VictorJuiz/thesis huggingface dataset:
Pure Likelihood-based Methods for Genetic Association Studies

In this thesis, we contribute to the growing literature on the Evidential methodology for genetic association studies. The Evidential Paradigm (EP) is an alternative statistical framework to the Frequentist and Bayesian paradigms for statistical inference, which uses likelihood ratios to measure the strength of statistical evidence. The EP has favorable operational characteristics, with small and bounded error probabilities, and the framework has been applied to genetic linkage and association studies. We discuss some of the well-recognized issues associated with the Frequentist framework in assessing association evidence in genetic association studies, and we develop novel approaches under the EP to address these issues. We first address the issue of prioritizing individual rare sequence variants within an associated region in case-control association studies. Rare variants are commonly ranked by Fisher's exact test p-values, however, depending on whether one- or two-sided p-values are used, the same set of rare variants can be ranked differently. Motivated by the EP, we propose a conditional likelihood ratio-based measure, maxLRc, to rank rare variants. We show analytically that the maxLRc is based on the same underlying model as Fisher's exact test, and it is always well-defined even when data is under separation. Through simulations, we show that the maxLRc outperforms the commonly used two-sided Fisher's exact p-values in most simulation settings. We then address another issue in large-scale genetic association studies: under the Frequentist paradigm, any small effect size could become statistically signicant with large enough sample size. We discuss an EP solution to this problem which extends the EP to accommodate composite hypotheses (EPc) and uses the generalized likelihood ratios (GLRs) to measure statistical evidence. To provide theoretical justication for the extension, we analytically derive the operational characteristics for the EPc. We show that the GLRs have small and bounded error probabilities for the Normal distribution and fixed-dimensional parametric models asymptotically. We show that the data can support either the null or the alternative hypothesis under the EPc, allowing association results to be more clearly demarcated; and the use of composite hypotheses can guard against statistically signicant but practically insignificant findings in large-scale association studies.

Advisor: Strug, Lisa
A Mechanism to Explain Repressive Epigenetic Memory Inheritance

Epigenetics describes heritable changes in gene expression that do not affect DNA sequence. Methylation of the histone tail can be associated with both gene activation and silencing. The Polycomb Repressive Complex 2 (PRC2) catalyzes the tri-methylation of H3K27 (H3K27me3) to create a repressive chromatin domain. A major question in the field concerns how epigenetic marks are transferred during DNA synthesis as these post-translational modifications cannot be duplicated by the replication machinery. A recent publication suggests a "self-maintenance" model of inheritance in which PRC2 travels with the replication fork through out S phase, coupling H3K27me3 transmission to replication fork progression. However, the exact mechanism and timing of PRC2 recruitment remains unknown. Our lab studies the regulation of interferon-Îł (IFNÎł) stimulated genes (ISGs) and our data indicate that PRC2 represses many ISGs. Furthermore, in an RNAi screen, we discovered that the histone chaperone CHAF1A, which facilitates nucleosome formation at replication forks, is required for maintenance of H3K27me3 marks and ISGs repression by PRC2. My data showed that PRC2 in fact localized to stable discrete foci during S phase and these foci coincide with replication forks primarily during early/mid S phase (S2/S3). Strikingly, with aniPOND, I found that H3K27 trimethylation also occurs during S2/S3. These observations argue against the current model of H3K27me3 inheritance. Knocking down CHAF1A rescues expression of many repressed PRC2 targets and disrupted the distribution of H3K27me3 without affecting the bulk levels. Interestingly, DNMT1 and DNA methylation patterns are also delocalized without CHAF1A, suggesting cross talk between the mechanisms that maintain DNA methylation and H3K27me3 during S phase. Collectively, results from this study furthered our current understanding regarding the timing of H3K27me3 transmission during S phase, and implicated a major role for CHAF1A in the propagation of repressive epigenetic memory by PRC2.

