VictorJuiz/thesis huggingface dataset:
Essays on Child Mental Health: Estimating Diagnostic Errors, Latent Risk, and Long-term Trajectories

Understanding diagnostic decision-making for child mental illness is the central focus of my dissertation research. I combine multiple quasi-experimental methods and machine learning tools with novel individual-level tax and survey data linkages to explore these issues. Over three papers, I address several sources of diagnostic and treatment errors in child mental illness, stemming from school and home environments. In the first paper, I study how a child's school starting age generates over-diagnosis of ADHD in young-for-grade and male students and missed diagnoses in relatively older students, especially females. Importantly, I demonstrate that teacher special education training mitigates these age-based assessment errors. The second paper investigates multiple sources of under-and over-utilization of mental health care by combining a machine learning-derived mental health risk prediction with multiple exogenous changes in diagnosis and treatment likelihood. These changes include the effect of school starting age on diagnosis and the role of Quebec's pharmaceutical insurance plan expansion on treatment uptake. I identify that over-diagnosis may be driven by over-weighting externalized behaviours, which are more common in males. At the same time, I additionally find that removing out-of-pocket costs increases treatment rates, specifically for high-risk children. The final paper expands upon this work to understand the long-term trajectories of children with mental health issues and heterogeneous treatment effects at the population level. I find that measured gaps in educational attainment, social assistance receipt and income due to child mental illness persist well into adulthood. I find evidence that diagnosis and treatment worsen human capital outcomes like educational attainment and unemployment for low-risk individuals. Nevertheless, treatment can help close mental health-related socioeconomic inequalities, but only for very high-risk children. Together these papers outline the growing issue of mental illness in childhood and its long-term implications. They highlight the potential for diagnostic mistakes or misallocation of care and the role of new data-driven tools to alleviate some of these medical errors. In my concluding chapter, I highlight some of the strengths and limitations of machine learning tools for improving mental illness detection and treatment going forward and point towards critical work required to make these tools useful for clinical practice.

Keywords: Child Health
Diagnostic Error
Health Economics
Machine Learning
Mental Health
Advisor: Laporte, Audrey
The Involvement of Cortical Inhibition, Plasticity, and Excitability in the Neurobiology and Treatment of Late-Life Depression

Several lines of evidence indicate that the pathophysiology of depression includes altered inhibitory and excitatory neurotransmission in the cortex. Most studies to date, however, have focused on younger and mid-life adults with depression. Advancing age has widespread effects on the structure and function of the brain, and late-life depression is often characterized by unique clinical features, including executive dysfunction and high relapse rates. Thus, the pathophysiology of depression may differ in older adults. This work aimed to uncover how neurophysiological mechanisms driven by inhibitory and excitatory neurotransmission are involved in the pathophysiology and treatment of late-life depression. We combined single-pulse and paired-pulse transcranial magnetic stimulation (TMS) with electromyography to measure inhibition, plasticity, and excitability in the motor cortex of older adults with depression. TMS measures were collected prior to treatment initiation, and after 1 week and 12 weeks of treatment with venlafaxine. We also measured cognitive functioning pre-treatment, and depressive symptom severity pre- and post-treatment. We hypothesized that TMS measures would be abnormal in older adults with depression compared to healthy controls, and that these TMS measures would be associated with executive dysfunction and treatment outcomes in late-life depression. First, compared to younger healthy controls, we observed similar reductions in GABAA receptor-mediated cortical inhibition in older and younger adults with depression, and older healthy controls, suggesting overlapping cortical inhibition deficits in advancing age and depression across the lifespan. Second, we found a specific relationship between worse executive function and heightened cortical plasticity in older adults with depression. Third, cortical inhibition and plasticity were not found to change after 1 or 12 weeks of venlafaxine treatment, regardless of clinical response to treatment, suggesting that conventional pharmacotherapy may not target abnormalities in these motor cortical processes in late-life depression. Lastly, we demonstrated that pre-treatment single-pulse TMS measures of cortical excitability were predictive of response and non-response to venlafaxine treatment. Together, these findings highlight the importance of biological aging to the neurobiology of late-life depression, and clarify the unique roles that cortical inhibition, plasticity, and excitability each play in late-life depression pathophysiology, cognitive functioning, and treatment outcomes.

