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-Aware Scheduling in Datacenters

Datacenters have emerged as the dominant form of computing infrastructure over the last two decades. The tremendous increase in the requirements of data analysis has led to a proportional increase in power consumption and datacenters are now one of the fastest growing electricity consumers in the United States. Another rising concern is the loss of throughput due to network congestion. Scheduling models that do not explicitly account for data placement may lead to a transfer of large amounts of data over the network causing unacceptable delays. In this dissertation, we study different scheduling models that are inspired by the dual objectives of minimizing energy costs and network congestion in a datacenter. As datacenters are equipped to handle peak workloads, the average server utilization in most datacenters is very low. As a result, one can achieve huge energy savings by selectively shutting down machines when demand is low. In this dissertation, we introduce the network-aware machine activation problem to find a schedule that simultaneously minimizes the number of machines necessary and the congestion incurred in the network. Our model significantly generalizes well-studied combinatorial optimization problems such as hard-capacitated hypergraph covering and is thus strongly NP-hard. As a result, we focus on finding good approximation algorithms. Data-parallel computation frameworks such as MapReduce have popularized the design of applications that require a large amount of communication between different machines. Efficient scheduling of these communication demands is essential to guarantee efficient execution of the different applications. In the second part of the thesis, we study the approximability of the co-flow scheduling problem that has been recently introduced to capture these application-level demands. Finally, we also study the question, "In what order should one process jobs?'' Often, precedence constraints specify a partial order over the set of jobs and the objective is to find suitable schedules that satisfy the partial order. However, in the presence of hard deadline constraints, it may be impossible to find a schedule that satisfies all precedence constraints. In this thesis we formalize different variants of job scheduling with soft precedence constraints and conduct the first systematic study of these problems.