuning mechanism by combining techniques from machine learning and optimization domains, and we embed it in the ECII pipeline. Using this cluster analysis pipeline with the CPU burst data of a parallel application, we provide the developer/analyst with a high-quality SPMD computation structure detection with the added value that reflects the fine grain of the computation regions.El análisis de conglomerados se usa ampliamente para estratificar datos en el mismo conglomerado cuando son similares según las métricas específicas. Nosotros puede usar el análisis de clúster para agrupar la ráfaga de CPU de una aplicación paralela y las regiones en cada proceso intermedio llamadas de comunicación o llamadas al tiempo de ejecución paralelo. Los clusters resultantes obtenidos son las diferentes tendencias computacionales o fases que aparecen en la solicitud. Estos clusters son útiles para entender el comportamiento de la parte de computación del aplicación y centrar los análisis en aquellos que presenten problemas de rendimiento. Aunque los algoritmos de agrupamiento basados en la densidad son una herramienta poderosa y eficiente para resumir este tipo de información, su La metodología tradicional de agrupación en clústeres guiada por el usuario tiene muchas deficiencias y deficiencias al tratar con la complejidad de los datos, la diversidad de estructuras de datos, la alta dimensionalidad de los datos y el aumento dramático en la cantidad de datos. En consecuencia, el La mayoría de los algoritmos similares a DBSCAN tienen debilidades para manejar datos de alta dimensionalidad y/o densidad múltiple, y son sensibles a su configuración de hiperparámetros. Además, extraer información de los clústeres obtenidos es una forma intuitiva y tarea manual Para mitigar estas debilidades, hemos propuesto un nuevo enfoque unificado para reemplazar el agrupamiento guiado por el usuario con un canalización de análisis de agrupamiento automatizado, llamada canalización de identificación e interpretación de clúster mejorada (ECII). para construir el tubería, proponemos técnicas novedosas que incluyen la selección robusta de características independientes, el mapa de curvatura del espacio de características, Análisis de componentes de la organización y ajuste de hiperparámetros para la selección de características, homogeneización de densidad, agrupación interpretación y selección de modelos, que son los componentes principales de nuestra canalización de aprendizaje automático. Esta tesis aporta cuatro nuevas técnicas al campo de Machine Learning con un caso de uso particular en el campo de Performance Analytics. La primera contribución es un enfoque novedoso no supervisado para la selección de características en datos ruidosos, llamado Robust Independent Feature. Selección (RIFS).Específicamente, elegimos un subconjunto de funciones que contiene la mayor parte de la información subyacente, utilizando el mismo criterios como el análisis de componentes independientes. Simultáneamente, el ruido se separa como un componente independiente. La segunda contribución de la tesis es un método de transformación multilineal paramétrica para homogeneizar densidades de clústeres mientras preservando la estructura topológica del conjunto de datos, llamado Mapa de Curvatura del Espacio de Características (FSCM). Presentamos un nuevo Gravitacional Mapa autoorganizado para modelar la curvatura del espacio característico conectando los conceptos de gravedad y estructura del espacio en el Algoritmo de mapa autoorganizado para describir matemáticamente la estructura de densidad de los datos. Para homogeneizar la densidad del racimo, introducimos un mecanismo de mapeo novedoso para proyectar los datos del espacio curvo no euclidiano a un nuevo plano euclidiano espacio. La tercera contribución es un nuevo método basado en topología para estudiar datos categorizados de alta dimensión potencialmente complejos mediante cuantificando sus formas y extrayendo información detallada de ellas para interpretar el resultado de la agrupación. presentamos nuestro Método de análisis de componentes de organización (OCA) para el estudio automático de forma arbitraria de conglomerados sin una suposición sobre el distribución de datos.Postprint (published version