Keywords: Inhibitory neurotransmission
Late-life depression
Membrane excitability
Neuroplasticity
Transcranial magnetic stimulation
Venlafaxine
Advisor: Blumberger, Daniel M
Daskalakis, Zafiris J
Corrosion Behaviour of Electrodeposited Nanocrystalline Nickel (Ni) and Nickel-Iron (NiFe) Alloys Compared to their Polycrystalline Coarse-Grained Counterparts

The corrosion behaviour of electrodeposited nanocrystalline Ni, 85Ni-15Fe, 80Ni-20Fe and 45Ni-55Fe was assessed in sulfate electrolytes and compared to their coarse-grained counterparts. The effect of grain size reduction on the corrosion behaviour of Ni and NiFe alloys was minimal, in particular at increasingly oxidizing conditions (i.e. increased anodic potential, increased pH), whereby the contribution of sulfur impurities (present in higher concentration in the nanostructured materials) was minimized. The consideration of other microstructural factors, in addition to grain size reduction, was critical in the appropriate interpretation of the corrosion performance.In acidic sulfate electrolytes, similar active-passive-transpassive polarization behaviour was observed, regardless of grain size. Differences in the region of active dissolution (e.g. enhanced current densities, increased passivation potential) were ascribed to the effects of sulfur impurities rather than grain size reduction; the nanomaterials contained increased sulfur due to additives used during their electrodeposition. Once passive, slightly enhanced passive current densities were observed with grain size reduction and attributed to differences in their passive film, as characterized using parallel angle-resolved X-ray photoelectron spectroscopy (PARXPS) to obtain non-destructive depth profiles. Regardless of grain size, the passive film of NiFe alloys consisted of inner Ni and Fe oxides, and an outer Ni hydroxide, with the relative Ni:Fe ratio remaining stoichiometric, relative to the bulk alloy composition; however, thicker passive films formed on nanostructured NiFe, as well as a higher concentration of Ni³⁺ in the form of defective Ni oxide. The slightly enhanced passive current densities with grain size reduction observed in Ni-rich NiFe were attributed to the influence of a defective Ni oxide. The cathodic stability of the passive film (i.e. Flade potential) was similar regardless of grain size, with only a minor increase that could be ascribed to grain size effects, as assessed using open circuit potential decay. Grain size reduction also impacted the corrosion morphology, leading to a more uniform topology with finer roughness. During transpassive dissolution, grain size reduction in Ni resulted in the delocalization of corrosion attack, from localized intergranular (coarse-grained) to more uniform (nanocrystalline).

Keywords: Corrosion
Electrodeposition
Nanomaterials
Passivity
Polarization
XPS
Advisor: Erb, Uwe
Revised Subunit Order of Mammalian Septin Complexes Explains their in Vitro Polymerization Properties

Septins are GTP-binding cytoskeletal proteins conserved from yeast to man. In humans, there are 13 genes that fall into 4 subfamilies and it is thought that two copies of a member of each subfamily assemble in an ordered array into hexamers or octamers that serve as the building blocks for larger filaments. Crystallography studies predicted the order of the hexamers to be SEPT7-SEPT6-SEPT2-SEPT2-SEPT6-SEPT7, while other studies showed SEPT9 interacted with SEPT7, implying a place at the ends of octamers. SEPT9 has many isoforms raising the possibility that isoform expression might influence octamer polymerization. However, based on this septin organization, octamers and hexamers would not be expected to co-polymerize due to incompatible ends. Here I describe a septin purification procedure used to isolate hexamers and octamers of specific composition from mammalian cells. I show that octamers containing each isoform of SEPT9 polymerize similarly. BORGs have been identified as septin binding proteins via their BD3 homology domains, but their contribution to septin polymerization is not understood. Addition of the BD3 domain of BORG3 results in dramatic bundling of septins that distinguishes hexamers and octamers. Unexpectedly, I show that hexamers and octamers can co-polymerize and that the organization of the septin complexes is inverted from what was previously predicted. This revised septin organization is congruent with the organization and behaviour of yeast septins suggesting that their properties are more conserved than was previously thought.

