DATA DRIVEN APPROACHES TO IDENTIFY DETERMINANTS OF HEART DISEASES AND CANCER RESISTANCE

Cancer and cardio-vascular diseases are the leading causes of death world-wide. Caused by systemic genetic and molecular disruptions in cells, these disorders are the manifestation of profound disturbance of normal cellular homeostasis. People suffering or at high risk for these disorders need early diagnosis and personalized therapeutic intervention. Successful implementation of such clinical measures can significantly improve global health. However, development of effective therapies is hindered by the challenges in identifying genetic and molecular determinants of the onset of diseases; and in cases where therapies already exist, the main challenge is to identify molecular determinants that drive resistance to the therapies. Due to the progress in sequencing technologies, the access to a large genome-wide biological data is now extended far beyond few experimental labs to the global research community. The unprecedented availability of the data has revolutionized the capabilities of computational researchers, enabling them to collaboratively address the long standing problems from many different perspectives. Likewise, this thesis tackles the two main public health related challenges using data driven approaches. Numerous association studies have been proposed to identify genomic variants that determine disease. However, their clinical utility remains limited due to their inability to distinguish causal variants from associated variants. In the presented thesis, we first propose a simple scheme that improves association studies in supervised fashion and has shown its applicability in identifying genomic regulatory variants associated with hypertension. Next, we propose a coupled Bayesian regression approach -- eQTeL, which leverages epigenetic data to estimate regulatory and gene interaction potential, and identifies combinations of regulatory genomic variants that explain the gene expression variance. On human heart data, eQTeL not only explains a significantly greater proportion of expression variance in samples, but also predicts gene expression more accurately than other methods. We demonstrate that eQTeL accurately detects causal regulatory SNPs by simulation, particularly those with small effect sizes. Using various functional data, we show that SNPs detected by eQTeL are enriched for allele-specific protein binding and histone modifications, which potentially disrupt binding of core cardiac transcription factors and are spatially proximal to their target. eQTeL SNPs capture a substantial proportion of genetic determinants of expression variance and we estimate that 58% of these SNPs are putatively causal. The challenge of identifying molecular determinants of cancer resistance so far could only be dealt with labor intensive and costly experimental studies, and in case of experimental drugs such studies are infeasible. Here we take a fundamentally different data driven approach to understand the evolving landscape of emerging resistance. We introduce a novel class of genetic interactions termed synthetic rescues (SR) in cancer, which denotes a functional interaction between two genes where a change in the activity of one vulnerable gene (which may be a target of a cancer drug) is lethal, but subsequently altered activity of its partner rescuer gene restores cell viability. Next we describe a comprehensive computational framework --termed INCISOR-- for identifying SR underlying cancer resistance. Applying INCISOR to mine The Cancer Genome Atlas (TCGA), a large collection of cancer patient data, we identified the first pan-cancer SR networks, composed of interactions common to many cancer types. We experimentally test and validate a subset of these interactions involving the master regulator gene mTOR. We find that rescuer genes become increasingly activated as breast cancer progresses, testifying to pervasive ongoing rescue processes. We show that SRs can be utilized to successfully predict patients' survival and response to the majority of current cancer drugs, and importantly, for predicting the emergence of drug resistance from the initial tumor biopsy. Our analysis suggests a potential new strategy for enhancing the effectiveness of existing cancer therapies by targeting their rescuer genes to counteract resistance. The thesis provides statistical frameworks that can harness ever increasing high throughput genomic data to address challenges in determining the molecular underpinnings of hypertension, cardiovascular disease and cancer resistance. We discover novel molecular mechanistic insights that will advance the progress in early disease prevention and personalized therapeutics. Our analyses sheds light on the fundamental biological understanding of gene regulation and interaction, and opens up exciting avenues of translational applications in risk prediction and therapeutics.

Data-Driven Wildfire Propagation Modeling with FARSITE-EnKF

The goal of this study is to provide a framework for future researchers to understand and use the FARSITE wildfire-forecasting model with data assimilation. Current wildfire models lack the ability to provide accurate prediction of fire front position faster than real-time. When FARSITE is coupled with a recursive ensemble filter, the data assimilation forecast method improves. The scope includes an explanation of the standalone FARSITE application, technical details on FARSITE integration with a parallel program coupler called OpenPALM, and a model demonstration of the FARSITE-Ensemble Kalman Filter software using the FireFlux I experiment by Craig Clements. The results show that the fire front forecast is improved with the proposed data-driven methodology than with the standalone FARSITE model.

