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Description
Biological systems are complex in many dimensions as endless transportation and communication networks all function simultaneously. Our ability to intervene within both healthy and diseased systems is tied directly to our ability to understand and model core functionality. The progress in increasingly accurate and thorough high-throughput measurement technologies has provided a deluge of data from which we may attempt to infer a representation of the true genetic regulatory system. A gene regulatory network model, if accurate enough, may allow us to perform hypothesis testing in the form of computational experiments. Of great importance to modeling accuracy is the acknowledgment of biological contexts within the models -- i.e. recognizing the heterogeneous nature of the true biological system and the data it generates. This marriage of engineering, mathematics and computer science with systems biology creates a cycle of progress between computer simulation and lab experimentation, rapidly translating interventions and treatments for patients from the bench to the bedside. This dissertation will first discuss the landscape for modeling the biological system, explore the identification of targets for intervention in Boolean network models of biological interactions, and explore context specificity both in new graphical depictions of models embodying context-specific genomic regulation and in novel analysis approaches designed to reveal embedded contextual information. Overall, the dissertation will explore a spectrum of biological modeling with a goal towards therapeutic intervention, with both formal and informal notions of biological context, in such a way that will enable future work to have an even greater impact in terms of direct patient benefit on an individualized level.
ContributorsVerdicchio, Michael (Author) / Kim, Seungchan (Thesis advisor) / Baral, Chitta (Committee member) / Stolovitzky, Gustavo (Committee member) / Collofello, James (Committee member) / Arizona State University (Publisher)
Created2013
Description
We are expecting hundreds of cores per chip in the near future. However, scaling the memory architecture in manycore architectures becomes a major challenge. Cache coherence provides a single image of memory at any time in execution to all the cores, yet coherent cache architectures are believed will not scale to hundreds and thousands of cores. In addition, caches and coherence logic already take 20-50% of the total power consumption of the processor and 30-60% of die area. Therefore, a more scalable architecture is needed for manycore architectures. Software Managed Manycore (SMM) architectures emerge as a solution. They have scalable memory design in which each core has direct access to only its local scratchpad memory, and any data transfers to/from other memories must be done explicitly in the application using Direct Memory Access (DMA) commands. Lack of automatic memory management in the hardware makes such architectures extremely power-efficient, but they also become difficult to program. If the code/data of the task mapped onto a core cannot fit in the local scratchpad memory, then DMA calls must be added to bring in the code/data before it is required, and it may need to be evicted after its use. However, doing this adds a lot of complexity to the programmer's job. Now programmers must worry about data management, on top of worrying about the functional correctness of the program - which is already quite complex. This dissertation presents a comprehensive compiler and runtime integration to automatically manage the code and data of each task in the limited local memory of the core. We firstly developed a Complete Circular Stack Management. It manages stack frames between the local memory and the main memory, and addresses the stack pointer problem as well. Though it works, we found we could further optimize the management for most cases. Thus a Smart Stack Data Management (SSDM) is provided. In this work, we formulate the stack data management problem and propose a greedy algorithm for the same. Later on, we propose a general cost estimation algorithm, based on which CMSM heuristic for code mapping problem is developed. Finally, heap data is dynamic in nature and therefore it is hard to manage it. We provide two schemes to manage unlimited amount of heap data in constant sized region in the local memory. In addition to those separate schemes for different kinds of data, we also provide a memory partition methodology.
ContributorsBai, Ke (Author) / Shrivastava, Aviral (Thesis advisor) / Chatha, Karamvir (Committee member) / Xue, Guoliang (Committee member) / Chakrabarti, Chaitali (Committee member) / Arizona State University (Publisher)
Created2014
Description
Given the process of tumorigenesis, biological signaling pathways have become of interest in the field of oncology. Many of the regulatory mechanisms that are altered in cancer are directly related to signal transduction and cellular communication. Thus, identifying signaling pathways that have become deregulated may provide useful information to better understanding altered regulatory mechanisms within cancer. Many methods that have been created to measure the distinct activity of signaling pathways have relied strictly upon transcription profiles. With advancements in comparative genomic hybridization techniques, copy number data has become extremely useful in providing valuable information pertaining to the genomic landscape of cancer. The purpose of this thesis is to develop a methodology that incorporates both gene expression and copy number data to identify signaling pathways that have become deregulated in cancer. The central idea is that copy number data may significantly assist in identifying signaling pathway deregulation by justifying the aberrant activity being measured in gene expression profiles. This method was then applied to four different subtypes of breast cancer resulting in the identification of signaling pathways associated with distinct functionalities for each of the breast cancer subtypes.