Advisor: Trimble, William
Cellular and Molecular Mechanisms of Endothelial Dysfunction in Diabetic Cardiomyopathy

Type 2 diabetes (T2D) is associated with cardiac microvascular dysfunction, which is thought to contribute to the development of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms responsible for HFpEF remain unclear, and no effective diagnostics or main-stay treatments are available. To gain insight into biomarkers and disease mechanisms we measured the microRNA content of circulating extracellular vesicles (EVs) during pathogenesis in two animal models of T2D-associated HFpEF (i.e., obese mouse [Lepr-/-] and lean rat [Goto Kakizaki]). We found that miR-30d and miR-30e were increased prior to echocardiographic evidence of diastolic dysfunction in T2D mice, and they were also elevated in T2D rats with established diastolic dysfunction. These microRNAs may serve as biomarkers of cardiac microvascular dysfunction as they are upregulated in the endothelial cells (ECs) of the left ventricle of the heart, but not other organs. Furthermore, the miR-30 family is secreted in response to activation of senescence pathways, a characteristic feature of diabetic ECs. Assessment of pathways regulated by miR-30d/e revealed a large number of target genes involved in fatty acid biosynthesis and metabolism. Importantly, over-expression of miR-30e in ECs increased fatty acid oxidation and the production of reactive oxygen species, while inhibiting the miR-30 family decreased fatty acid oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to dramatically down-regulate the expression of eNOS, an important regulator of microvascular and cardiomyocyte function. Thus, miR-30d/e may represent early biomarkers of diastolic dysfunction that reflect altered fatty acid metabolism and microvascular dysfunction in the heart. Furthermore, the pathways regulated by miR-30 may represent therapeutic targets for diabetes-associated HFpEF.

Keywords: Diabetes
Diastolic dysfunction
Endothelial cell
Extracellular vesicles
microRNA
Microvasculature
Advisor: Fish, Jason E.
Secondary Prevention of Anal Cancer among Men living with HIV: Acceptability and Suitability of Anal Pap Cytology and HPV DNA Type Testing

The risk of anal cancer is magnitudes higher among men living HIV than the general population. To contribute to an evidence-base in support of anal cancer screening guidelines, this dissertation evaluates the acceptability of screening among men living with HIV and sets the foundation for work examining the suitability of anal cytology and HPV DNA type testing for screening this population. A sample of 1677 men living with HIV enrolled in the Ontario HIV Treatment Network Cohort study completed a questionnaire module on HPV, its associated diseases, and their prevention in 2016-2017. Three objectives examined acceptability of anal cancer screening by 1) quantifying prevalence of screening, 2) examining the role of past screening on beliefs and willingness to be screened, and 3) evaluating facilitators to screening, HPV knowledge and self-perceived risk for anal cancer. In this sample, disparities in anal cancer screening were observed, wherein men from some racialized groups and heterosexual men were less likely to have discussed screening or to have been screened. The vast majority (90%) of men, however, were willing to undergo screening in the future. Positive beliefs regarding screening were associated with higher willingness. Behavioural intention does not ensure uptake, however, and factors such as health literacy and perceived susceptibility can influence men’s participation. Half of the study sample were unaware of HPV and the majority (73%) felt they had no or low chance of getting anal cancer. Specific risk-focused knowledge was associated with higher perceptions of risk. Findings will inform community-led health literacy efforts to improve participation in anal cancer screening. The final objective provides methodological guidance for the analysis of screening studies when verification of screening results is not possible for all participants. This simulation study assessed the utility of statistical methods to account for verification bias that arises in these scenarios. Findings suggest multiple imputation may be most suitable for handling complex missing data scenarios common to screening studies. This work will inform the analysis of data from a forthcoming anal cancer screening study to determine the best algorithm by which to screen for anal cancer among men living with HIV.