Keywords: aniPOND
Cell Cycle
CHAF1A
DNA Replication
Epigenetics
PRC2
Advisor: Bremner, Rod
Neurochemical Substrates of Asymmetrical Sleep in the Fur Seal

Several neuronal systems contribute to the generation and maintenance of sleep and waking. Knowledge pertaining to the neurotransmitters involved in sleep-wake regulation has been derived primarily from species that display bilaterally symmetric EEG states (e.g. cats, dogs, rats, and mice). However, these studies do not indicate which aspects of sleep these neurotransmitters are specifically linked to. Fur seals display both bilateral (BSWS) and asymmetrical sleep slow-wave sleep (ASWS); this unusual sleeping pattern provides a unique opportunity to determine which of the many physiological and neurochemical changes seen bilaterally in terrestrial mammals are linked to the cortical EEG changes and which may be linked to the motor and/or autonomic aspects of sleep. In studying this remarkable feature of the fur seal, we can dissociate the thalamocortical EEG activity in each hemisphere from aspects of behavioural state and study each independently as they relate to neurotransmitter release. The overall aim of my thesis was to examine, simultaneously in both hemispheres, the release of key neurotransmitters in the cortex across the sleep-wake cycle in the northern fur seal, and to specifically compare levels during BSWS and ASWS. In vivo microdialysis and high-performance liquid chromatography were used to monitor the release of neurotransmitters during polygraphically defined states. Neurotransmitters previously thought to contribute equally to the waking state, actually behave quite differently in a brain that is half awake and half asleep. Cortical acetylcholine (ACh) release was highly lateralized during ASWS, with greater release in the activated hemisphere, whereas cortical serotonin (5-HT), noradrenaline (NA), and histamine (HA) were symmetrically released during ASWS. Of the arousal systems studied so far, only ACh is involved in the lateralized cortical EEG activation manifested in asymmetric sleep. Bilaterally symmetric levels of the monoaminergic transmitters studied to date are compatible with interhemispheric EEG asymmetry. Findings suggest distinct functional roles for ACh, 5-HT, NA, and HA in the regulation of wakefulness, with respect to cortical activation and behavioural arousal.

Keywords: acetylcholine
asymmetrical sleep
cortical activation
fur seal
microdialysis
unihemispheric sleep
Advisor: Peever, John
Siegel, Jerome
Experimental Study of Turbulent Premixed Combustion in V-shaped Flames

Characteristics of turbulent premixed flames were investigated experimentally. The investigations were performed using Mie scattering, Particle Image Velocimetry, Rayleigh scattering, and broad-band luminosity imaging techniques. Methane-air flames associated with a relatively wide range of turbulence intensities, fuel-air equivalence ratios, and mean bulk flow velocities were investigated. For a relatively moderate value of turbulence intensity, a new concept is introduced and utilized to provide a detailed description associated with interaction of turbulent flow and flame front. The concept pertains to reactants velocity estimated at the vicinity of the flame front and is referred to as the edge velocity. Specifically, it is shown that fluctuations of the flame front position are induced by fluctuations of the edge velocity. For a relatively wide range of turbulence intensity, several characteristics of turbulent premixed flames, namely, front topology, brush thickness, surface density, and consumption speeds are investigated. For the first time, several flame front structures are identified and studied. It is shown that, due to formation of these front structures, the regime of turbulent premixed combustion transitions from the regime of counter-gradient diffusion to that of the gradient diffusion. In addition to these, a comprehensive study is performed to investigate influence of flame configuration on several flame front characteristics. It is obtained that, although changing the flame configuration influences several flame characteristics, the trends associated with the effects of governing parameters on the characteristics are nearly independent of the flame configuration.

