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.

A rehabilitation intervention to promote physical recovery following intensive care: a detailed description of construct development, rationale and content together with proposed taxonomy to capture processes in a randomised controlled trial.

Background: increasing numbers of patients are surviving critical illness, but survival may be associated with a constellation of physical and psychological sequelae that can cause on going disability and reduced health-related quality of life. Limited evidence currently exists to guide the optimum structure, timing, and content of rehabilitation programmes. There is a need to both develop and evaluate interventions to support and expedite recovery during the post-ICU discharge period. This paper describes the construct development for a complex rehabilitation intervention intended to promote physical recovery following critical illness. The intervention is currently being evaluated in a randomised trial (ISRCTN09412438; funder Chief Scientists Office, Scotland). Methods: the intervention was developed using the Medical Research Council (MRC) framework for developing complex healthcare interventions. We ensured representation from a wide variety of stakeholders including content experts from multiple specialties, methodologists, and patient representation. The intervention construct was initially based on literature review, local observational and audit work, qualitative studies with ICU survivors, and brainstorming activities. Iterative refinement was aided by the publication of a National Institute for Health and Care Excellence guideline (No. 83), publicly available patient stories (Healthtalkonline), a stakeholder event in collaboration with the James Lind Alliance, and local piloting. Modelling and further work involved a feasibility trial and development of a novel generic rehabilitation assistant (GRA) role. Several rounds of external peer review during successive funding applications also contributed to development. Results: the final construct for the complex intervention involved a dedicated GRA trained to pre-defined competencies across multiple rehabilitation domains (physiotherapy, dietetics, occupational therapy, and speech/language therapy), with specific training in post-critical illness issues. The intervention was from ICU discharge to 3 months post-discharge, including inpatient and post-hospital discharge elements. Clear strategies to provide information to patients/families were included. A detailed taxonomy was developed to define and describe the processes undertaken, and capture them during the trial. The detailed process measure description, together with a range of patient, health service, and economic outcomes were successfully mapped on to the modified CONSORT recommendations for reporting non-pharmacologic trial interventions. Conclusions: the MRC complex intervention framework was an effective guide to developing a novel post-ICU rehabilitation intervention. Combining a clearly defined new healthcare role with a detailed taxonomy of process and activity enabled the intervention to be clearly described for the purpose of trial delivery and reporting. These data will be useful when interpreting the results of the randomised trial, will increase internal and external trial validity, and help others implement the intervention if the intervention proves clinically and cost effective.

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.

Searching for return: How Google search engine query data can beat the market

Throughout the last years technologic improvements have enabled internet users to analyze and retrieve data regarding Internet searches. In several fields of study this data has been used. Some authors have been using search engine query data to forecast economic variables, to detect influenza areas or to demonstrate that it is possible to capture some patterns in stock markets indexes. In this paper one investment strategy is presented using Google Trends’ weekly query data from major global stock market indexes’ constituents. The results suggest that it is indeed possible to achieve higher Info Sharpe ratios, especially for the major European stock market indexes in comparison to those provided by a buy-and-hold strategy for the period considered.

Exploring Hidden Coherent Feature Groups and Temporal Semantics for Multimedia Big Data Analysis

Thanks to the advanced technologies and social networks that allow the data to be widely shared among the Internet, there is an explosion of pervasive multimedia data, generating high demands of multimedia services and applications in various areas for people to easily access and manage multimedia data. Towards such demands, multimedia big data analysis has become an emerging hot topic in both industry and academia, which ranges from basic infrastructure, management, search, and mining to security, privacy, and applications. Within the scope of this dissertation, a multimedia big data analysis framework is proposed for semantic information management and retrieval with a focus on rare event detection in videos. The proposed framework is able to explore hidden semantic feature groups in multimedia data and incorporate temporal semantics, especially for video event detection. First, a hierarchical semantic data representation is presented to alleviate the semantic gap issue, and the Hidden Coherent Feature Group (HCFG) analysis method is proposed to capture the correlation between features and separate the original feature set into semantic groups, seamlessly integrating multimedia data in multiple modalities. Next, an Importance Factor based Temporal Multiple Correspondence Analysis (i.e., IF-TMCA) approach is presented for effective event detection. Specifically, the HCFG algorithm is integrated with the Hierarchical Information Gain Analysis (HIGA) method to generate the Importance Factor (IF) for producing the initial detection results. Then, the TMCA algorithm is proposed to efficiently incorporate temporal semantics for re-ranking and improving the final performance. At last, a sampling-based ensemble learning mechanism is applied to further accommodate the imbalanced datasets. In addition to the multimedia semantic representation and class imbalance problems, lack of organization is another critical issue for multimedia big data analysis. In this framework, an affinity propagation-based summarization method is also proposed to transform the unorganized data into a better structure with clean and well-organized information. The whole framework has been thoroughly evaluated across multiple domains, such as soccer goal event detection and disaster information management.

High body mass index is not a barrier to physical activity: Analysis of international rugby players' anthropometric data

Recent data indicate that levels of overweight and obesity are increasing at an alarming rate throughout the world. At a population level (and commonly to assess individual health risk), the prevalence of overweight and obesity is calculated using cut-offs of the Body Mass Index (BMI) derived from height and weight. Similarly, the BMI is also used to classify individuals and to provide a notional indication of potential health risk. It is likely that epidemiologic surveys that are reliant on BMI as a measure of adiposity will overestimate the number of individuals in the overweight (and slightly obese) categories. This tendency to misclassify individuals may be more pronounced in athletic populations or groups in which the proportion of more active individuals is higher. This differential is most pronounced in sports where it is advantageous to have a high BMI (but not necessarily high fatness). To illustrate this point we calculated the BMIs of international professional rugby players from the four teams involved in the semi-finals of the 2003 Rugby Union World Cup. According to the World Health Organisation (WHO) cut-offs for BMI, approximately 65% of the players were classified as overweight and approximately 25% as obese. These findings demonstrate that a high BMI is commonplace (and a potentially desirable attribute for sport performance) in professional rugby players. An unanswered question is what proportion of the wider population, classified as overweight (or obese) according to the BMI, is misclassified according to both fatness and health risk? It is evident that being overweight should not be an obstacle to a physically active lifestyle. Similarly, a reliance on BMI alone may misclassify a number of individuals who might otherwise have been automatically considered fat and/or unfit.

A Petrov-Galerkin method for a singularly perturbed ordinary differential equation with non-smooth data

In this paper, a singularly perturbed ordinary differential equation with non-smooth data is considered. The numerical method is generated by means of a Petrov-Galerkin finite element method with the piecewise-exponential test function and the piecewise-linear trial function. At the discontinuous point of the coefficient, a special technique is used. The method is shown to be first-order accurate and singular perturbation parameter uniform convergence. Finally, numerical results are presented, which are in agreement with theoretical results.