Keywords: Anal cancer
Cancer screening
HIV
Human papillomavirus
Men living with HIV
Advisor: Burchell, Ann N
Raboud, Janet M
Optimization and Mechanistic Exploration of Intravenous Human Immunoglobulin G for Treatment of Traumatic Cervical Spinal Cord Injury

Spinal cord injury (SCI) causes devastating functional impairments and socioeconomic consequences for patients and family members. The pathology is characterized by an initial physical trauma which is amplified by secondary injury mechanisms including vascular and inflammatory processes. The blood-spinal cord-barrier (BSCB) consists of pericytes, astrocytes and endothelial cells, which collectively form the neurovascular unit (NVU). After SCI, a compromised BSCB enables peripheral immune cells to enter the injury site. This inflammatory response has polarizing effects. While immune cells are beneficial by secreting growth factors that promote regeneration after SCI, they also propagate injury when sterilizing the injured area. Thus, immunomodulation is becoming the preferred clinical intervention to immunosuppression when resolving neuroinflammation. Approved by regulatory authorities as an immunomodulatory therapy, intravenous human immunoglobulin G (IVIg) may be suitable for treating SCI. While prior work has suggested a possible beneficial role for IVIg in the treatment of acute SCI, the clinical translation of this work has been hindered by critical knowledge gaps including uncertainty around mechanism of action, the optimal dosing and the post-injury therapeutic window. Therefore, this thesis aims to use a clinically relevant rat model of SCI to provide insights into the optimal dose, therapeutic time window and mechanism of action. My work determined that the optimal therapeutic dose of IVIg is 2g/kg and that beneficial effects were maintained when administered up to 4 hours post-SCI. My work showed that IVIg binds to BSCB cells, strengthening the BSCB and reducing neutrophil infiltration at 24 hours post-SCI. This is associated with long-term motor and sensory recovery and spinal cord tissue preservation. Immunomodulatory effects mediated by IVIg (2g/kg) might be explained in two-fold, where human immunoglobulin G (hIgG) antagonizes neutrophil infiltration into the spinal cord by co-localizing with endothelial cell ligands that mediate neutrophil extravasation. Moreover, IVIg traffics neutrophils to the spleen by increasing expression of neutrophil chemoattractants in spleen and sera. In conclusion, this work demonstrates that IVIg might be a suitable treatment for SCI with potential for clinical translation. IVIg (2g/kg) enhances short-term and long-term benefits after SCI by modulating local and systemic neuroinflammatory cascades.

Keywords: Immunomodulation
Immunosuppression
Intravenous human immunoglobulin G
Neuroinflammation
Neutrophils
Spinal cord injury
Advisor: Fehlings, Michael
Structural properties of the human cerebral cortex in health and disease

