Petri Net Siphon Analysis and Network Centrality Measures for Identifying Combination Therapies in Signaling Pathways

Aberrant behavior of biological signaling pathways has been implicated in diseases such as cancers. Therapies have been developed to target proteins in these networks in the hope of curing the illness or bringing about remission. However, identifying targets for drug inhibition that exhibit good therapeutic index has proven to be challenging since signaling pathways have a large number of components and many interconnections such as feedback, crosstalk, and divergence. Unfortunately, some characteristics of these pathways such as redundancy, feedback, and drug resistance reduce the efficacy of single drug target therapy and necessitate the employment of more than one drug to target multiple nodes in the system. However, choosing multiple targets with high therapeutic index poses more challenges since the combinatorial search space could be huge. To cope with the complexity of these systems, computational tools such as ordinary differential equations have been used to successfully model some of these pathways. Regrettably, for building these models, experimentally-measured initial concentrations of the components and rates of reactions are needed which are difficult to obtain, and in very large networks, they may not be available at the moment. Fortunately, there exist other modeling tools, though not as powerful as ordinary differential equations, which do not need the rates and initial conditions to model signaling pathways. Petri net and graph theory are among these tools. In this thesis, we introduce a methodology based on Petri net siphon analysis and graph network centrality measures for identifying prospective targets for single and multiple drug therapies. In this methodology, first, potential targets are identified in the Petri net model of a signaling pathway using siphon analysis. Then, the graph-theoretic centrality measures are employed to prioritize the candidate targets. Also, an algorithm is developed to check whether the candidate targets are able to disable the intended outputs in the graph model of the system or not. We implement structural and dynamical models of ErbB1-Ras-MAPK pathways and use them to assess and evaluate this methodology. The identified drug-targets, single and multiple, correspond to clinically relevant drugs. Overall, the results suggest that this methodology, using siphons and centrality measures, shows promise in identifying and ranking drugs. Since this methodology only uses the structural information of the signaling pathways and does not need initial conditions and dynamical rates, it can be utilized in larger networks.

Functional and Physiological Determinants of Perceived Disability in Individuals Diagnosed with Osteoarthritis of the Hip

Objectives: The main objective of this pilot study was to investigate which standardized functional and physiological test best predicted perceived disability in a single group of 21 individuals diagnosed with osteoarthritis of the hip. Design: Men and women between 60 and 70 years old with osteoarthritis of the hip were selected. If participants passed study criteria, the Western Ontario McMaster University questionnaire (WOMAC), 6 Minute Walk Test (6MWT) and Timed up and Go (TUG), strength testing and aerobic testing were obtained in one single assessment. Results: Regression analysis revealed that wait time, hip abduction strength of the affected side, Aerobic Capacity (VO2 Peak), hip Extension Peak Torque, hip Flexion Peak Torque, TUG and 6MWT were significantly correlated with the WOMAC. Yet, the 6MWT had the highest significant correlation (r = -0.86, p ≤ 0.0001); R2 = 0.75 or 75% with the WOMAC total scores, (r = -0.82, p ≤ 0.0001); R2 = 0.67 or 67% with the WOMAC function and (r = -0.60, p = .002); R2 = 0.36 or 36% with the WOMAC stiffness. While the VO2 Peak revealed the highest significant correlation (r = 0.76, p ≤ .0001); R2 = 0.57 or 57% with the WOMAC pain. Conclusions: The 6MWT and the VO2 Peak seem to be essential functional and physiological assessment tools to determine perceived disability in individuals with hip OA. The perceived disability may provide new or comprehensive knowledge of the disability problems experienced by individuals with osteoarthritis of the hip, and the association of patient perception with objective measures of functional and physiological capacity might strengthen the clinical value of this knowledge.

Examining Cognitive Processing in Children with an Arithmetic Disability

Currently there is no consensus as to the specific cognitive impairments that characterize mathematical disabilities (MD) or specific subtypes such as an arithmetic disability (AD). The present study sought to address this concern by examining cognitive processes that might undergird AD in children. The present study utilized archival data to conduct two investigations. The first investigation examined the executive functioning and working memory of children with AD. An age-matched achievement-matched design was employed to explore whether children with AD exhibit developmental lags or deficits in these cognitive domains. While children with AD did not exhibit impairments in verbal working memory or colour word inhibition, they did demonstrate impairments in shifting attention, visual-spatial working memory, and quantity inhibition. As children with AD did not perform more poorly than their younger achievement-matched peers on any of these tasks, impairments in specific areas of executive functioning and working memory appeared to reflect a developmental lag rather than a cognitive deficit. The second study examined the phonological processing performance of children with AD compared to children with comorbid disabilities in arithmetic and word recognition (AD/WRD) and to typically achieving (TA) children. Results indicated that, while children with AD did demonstrate impairments on all isolated naming speed tasks, trail making digits, and memory for digits, they did not demonstrate impairments on measures of phonological awareness, nonword repetition, serial processing speed, or serial naming speed. In contrast, children with AD/WRD demonstrated impairments on measures of phonological awareness, phonological short-term memory, isolated naming speed, serial processing speed, and the alphabet a-z task. Overall, results suggested that phonological processing impairments are more prominent in children with a WRD than children with an AD. Together, these studies further our understanding of the nature of the cognitive processes that underlie AD by focusing upon rarely used methods (i.e., age-matched achievement-matched design) and under-examined cognitive domains (i.e., phonological processing).