Keywords: Fluid Mechanics
Turbulent Premixed Combustion
Advisor: Gülder, Ömer L.
Tripping the Flow past a Circular Cylinder: Use of Multiple Large-Scale Spanwise Protrusions

An experimental study is carried out to investigate if the collective influence of multiple spanwise tripwires fitted on a circular cylinder in subcritical flow can be correlated to the knowledge accumulated by previous studies on the influence of only one tripwire on its own. In an effort to explore this, the vortex shedding frequency, characteristics of the near wake flow topology, shear layer separation behaviour, and the strength and coherence of the von Kármán vortex shedding were determined for cylinders fitted with one, two, three, four, five, and eighteen spanwise tripwires using measurement techniques such as Particle Image Velocimetry (PIV), Constant Temperature Anemometry (CTA), and Hydrogen Bubble Flow Visualization. The single-wire tripping was selected as the baseline case because it is the simplest form of tripping, and much is known about its effects from previous studies. Based upon the effective range of angles from θt to θb, defined by Nebres and Batill (1992), four scenarios could be identified for a multi-wire fitted cylinder. If none of the tripwires of the multi-wire fitted cylinder were within this range, the cylinder was analogous to a smooth cylinder. If only one tripwire was within the θt to θb range, the flow around the multiple-wire fitted cylinder can be exactly inferred from the flow around the single-wire fitted cylinder. If two tripwires of the multi-wire fitted cylinder were within the θt to θb range, the Strouhal number could be inferred by considering an accumulative influence of both of the tripwires. The fundamental angles such as the first and the second critical angles could also be found for the multi-wire-fitted cases by considering the fundamental angles of the single-wire-fitted case. Here, the total amount of fluid available to be entrained in the shear layers needs to be considered to predict the near wake flow behaviour; which may cause a delay in the location of the first critical angle (θc1) in certain special circumstances. For the cases considered in the present study, when more than two tripwires are within the θt to θb range, the Strouhal number of the multi-wire fitted cylinders is similar to that of the smooth cylinder. In the last scenario, the whole cylindrical configuration needs to be considered at once rather than using the data from a single-wire fitted-cylinder to infer the properties of the flow.

Keywords: Cylinder flow
Flow control
protrusion devices
Tripwires
von Karman shedding
Vortex induced vibrations
Advisor: Ekmekci, Alis
Health Literate Discharge Practices in Ontario Hospitals

Health literate discharge practices meet the health literacy needs of patients and families at the time of hospital discharge. This dissertation used a mixed methods, sequential design to gain insight into the use of these practices in Ontario hospitals. The Health Literate Care Model was used to guide the first two studies. The first study used a Delphi panel to find the best indicators of health literate discharge practices, based on the indicators of Project RED (Re-Engineered Discharge). This led to the development of 36 indicators, which were contextualized to Ontario, and were used to create an organizational survey tool. This survey was administered to 143 hospitals in Ontario. There were 99 participants from 79 hospitals (participation rate 55%). Exploratory factor analysis was done and reliability of the survey was established. The third study used organizational learning theory to examine how acute care hospitals take on health literate discharge practices by interviewing managers, educators and front-line staff in 10 hospitals that participated in the survey. In the fourth study, multiple regression analysis was used to examine the relationship between organizational characteristics and use of health literate discharge practices, as determined by the survey results. Smaller hospital size was associated with greater use, and survey scores were found to be highest in the North region. A significant interaction was found between size and location. The development of the organizational survey tool could be used by researchers, hospitals and policy makers to measure and monitor the use of health literate discharge practices in Ontario hospitals. The results of the qualitative study offer insights into how organizational learning is used by hospital managers and leaders to adopt health literate discharge practices.