Model Reduction of Synchronized Lur'e Networks

In this talk, we investigate a model order reduction schemethat reduces the complexity of uncertain dynamical networks consisting of diffusively interconnected nonlinearLure subsystems. We aim to reduce the dimension ofeach subsystem and meanwhile preserve the synchronization property of the overall network. Using the upperbound of the Laplacian spectral radius, we first characterize the robust synchronization of the Lure network bya linear matrix equation (LMI), whose solutions can betreated as generalized Gramians of each subsystem, andthus the balanced truncation can be performed on the linear component of each Lure subsystem. As a result, thedimension of the each subsystem is reduced, and the dynamics of the network is simplified. It is verified that, withthe same communication topology, the resulting reducednetwork system is still robustly synchronized, and the apriori bound on the approximation error is guaranteed tocompare the behaviors of the full-order and reduced-orderLure subsyste

Theoretically-Efficient and Practical Parallel DBSCAN

The DBSCAN method for spatial clustering has received significant attention due to its applicability in a variety of data analysis tasks. There are fast sequential algorithms for DBSCAN in Euclidean space that take $O(n\log n)$ work for two dimensions, sub-quadratic work for three or more dimensions, and can be computed approximately in linear work for any constant number of dimensions. However, existing parallel DBSCAN algorithms require quadratic work in the worst case, making them inefficient for large datasets. This paper bridges the gap between theory and practice of parallel DBSCAN by presenting new parallel algorithms for Euclidean exact DBSCAN and approximate DBSCAN that match the work bounds of their sequential counterparts, and are highly parallel (polylogarithmic depth). We present implementations of our algorithms along with optimizations that improve their practical performance. We perform a comprehensive experimental evaluation of our algorithms on a variety of datasets and parameter settings. Our experiments on a 36-core machine with hyper-threading show that we outperform existing parallel DBSCAN implementations by up to several orders of magnitude, and achieve speedups by up to 33x over the best sequential algorithms