ContributorsTrevino, Robert (Author) / Kim, Seungchan (Thesis advisor) / Ringner, Markus (Committee member) / Liu, Huan (Committee member) / Arizona State University (Publisher)
Created2011
Description
In many classication problems data samples cannot be collected easily, example in drug trials, biological experiments and study on cancer patients. In many situations the data set size is small and there are many outliers. When classifying such data, example cancer vs normal patients the consequences of mis-classication are probably more important than any other data type, because the data point could be a cancer patient or the classication decision could help determine what gene might be over expressed and perhaps a cause of cancer. These mis-classications are typically higher in the presence of outlier data points. The aim of this thesis is to develop a maximum margin classier that is suited to address the lack of robustness of discriminant based classiers (like the Support Vector Machine (SVM)) to noise and outliers. The underlying notion is to adopt and develop a natural loss function that is more robust to outliers and more representative of the true loss function of the data. It is demonstrated experimentally that SVM's are indeed susceptible to outliers and that the new classier developed, here coined as Robust-SVM (RSVM), is superior to all studied classier on the synthetic datasets. It is superior to the SVM in both the synthetic and experimental data from biomedical studies and is competent to a classier derived on similar lines when real life data examples are considered.
ContributorsGupta, Sidharth (Author) / Kim, Seungchan (Thesis advisor) / Welfert, Bruno (Committee member) / Li, Baoxin (Committee member) / Arizona State University (Publisher)
Created2011
Description
Reverse engineering gene regulatory networks (GRNs) is an important problem in the domain of Systems Biology. Learning GRNs is challenging due to the inherent complexity of the real regulatory networks and the heterogeneity of samples in available biomedical data. Real world biological data are commonly collected from broad surveys (profiling studies) and aggregate highly heterogeneous biological samples. Popular methods to learn GRNs simplistically assume a single universal regulatory network corresponding to available data. They neglect regulatory network adaptation due to change in underlying conditions and cellular phenotype or both. This dissertation presents a novel computational framework to learn common regulatory interactions and networks underlying the different sets of relatively homogeneous samples from real world biological data. The characteristic set of samples/conditions and corresponding regulatory interactions defines the cellular context (context). Context, in this dissertation, represents the deterministic transcriptional activity within the specific cellular regulatory mechanism. The major contributions of this framework include - modeling and learning context specific GRNs; associating enriched samples with contexts to interpret contextual interactions using biological knowledge; pruning extraneous edges from the context-specific GRN to improve the precision of the final GRNs; integrating multisource data to learn inter and intra domain interactions and increase confidence in obtained GRNs; and finally, learning combinatorial conditioning factors from the data to identify regulatory cofactors. The framework, Expattern, was applied to both real world and synthetic data. Interesting insights were obtained into mechanism of action of drugs on analysis of NCI60 drug activity and gene expression data. Application to refractory cancer data and Glioblastoma multiforme yield GRNs that were readily annotated with context-specific phenotypic information. Refractory cancer GRNs also displayed associations between distinct cancers, not observed through only clustering. Performance comparisons on multi-context synthetic data show the framework Expattern performs better than other comparable methods.
ContributorsSen, Ina (Author) / Kim, Seungchan (Thesis advisor) / Baral, Chitta (Committee member) / Bittner, Michael (Committee member) / Konjevod, Goran (Committee member) / Arizona State University (Publisher)
Created2011
Description
Limited Local Memory (LLM) multicore architectures are promising powerefficient architectures will scalable memory hierarchy. In LLM multicores, each core can access only a small local memory. Accesses to a large shared global memory can only be made explicitly through Direct Memory Access (DMA) operations. Standard Template Library (STL) is a powerful programming tool and is widely used for software development. STLs provide dynamic data structures, algorithms, and iterators for vector, deque (double-ended queue), list, map (red-black tree), etc. Since the size of the local memory is limited in the cores of the LLM architecture, and data transfer is not automatically supported by hardware cache or OS, the usage of current STL implementation on LLM multicores is limited. Specifically, there is a hard limitation on the amount of data they can handle. In this article, we propose and implement a framework which manages the STL container classes on the local memory of LLM multicore architecture. Our proposal removes the data size limitation of the STL, and therefore improves the programmability on LLM multicore architectures with little change to the original program. Our implementation results in only about 12%-17% increase in static library code size and reasonable runtime overheads.
