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.

Connecting the dots: Examining the role of parental beliefs and preschoolers’ affect and engagement in predicting parent-child number exploration during a meaningful math experience

The current study examined the frequency and quality of how 3- to 4-year-old children and their parents explore the relations between symbolic and non-symbolic quantities in the context of a playful math experience, as well as the role of both parent and child factors in this exploration. Preschool children’s numerical knowledge was assessed while parents completed a survey about the number-related experiences they share with their children at home, and their math-related beliefs. Parent-child dyads were then videotaped playing a modified version of the card game War. Results suggest that parents and children explored quantity explicitly on only half of the cards and card pairs played, and dyads of young children and those with lower number knowledge tended to be most explicit in their quantity exploration. Dyads with older children, on the other hand, often completed their turns without discussing the numbers at all, likely because they were knowledgeable enough about numbers that they could move through the game with ease. However, when dyads did explore the quantities explicitly, they focused on identifying numbers symbolically, used non-symbolic card information interchangeably with symbolic information to make the quantity comparison judgments, and in some instances, emphasized the connection between the symbolic and non-symbolic number representations on the cards. Parents reported that math experiences such as card game play and quantity comparison occurred relatively infrequently at home compared to activities geared towards more foundational practice of number, such as counting out loud and naming numbers. However, parental beliefs were important in predicting both the frequency of at-home math engagement as well as the quality of these experiences. In particular, parents’ specific beliefs about their children’s abilities and interests were associated with the frequency of home math activities, while parents’ math-related ability beliefs and values along with children’s engagement in the card game were associated with the quality of dyads’ number exploration during the card game. Taken together, these findings suggest that card games can be an engaging context for parent-preschooler exploration of numbers in multiple representations, and suggests that parents’ beliefs and children’s level of engagement are important predictors of this exploration.