Coping With New Challengens for Density-Based Clustering

Knowledge Discovery in Databases (KDD) is the non-trivial process of identifying valid, novel, potentially useful, and ultimately understandable patterns in data. The core step of the KDD process is the application of a Data Mining algorithm in order to produce a particular enumeration of patterns and relationships in large databases. Clustering is one of the major data mining tasks and aims at grouping the data objects into meaningful classes (clusters) such that the similarity of objects within clusters is maximized, and the similarity of objects from different clusters is minimized. Beside many others, the density-based clustering notion underlying the algorithm DBSCAN and its hierarchical extension OPTICS has been proposed recently, being one of the most successful approaches to clustering. In this thesis, our aim is to advance the state-of-the-art clustering, especially density-based clustering by identifying novel challenges for density-based clustering and proposing innovative and solid solutions for these challenges. We describe the development of the industrial prototype BOSS (Browsing OPTICS plots for Similarity Search) which is a first step towards developing a comprehensive, scalable and distributed computing solution designed to make the efficiency and analytical capabilities of OPTICS available to a broader audience. For the development of BOSS, several key enhancements of OPTICS are required which are addressed in this thesis. We develop incremental algorithms of OPTICS to efficiently reconstruct the hierarchical clustering structure in frequently updated databases, in particular, when a set of objects is inserted in or deleted from the database. We empirically show that these incremental algorithms yield significant speed-up factors over the original OPTICS algorithm. Furthermore, we propose a novel algorithm for automatic extraction of clusters from hierarchical clustering representations that outperforms comparative methods, and introduce two novel approaches for selecting meaningful representatives, using the density-based concepts of OPTICS and producing better results than the related medoid approach. Another major challenge for density-based clustering is to cope with high dimensional data. Many today's real-world data sets contain a large number of measurements (or features) for a single data object. Usually, global feature reduction techniques cannot be applied to these data sets. Thus, the task of feature selection must be combined with and incooperated into the clustering process. In this thesis, we present original extensions and enhancements of the density-based clustering notion to cope with high dimensional data. In particular, we propose an algorithm called SUBCLU (density based SUBspace CLUstering) that extends DBSCAN to the problem of subspace clustering. SUBCLU efficiently computes all clusters that would have been found if DBSCAN is applied to all possible subspaces of the feature space. An experimental evaluation on real-world data sets illustrates that SUBCLU is more effective than existing subspace clustering algorithms because it is able to find clusters of arbitrary size and shape, and produces determine results. A semi-hierarchical extension of SUBCLU called RIS (Ranking Interesting Subspaces) is proposed that does not compute the subspace clusters directly, but generates a list of subspaces ranked by their clustering characteristics. A hierarchical clustering algorithm can be applied to these interesting subspaces in order to compute a hierarchical (subspace) clustering. A comparative evaluation of RIS and SUBCLU shows that RIS in combination with OPTICS can achieve an information gain over SUBCLU. In addition, we propose the algorithm 4C (Computing Correlation Connected Clusters) that extends the concepts of DBSCAN to compute density-based correlation clusters. 4C benefits from an innovative, well-defined and effective clustering model, outperforming related approaches in terms of clustering quality on real-world data sets.Knowledge Discovery in Databases (KDD) ist der Prozess der (semi-)automatischen Extraktion von Wissen aus Datenbanken, das gültig, bisher unbekannt und potentiell nützlich für eine gegebene Anwendung ist. Der zentrale Schritt des KDD-Prozesses ist das Data Mining. Eine der wichtigsten Aufgaben des Data Mining ist Clustering. Dabei sollen die Objekte einer Datenbank in Gruppen (Cluster) partitioniert werden, so dass Objekte eines Clusters möglichst ähnlich und Objekte verschiedener Cluster möglichst unähnlich zu einander sind. Das dichtebasierte Clustermodell und die darauf aufbauenden Algorithmen DBSCAN und OPTICS sind unter einer Vielzahl anderer Clustering-Ansätze eine der erfolgreichsten Methoden zum Clustering. Im Rahmen dieser Dissertation wollen wir den aktuellen Stand der Technik im Bereich Clustering und speziell im Bereich dichtebasiertes Clustering voranbringen. Dazu erarbeiten wir neue Herausforderungen für das dichtebasierte Clustermodell und schlagen dazu innovative Lösungen vor. Zunächst steht die Entwicklung des industriellen Prototyps BOSS (Browsing OPTICS plots for Similarity Search) im Mittelpunkt dieser Arbeit. BOSS ist ein erster Beitrag zu einer umfassenden, skalierbaren und verteilten Softwarelösung, die eine Nutzung der Effizienzvorteile und die analytischen Möglichkeiten des dichtebasierten, hierarchischen Clustering-Algorithmus OPTICS für ein breites Publikum ermöglichen. Zur Entwicklung von BOSS werden drei entscheidende Erweiterungen von OPTICS benötigt: Wir entwickeln eine inkrementelle Version von OPTICS um nach einem Update der Datenbank (Einfügen/Löschen einer Menge von Objekten) die hierarchische Clustering Struktur effizient zu reorganisieren. Anhand von Experimenten mit synthetischen und realen Daten zeigen wir, dass die vorgeschlagenen, inkrementellen Algorithmen deutliche Beschleunigungsfaktoren gegenüber dem originalen OPTICS-Algorithmus erzielen. Desweiteren schlagen wir einen neuen Algorithmus zur automatischen Clusterextraktion aus hierarchischen Repräsentationen und zwei innovative Methoden zur automatischen Auswahl geeigneter Clusterrepräsentaten vor. Unsere neuen Techniken erzielen bei Tests auf mehreren realen Datenbanken im Vergleich zu den konkurrierenden Verfahren bessere Ergebnisse. Eine weitere Herausforderung für Clustering-Verfahren stellen hochdimensionale Featureräume dar. Reale Datensätze beinhalten dank moderner Verfahren zur Datenerhebung häufig sehr viele Merkmale. Teile dieser Merkmale unterliegen oft Rauschen oder Abhängigkeiten und können meist nicht im Vorfeld ausgesiebt werden, da diese Effekte jeweils in Teilen der Datenbank unterschiedlich ausgeprägt sind. Daher muss die Wahl der Features mit dem Data-Mining-Verfahren verknüpft werden. Im Rahmen dieser Arbeit stellen wir innovative Erweiterungen des dichtebasierten Clustermodells für hochdimensionale Daten vor. Wir entwickeln SUBCLU (dichtebasiertes SUBspace CLUstering), ein auf DBSCAN basierender Subspace Clustering Algorithmus. SUBCLU erzeugt effizient alle Cluster, die gefunden werden, wenn man DBSCAN auf alle möglichen Teilräume des Datensatzes anwendet. Experimente auf realen Daten zeigen, dass SUBCLU effektiver als vergleichbare Algorithmen ist. RIS (Ranking Interesting Subspaces), eine semi-hierarchische Erweiterung von SUBCLU, wird vorgeschlagen, das nicht mehr direkt die Teilraumcluster berechnet, sondern eine Liste von Teilräumen geordnet anhand ihrer Clustering-Qualität erzeugt. Dadurch können hierarchische Partitionierungen auf ausgewählten Teilräumen erzeugt werden. Experimente belegen, dass RIS in Kombination mit OPTICS ein Informationsgewinn gegenüber SUBCLU erreicht. Außerdem stellen wir den neuartigen Korrelationscluster Algorithmus 4C (Computing Correlation Connected Clusters) vor. 4C basiert auf einem innovativen und wohldefinierten Clustermodell und erzielt in unseren Experimenten mit realen Daten bessere Ergebnisse als vergleichbare Clustering-Ansätze