Keywords: care transitions
health literacy
hospital discharge
hospitals
Advisor: Barnsley, Jan
Berta, Whitney B
The Use of Susceptibility Effects for Tracking and Encoding in MR-guided Interventional Procedures

Magnetic Resonance Imaging (MRI) provides volumetric imaging with superior soft tissue contrast and is now standard-of-care for many diagnostic applications. A growing area is the use of MRI for minimally invasive procedures (a.k.a interventions) such as MRI-guided biopsy. In this thesis, the target procedure was placement of a drainage catheter in the upper urinary tract, the technical term for which is nephrostomy. Tracking and visualization of the interventional devices is crucial in achieving a successful outcome of the procedure. This thesis is a study of MRI methodologies to track interventional devices in MRI-guided procedures. A particular focus was the application of magnetic materials used to perturb the main magnetic field, an effect that was used to develop tools and techniques for tracking devices and making images at the device tip. The experiments in Chapter 2 led to the development of a new technique using spectrally selective excitation, which is capable of simultaneously measuring the location and orientation of an interventional device. In Chapter 3, a new mechanism for tracking is proposed based on the magneto-optical effect in nickel nanoparticles, where fiber optics were used to deliver photons from a near infrared (NIR) laser. This development is intended to enable the incorporation of small tracking devices attached to the interventional tools, which can be pulsed on and off using a laser waveform. In Chapter 4, magnetic materials have been used to generate spatial encoding fields at the tip of a device, to generate endoscopic MR images. These results have contributed to the development of tracking devices and to the advancement of MRI acquisition methods for passive tracking in MR-guided procedures, with an outlook towards clinical application in nephrostomy and beyond.

Keywords: Interventions
Magnetic susceptibility
MRI
Advisor: Cunningham, Charles H.
The Wandering Mind: A Philosophical Study of Thinking

Although mind-wandering occupies up to half of our waking thoughts, it is seldom discussed within philosophy. My dissertation proposes a new theory of mind-wandering as unguided attention, then uses mind-wandering to illuminate three general philosophical topics: mental action/activity, attention, and thinking. Chapter one identifies two core tasks for the philosophy of mind-wandering, which current theories cannot accomplish. First, we must resolve a puzzle: mind-wandering seems essentially passive, yet it is under the influence of our goals in a way that seems active. Second, we must distinguish mind-wandering from two antithetical forms of cognition: rumination (e.g. fixation on one’s distress) and absorption (e.g. engrossment in a line of reasoning). Chapter two proposes that mind-wandering is unguided attention. Roughly speaking, an individual’s attention is guided when she would feel pulled back, were she distracted. In contrast, a wandering attention drifts from topic to topic unchecked. I argue that mind-wandering is active in one way––it can be motivated––but passive in another––it is never guided. Furthermore, mind-wandering differs from rumination and absorption because the latter two are guided. Chapter three addresses a methodological problem about how to individuate mind-wandering. I argue that we needn’t individuate mind-wandering, because it is atelic. Because I distinguish telic from atelic attention, I elucidate core cases of attention and undermine Koralus’ recent theory of attention. Chapter four argues that mind-wandering is a rare choice point between agency-based and consciousness-based theories of attention, which should classify mind-wandering as attentive and as inattentive, respectively. I contend that each view contains part of the truth. Drawing on White (1964), I distinguish between spectator attention (focused consciousness), which becomes agent or patient attention when it is guided. Mind-wandering is a choice point because it is pure spectator attention. My final chapter argues that mind-wandering does not fit cleanly into dual process theory, since it is neither unconscious and automatic (Type 1) nor conscious and analytic (Type 2). To accommodate mind-wandering, we must enrich dual process theory in a novel way: we must distinguish Type 2 processes that are guided (e.g. reasoning, planning) from those that are unguided (e.g. mind-wandering, brainstorming).

