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.

A Visual Analytics Approach to Comparing Cohorts of Event Sequences

Sequences of timestamped events are currently being generated across nearly every domain of data analytics, from e-commerce web logging to electronic health records used by doctors and medical researchers. Every day, this data type is reviewed by humans who apply statistical tests, hoping to learn everything they can about how these processes work, why they break, and how they can be improved upon. To further uncover how these processes work the way they do, researchers often compare two groups, or cohorts, of event sequences to find the differences and similarities between outcomes and processes. With temporal event sequence data, this task is complex because of the variety of ways single events and sequences of events can differ between the two cohorts of records: the structure of the event sequences (e.g., event order, co-occurring events, or frequencies of events), the attributes about the events and records (e.g., gender of a patient), or metrics about the timestamps themselves (e.g., duration of an event). Running statistical tests to cover all these cases and determining which results are significant becomes cumbersome. Current visual analytics tools for comparing groups of event sequences emphasize a purely statistical or purely visual approach for comparison. Visual analytics tools leverage humans' ability to easily see patterns and anomalies that they were not expecting, but is limited by uncertainty in findings. Statistical tools emphasize finding significant differences in the data, but often requires researchers have a concrete question and doesn't facilitate more general exploration of the data. Combining visual analytics tools with statistical methods leverages the benefits of both approaches for quicker and easier insight discovery. Integrating statistics into a visualization tool presents many challenges on the frontend (e.g., displaying the results of many different metrics concisely) and in the backend (e.g., scalability challenges with running various metrics on multi-dimensional data at once). I begin by exploring the problem of comparing cohorts of event sequences and understanding the questions that analysts commonly ask in this task. From there, I demonstrate that combining automated statistics with an interactive user interface amplifies the benefits of both types of tools, thereby enabling analysts to conduct quicker and easier data exploration, hypothesis generation, and insight discovery. The direct contributions of this dissertation are: (1) a taxonomy of metrics for comparing cohorts of temporal event sequences, (2) a statistical framework for exploratory data analysis with a method I refer to as high-volume hypothesis testing (HVHT), (3) a family of visualizations and guidelines for interaction techniques that are useful for understanding and parsing the results, and (4) a user study, five long-term case studies, and five short-term case studies which demonstrate the utility and impact of these methods in various domains: four in the medical domain, one in web log analysis, two in education, and one each in social networks, sports analytics, and security. My dissertation contributes an understanding of how cohorts of temporal event sequences are commonly compared and the difficulties associated with applying and parsing the results of these metrics. It also contributes a set of visualizations, algorithms, and design guidelines for balancing automated statistics with user-driven analysis to guide users to significant, distinguishing features between cohorts. This work opens avenues for future research in comparing two or more groups of temporal event sequences, opening traditional machine learning and data mining techniques to user interaction, and extending the principles found in this dissertation to data types beyond temporal event sequences.