Turn-Key Stabilization and Digital Control of Scalable, N GTI Resonator Based Coherent Pulse Stacking Systems

Coherent Pulse Stacking Amplification (CPSA) is a new time-domain coherent addition technique that overcomes the limitations on pulse energies achievable from optical amplifiers. It uses reflecting resonators to transform a sequence of phase- and amplitude-modulated optical pulses into a single output pulse enabling high pulse energy for fiber lasers. This thesis focuses on utilizing efficient algorithms for stabilization and optimization aspects of CPSA and developing a robust, scalable, and distributed digital control system with firmware and software integration for algorithms, to support the CPS (Coherent Pulse Stacking) application. We have presented the theoretical foundation of the stochastic parallel gradient descent (SPGD) for phase stabilization, discussed its performance criteria, its convergence, and its stability. We have presented our software and hardware development for time-domain coherent combing stabilization (specifically, an FPGA (Field Programmable Gate Array)-based Control system with software/firmware development to support stabilization and optimization algorithms). Analytical formulations of output stacked pulse profile as a function of input pulse train amplitudes and phase and stacker cavity parameters have been derived so as to build up a foundation for a GTI (Gires-Tournois-Interferometer) Cavity-based noise measurement technique. Time-domain and frequency domain characterization techniques have been presented to analyze phase and amplitude noise in the stacking system. Stacking sensitivity to errors in different control parameters (stacker cavity phase, pulse amplitude, and phases) for different stacker configurations have been analyzed. Noise measurement results using GTI cavities with different round-trip time has have been presented and we have shown how effectively the stacking phase noise in the system can be reduced by improving the noise performance of the mode-locked oscillator. Simulation and Experimental results for stabilizing different stacker configurations have been presented. Finally an algorithmic control system along with software/hardware development for optimizing amplitudes and phases of the input burst has been implemented to increase stacking fidelity. A complete detailed description, and simulation of the Genetic Algorithm as an alternative algorithm for optimizing the stacked pulse fidelity has been presented. Comparison between SPGD and Genetic Algorithm results has been done to evaluate their performance. To summarize, this thesis provides theoretical, experimental, and implementation aspects of controlling CPSA system by introducing efficient control algorithms and developing a turn-key digital control system which is scalable to large number of stacker cavities.PHDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147664/1/msheikhs_1.pd