Keywords: Attention
Daydreaming
Dual Process Theory
Mental Action
Mind-Wandering
Thinking
Advisor: Raffman, Diana
Thompson, Evan T
Hiring for Diversity: Changing the Face of Ontario's Teacher Workforce

Changing the face of Ontario’s teachers is a topic that draws both ardent support and profound criticism by those closest to school governance. It surfaces questions about teacher quality, student achievement, inequity, diversity, politics, public trust, the past, the present, and the future. In the centre are teachers applying for jobs, and principals making decisions about whom to hire, and why. Influencing these decisions are a number of elements that range from the rational procedures that underlie human resources management to the intuitive, difficult to define factors borne of principals’ experiences and perspectives on teacher excellence. This study attempts to examine the processes at play as principals go about hiring teachers for the specific purpose of diversifying the teacher complement in their schools. Despite pressure from public policy since the 1980s, movement towards greater diversity in the teacher workforce has been slow, showing only modest change while the ethno-racial diversity of Ontario’s large urban centres approaches or surpasses fifty percent. Surveys from nearly a quarter of the principals in District A (a large, suburban school district in the Greater Toronto Area) and follow-up interviews with ten of their colleagues provide data that reflect how principals position diversity relative to other teacher qualities when hiring, their understanding of policy intimating the need for more teachers from diverse backgrounds, and the internal and external hurdles they face when hiring teachers. The data also show that these factors do not often include dimensions of teachers’ diverse identities. This finding remains surprisingly consistent among principals across variables such as experience, the number of interviews they conduct, and the student diversity of their respective schools. Data collected from personal interviews, however, show more nuanced differences between principals’ hiring stories and reflect a strong, unresolved tension between a belief in the benefits of teachers from diverse backgrounds and the hiring decisions that manifest this belief. Of note: the vast majority of participants in both the survey and interviews self-identify as White European. As such, the data are interpreted as a representative sample of principals in District A, but also as the prevailing identity of those charged with hiring teachers.

Keywords: decision-making
diversity
hiring
Advisor: Ryan, James
Synthesis of New Nanocrystal Materials

Abstract Colloidal semiconductor nanocrystals (NCs) have sparked great excitement in the scientific community in last two decades. NCs are useful for both fundamental research and technical applications in various fields owing to their size and shape-dependent properties and their potentially inexpensive and excellent chemical processability. These NCs are versatile fluorescence probes with unique optical properties, including tunable luminescence, high extinction coefficient, broad absorption with narrow photoluminescence, and photobleaching resistance. In the past few years, a lot of attention has been given to nanotechnology based on using these materials as building blocks to design light harvesting assemblies. For instant, the pioneering applications of NCs are light-emitting diodes, lasers, and photovoltaic devices. Synthesis of the colloidal stable semiconductor NCs using the wet method of the pyrolysis of organometallic and chalcogenide precursors, known as hot-injection approach, is the chart-topping preparation method in term of high quality and monodisperse sized NCs. The advancement in the synthesis of these artificial materials is the core step toward their applications in a broad range of technologies. This dissertation focuses on exploring various innovative and novel synthetic methods of different types of colloidal nanocrystals, both inorganic semiconductors NCs, also known as quantum dots (QDs), and organic-inorganic metal halide-perovskite materials, known as perovskites. The work presented in this thesis focuses on pursuing fundamental understanding of the synthesis, material properties, photophysics, and spectroscopy of these nanostructured semiconductor materials. This thesis contains 6 chapters and conclusions. Chapters 1ď ­3 focus on introducing theories and background of the materials being synthesized in the thesis. Chapter 4 demonstrates our synthesis of colloidal linker-free TiO2/CdSe NRs heterostructures with CdSe QDs grown in the presence of TiO2 NRs using seededâ growth type colloidal injection approach. Chapter 5 explores a novel approach of directly synthesized CdSe NCs with electroactive ligands. The last Chapter focuses on a new class of perovskites. I describe my discovery of a (bottom-up) simple method to synthesize colloidally stable methyl ammonium lead halide perovskite nanocrystals seeded from high quality PbX2 NCs with a pre-targeted size. This chapter reports advances in preparation of both these materials (PbX2, and lead halide perovskite NCs).

Keywords: Nanocrystals
Perovskites
Quantum confinement
Quantum Dots
Semiconductors
Solar Energy
Advisor: Scholes, Gregory D
Winnik, Mitchell A