In vivo magnetic resonance imaging (MRI) has shown profound structural differences in the human cerebral cortex – varying across regions – during development, aging, and in clinical conditions such as mental illness. The neurobiology underlying these MRI-derived structural variations remains largely unknown. Herein, we develop a novel bioinformatics approach to probe the underlying biological processes behind structural variations of the cerebral cortex by integrating single-cell and bulk transcriptomics with MRI-derived measures. This approach was first applied to a multi-modal dataset linking biophysical MR properties in cortical tissue, commonly used to index tissue microstructure, with shared and unique cellular elements of pyramidal neurons and oligodendrocytes. Then, using an independent dataset, we link microstructural change in the cerebral cortex during adolescence with intra-cortical myelination. Finally, this approach was used to probe the neurobiological and developmental origins of cortical thickness and surface area in psychiatric disorders. Group differences in cortical thickness were quantified in individuals with mental illness (n=28,321), namely attention-deficit/hyperactivity disorder (ADHD), autism spectrum (ASD), bipolar (BD), major depressive (MDD), obsessive-compulsive (OCD), and schizophrenia (SCZ). There was a shared profile in group differences of thickness among the six disorders and was associated with pyramidal-specific expression. Co-expression analysis of genes implicated in thickness differences revealed two clusters: a prenatal cluster involved in neurodevelopmental processes and 2) a postnatal cluster involved in synaptic activity/plasticity. Next, we investigated group differences in cortical surface area – a phenotype largely determined during gestation – in those with ADHD, ASD, BD, MDD, SCZ, and high psychopathology (n=27,359). Group differences in area were predominantly in transmodal association cortices, and associated with inter-regional profiles of fetal gene-expression specific to proliferative cells, namely radial glia and intermediate progenitor cells, and differentiated cells, namely excitatory neurons, endothelial and mural cells. We also show that these cell types intersect with genes associated with known pre-/perinatal risk factors for mental illness. Taken together, these findings support a model of mental illness, whereby deviations in neurodevelopment confer vulnerability later in life, and subsequent postnatal perturbations contribute to clinical manifestation. Ultimately, this body of work provides an analytical framework to explain variations within the human cerebral cortex.

Keywords: Cerebral cortex
Cortical thickness
cortical surface area
MRI
magnetic resonance imaging
Neurodevelopment
Psychiatry
Transcriptomics
Advisor: Paus, Tomas
Novel Operation and Maintenance Practices for Permeable Pavements

This thesis investigates several opportunities for operation and maintenance to improve the performance of permeable pavements by testing strategies to rejuvenate old pavements, improve winter stormwater quality, and enhance stormwater infiltration. Testing of pre-treatment maintenance followed by street sweeping on mature permeable interlocking concrete pavement parking lots in 2016 revealed that pre-treatment with pressure wash significantly improves the effectiveness of vacuum sweeping. Pavement age and usage were found to affect the restoration of surface infiltration significantly. Older pavements and high traffic areas were considerably more challenging to restore for both control and test groups. Power brushing gave inconclusive results across test groups. Chloride concentrations in surface runoff and zero-exfiltration permeable pavement effluent were measured between Jan 2016 to May 2017 and compared with concentration in runoff from a conventional asphalt pavement. Runoff from asphalt generated large spikes in chloride concentration over 21,800 mg/L. However, when combined with the flashier runoff hydrograph, these high instantaneous chloride levels, lasting a few hours, resulted in less exposure to elevated concentrations. Permeable pavements, in contrast, attenuated peak chloride concentrations during winter. Furthermore, chloride was retained only temporarily and flushed from the pavement reservoir during spring melt, suggesting that attenuated chloride release from permeable pavement effluent is unlikely throughout the summer or fall months. Smart adaptive operation of PICP underdrains was tested to increase stormwater infiltration on low permeability soils. This unique study is the first demonstration of ‘smart’ operations for permeable pavements. The three-year evaluation, 2016-2018, confirmed that extended detention of stormwater could allow permeable pavements to control and infiltrate excess stormwater run-on and increase the probability of managing extreme events in non-run-on situations. The study also noted that high volume reductions could be achieved even when low permeability soils are present on site. Overall, the thesis bridges the gap between theory and practice by guiding how to improve operation and maintenance techniques for permeable pavements. This research aims to benefit permeable pavement manufacturers, suppliers, and installers in Canada by highlighting opportunities to improve permeable pavements' environmental benefits and management practices.

Keywords: Chloride
low impact development
Maintenance
permeable pavement
PICP
Smart Infrastructure
Advisor: Drake, Jennifer