ContributorsLu, Di (Author) / Shrivastava, Aviral (Thesis advisor) / Chatha, Karamvir (Committee member) / Dasgupta, Partha (Committee member) / Arizona State University (Publisher)
Created2012
Description
Threshold logic has been studied by at least two independent group of researchers. One group of researchers studied threshold logic with the intention of building threshold logic circuits. The earliest research to this end was done in the 1960's. The major work at that time focused on studying mathematical properties of threshold logic as no efficient circuit implementations of threshold logic were available. Recently many post-CMOS (Complimentary Metal Oxide Semiconductor) technologies that implement threshold logic have been proposed along with efficient CMOS implementations. This has renewed the effort to develop efficient threshold logic design automation techniques. This work contributes to this ongoing effort. Another group studying threshold logic did so, because the building block of neural networks - the Perceptron, is identical to the threshold element implementing a threshold function. Neural networks are used for various purposes as data classifiers. This work contributes tangentially to this field by proposing new methods and techniques to study and analyze functions implemented by a Perceptron After completion of the Human Genome Project, it has become evident that most biological phenomenon is not caused by the action of single genes, but due to the complex interaction involving a system of genes. In recent times, the `systems approach' for the study of gene systems is gaining popularity. Many different theories from mathematics and computer science has been used for this purpose. Among the systems approaches, the Boolean logic gene model has emerged as the current most popular discrete gene model. This work proposes a new gene model based on threshold logic functions (which are a subset of Boolean logic functions). The biological relevance and utility of this model is argued illustrated by using it to model different in-vivo as well as in-silico gene systems.
ContributorsLinge Gowda, Tejaswi (Author) / Vrudhula, Sarma (Thesis advisor) / Shrivastava, Aviral (Committee member) / Chatha, Karamvir (Committee member) / Kim, Seungchan (Committee member) / Arizona State University (Publisher)
Created2012
Description
Debugging is a hard task. Debugging multi-threaded applications with their inherit non-determinism is all the more difficult. Non-determinism of any kind adds to the difficulty of cyclic debugging. In Android applications which are written in Java, threads and concurrency constructs introduce non-determinism to the program execution. Even with the same input, consecutive runs may not be the same and reproducing the same bug is a challenging task. This makes it difficult to understand and analyze the execution behavior or to understand the source of a failing execution. This thesis introduces a replay mechanism for Android applications written in Java and is based on the Lamport Clock. This tool provides the user with a controlled debugging environment, where the program execution follows the identical partially ordered happened-before dependency among threads, as during the recorded execution. In this, certain significant events like thread creation, synchronization etc. are recorded during run-time. They can later be replayed off-line, as many times as needed to pinpoint and fix an error in the application. It is software based approach and has been implemented by modifying the Dalvik Virtual Machine in the Android platform. The method of replay described in this thesis is independent of the underlying operating system scheduler.
ContributorsGirme, Rohit (Author) / Lee, Yann-Hang (Thesis advisor) / Chatha, Karamvir (Committee member) / Li, Baoxin (Committee member) / Arizona State University (Publisher)
Created2011
Description
As we migrate into an era of personalized medicine, understanding how bio-molecules interact with one another to form cellular systems is one of the key focus areas of systems biology. Several challenges such as the dynamic nature of cellular systems, uncertainty due to environmental influences, and the heterogeneity between individual patients render this a difficult task. In the last decade, several algorithms have been proposed to elucidate cellular systems from data, resulting in numerous data-driven hypotheses. However, due to the large number of variables involved in the process, many of which are unknown or not measurable, such computational approaches often lead to a high proportion of false positives. This renders interpretation of the data-driven hypotheses extremely difficult. Consequently, a dismal proportion of these hypotheses are subject to further experimental validation, eventually limiting their potential to augment existing biological knowledge. This dissertation develops a framework of computational methods for the analysis of such data-driven hypotheses leveraging existing biological knowledge. Specifically, I show how biological knowledge can be mapped onto these hypotheses and subsequently augmented through novel hypotheses. Biological hypotheses are learnt in three levels of abstraction -- individual interactions, functional modules and relationships between pathways, corresponding to three complementary aspects of biological systems. The computational methods developed in this dissertation are applied to high throughput cancer data, resulting in novel hypotheses with potentially significant biological impact.
ContributorsRamesh, Archana (Author) / Kim, Seungchan (Thesis advisor) / Langley, Patrick W (Committee member) / Baral, Chitta (Committee member) / Kiefer, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2012