INVISIBLE LABOR FOR DATA: INSTITUTIONS, INFRASTRUCTURE, AND VIRTUAL SPACE

Americans are accustomed to a wide range of data collection in their lives: census, polls, surveys, user registrations, and disclosure forms. When logging onto the Internet, users’ actions are being tracked everywhere: clicking, typing, tapping, swiping, searching, and placing orders. All of this data is stored to create data-driven profiles of each user. Social network sites, furthermore, set the voluntarily sharing of personal data as the default mode of engagement. But people’s time and energy devoted to creating this massive amount of data, on paper and online, are taken for granted. Few people would consider their time and energy spent on data production as labor. Even if some people do acknowledge their labor for data, they believe it is accessory to the activities at hand. In the face of pervasive data collection and the rising time spent on screens, why do people keep ignoring their labor for data? How has labor for data been become invisible, as something that is disregarded by many users? What does invisible labor for data imply for everyday cultural practices in the United States? Invisible Labor for Data addresses these questions. I argue that three intertwined forces contribute to framing data production as being void of labor: data production institutions throughout history, the Internet’s technological infrastructure (especially with the implementation of algorithms), and the multiplication of virtual spaces. There is a common tendency in the framework of human interactions with computers to deprive data and bodies of their materiality. My Introduction and Chapter 1 offer theoretical interventions by reinstating embodied materiality and redefining labor for data as an ongoing process. The middle Chapters present case studies explaining how labor for data is pushed to the margin of the narratives about data production. I focus on a nationwide debate in the 1960s on whether the U.S. should build a databank, contemporary Big Data practices in the data broker and the Internet industries, and the group of people who are hired to produce data for other people’s avatars in the virtual games. I conclude with a discussion on how the new development of crowdsourcing projects may usher in the new chapter in exploiting invisible and discounted labor for data.

Structured Approaches for Exploring Interpersonal Relationships in Natural Language Text

Human relationships have long been studied by scientists from domains like sociology, psychology, literature, etc. for understanding people's desires, goals, actions and expected behaviors. In this dissertation we study inter-personal relationships as expressed in natural language text. Modeling inter-personal relationships from text finds application in general natural language understanding, as well as real-world domains such as social networks, discussion forums, intelligent virtual agents, etc. We propose that the study of relationships should incorporate not only linguistic cues in text, but also the contexts in which these cues appear. Our investigations, backed by empirical evaluation, support this thesis, and demonstrate that the task benefits from using structured models that incorporate both types of information. We present such structured models to address the task of modeling the nature of relationships between any two given characters from a narrative. To begin with, we assume that relationships are of two types: cooperative and non-cooperative. We first describe an approach to jointly infer relationships between all characters in the narrative, and demonstrate how the task of characterizing the relationship between two characters can benefit from including information about their relationships with other characters in the narrative. We next formulate the relationship-modeling problem as a sequence prediction task to acknowledge the evolving nature of human relationships, and demonstrate the need to model the history of a relationship in predicting its evolution. Thereafter, we present a data-driven method to automatically discover various types of relationships such as familial, romantic, hostile, etc. Like before, we address the task of modeling evolving relationships but don't restrict ourselves to two types of relationships. We also demonstrate the need to incorporate not only local historical but also global context while solving this problem. Lastly, we demonstrate a practical application of modeling inter-personal relationships in the domain of online educational discussion forums. Such forums offer opportunities for its users to interact and form deeper relationships. With this view, we address the task of identifying initiation of such deeper relationships between a student and the instructor. Specifically, we analyze contents of the forums to automatically suggest threads to the instructors that require their intervention. By highlighting scenarios that need direct instructor-student interactions, we alleviate the need for the instructor to manually peruse all threads of the forum and also assist students who have limited avenues for communicating with instructors. We do this by incorporating the discourse structure of the thread through latent variables that abstractly represent contents of individual posts and model the flow of information in the thread. Such latent structured models that incorporate the linguistic cues without losing their context can be helpful in other related natural language understanding tasks as well. We demonstrate this by using the model for a very different task: identifying if a stated desire has been fulfilled by the end of a story.

FLOW REGIME DRIVEN THERMAL ENHANCEMENT IN INTERNALLY-GROOVED TUBES

Internally-grooved refrigeration tubes maximize tube-side evaporative heat transfer rates and have been identified as a most promising technology for integration into compact cold plates. Unfortunately, the absence of phenomenological insights and physical models hinders the extrapolation of grooved-tube performance to new applications. The success of regime-based heat transfer correlations for smooth tubes has motivated the current effort to explore the relationship between flow regimes and enhanced heat transfer in internally-grooved tubes. In this thesis, a detailed analysis of smooth and internally-grooved tube data reveals that performance improvement in internally-grooved tubes at low-to-intermediate mass flux is a result of early flow regime transition. Based on this analysis, a new flow regime map and corresponding heat transfer coefficient correlation, which account for the increased wetted angle, turbulence, and Gregorig effects unique to internally-grooved tubes, were developed. A two-phase test facility was designed and fabricated to validate the newly-developed flow regime map and regime-based heat transfer coefficient correlation. As part of this setup, a non-intrusive optical technique was developed to study the dynamic nature of two-phase flows. It was found that different flow regimes result in unique temporally varying film thickness profiles. Using these profiles, quantitative flow regime identification measures were developed, including the ability to explain and quantify the more subtle transitions that exist between dominant flow regimes. Flow regime data, based on the newly-developed method, and heat transfer coefficient data, using infrared thermography, were collected for two-phase HFE-7100 flow in horizontal 2.62mm - 8.84mm diameter smooth and internally-grooved tubes with mass fluxes from 25-300 kg/m²s, heat fluxes from 4-56 kW/m², and vapor qualities approaching 1. In total, over 6500 combined data points for the adiabatic and diabatic smooth and internally-grooved tubes were acquired. Based on results from the experiments and a reinterpretation of data from independent researchers, it was established that heat transfer enhancement in internally-grooved tubes at low-to-intermediate mass flux is primarily due to early flow regime transition to Annular flow. The regime-based heat transfer coefficient outperformed empirical correlations from the literature, with mean and absolute deviations of 4.0% and 32% for the full range of data collected.