Self-efficacy in depression: Bridging the gap between competence and real-world functioning

Background: Depression is the largest contributing factor to years lost to disability, and symptom remission does not always result in functional improvement. Comprehensive analysis of functioning requires investigation both of the competence to perform behaviours, as well as actual performance in the real world. Further, two independent domains of functioning have been proposed: adaptive (behaviours conducive to daily living skills and independent functioning) and interpersonal (behaviours conducive to the successful initiation and maintenance of social relationships). To date, very little is known about the relationship between these constructs in depression, and the factors that may play a key role in the disparity between competence and real-world performance in adaptive and interpersonal functioning. Purpose: This study used a multidimensional (adaptive and interpersonal functioning), multi-level (competence and performance) approach to explore the potential discrepancy between competence and real-world performance in depression, specifically investigating whether self-efficacy (one’s beliefs of their capability to perform particular actions) predicts depressed individuals’ underperformance in the real world relative to their ability. A comparison sample of healthy participants was included to investigate the level of depressed individuals’ impairment, across variables, relative to healthy individuals. Method: Forty-two participants with depression and twenty healthy participants without history of, or current, psychiatric illness were recruited in the Kingston, Ontario community. Competence, self-efficacy, and real-world functioning all in both adaptive and interpersonal domains, and symptoms were assessed during a single-visit assessment. Results: Relative to healthy individuals, depressed individuals showed significantly poorer adaptive and interpersonal competence, adaptive and interpersonal functioning, and significantly lower self-efficacy for adaptive and interpersonal behaviours. Self-efficacy significantly predicted functional disability both in the domain of adaptive and interpersonal functioning. Interpersonal self-efficacy accounted for significant variance in the discrepancy between interpersonal competence and functioning. Conclusions: The current study provides the first data regarding relationships among competence, functioning, and self-efficacy in depression. Self-efficacy may play an important role in the deployment of functional skills in everyday life. This has implications for therapeutic interventions aimed at enhancing depressed individuals’ engagement in functional activities. There may be additional intrinsic or extrinsic factors that influence the relationships among competence and functioning in depression.

Understanding and Developing Parental Involvement In My School

In the early years of the current decade, I spearheaded my school's and school board's participation in a research program on parental involvement led by Kenneth Leithwood from the Ontario Institute for Students in Education (OISE) at the University of Toronto. Despite all the extensive work I did as part of this research program and the ongoing professional reading I have done with respect to parental involvement and engagement, I have yet to share fully the knowledge gained with my staff or our parent community. Therefore, this purpose of this master's project is to provide a means for such dissemination. To do so, I have created two parallel presentations/workshops: one for staff during out first professional development day in September and one for parents at their second Parent Council meeting in October. The final chapter moves beyond these workshops to allow me to reflect on the progress made to date with parental engagement in my school and to look forward toward where I as Principal hope to lead my school community in the future.

The Comparative Effectiveness of EEG Biomarkers in Antidepressant Response and Illness Prediction in Major Depressive Disorder

Background: There is growing evidence that individual EEG differences may aid in classifying patients with major depressive disorder (MDD) and also help predict clinical response to antidepressant treatment. This study aims to compare the effectiveness of EEG frequency band power, alpha asymmetry and prefrontal theta cordance towards escitalopram response prediction and MDD diagnosis, in a multi-site initiative. Methods: Resting EEG (eyes open and closed) was recorded from 64 electrodes in 44 depressed patients and 20 healthy controls at baseline, 2 weeks post-treatment and 8 weeks post-treatment. Clinical response was measured as change from baseline MADRS of 50% or more. EEG measures were analyzed (1) at baseline (2) at 2 weeks post-treatment and (3) as an ‘‘early change” variable defined as change in EEG from baseline to 2 weeks post-treatment. Results: At baseline, responders exhibited greater absolute alpha power in the left hemisphere versus the right while non-responders showed the opposite. Responders further exhibited a cortical asymmetry of greater right relative to left activity in parietal areas. Groups also differed in baseline relative delta power with responders showing greater power in the right hemisphere versus the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to right and the opposite was noted for non-responders. The opposite pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reduction in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance. Absolute delta power helped distinguish MDD patients from healthy controls. Conclusions: Hemispheric asymmetries in the alpha and delta bands at pre-treatment baseline and at 2 weeks post-treatment have moderate to moderately strong predictive utility towards antidepressant treatment response. These findings have significant potential for improving clinical practice in psychiatry by eventually guiding clinical choice of treatments. This would greatly benefit patients awaiting relief from depressive symptoms as treatment optimization would help overcome problems associated with delayed recovery. Our results also indicate that resting EEG activity may have clinical utility in predicting MDD diagnosis.

Disability in the Digital Age: Reconfiguring Access, Inclusion and Equality

There is an abundance of research that examines disability and technology in the context of computers and the Internet, however few have examined disability and mobile devices. Also largely absent from existing literature are the voices of disabled people themselves. This dissertation draws upon science and technology studies (STS) and disability studies to address these gaps by conducting in-depth qualitative research that examines disabled people’s experiences using smartphones and tablets. At its core, this dissertation aims to provide insight on the following: 1) an understanding of how disability is perceived in the digital age and the subjective meanings of access, inclusion and equality; 2) the ways in which mobile devices impact the lived experience of disability; and 3) how perspectives in disability studies and STS can be applied to understand the relationship between the body, disability and technology. The empirical contribution of this research draws from participant diaries and interviews with disabled people, as well as from open-ended questionnaires completed by mobile app developers. The concept of ‘subjectivities of disability’ is introduced to refer to the uniquely personal and individual experience of disability. Findings reveal that mobile device use amongst disabled people redefines their subjectivities of disability through socio-technical interactions whereby disabled people use their devices in ways that are integrated into their everyday lives and positively shapes how they view themselves in relation to their experience of disability. The responses from app developers reveal that there is a place for disability in the mobile market and that disabled people play a key role in making apps accessible. The data suggests that mobile devices facilitate access, inclusion and equality by integrating the body in ways that recognize and accommodate diversity. The results furthermore make it clear that the interaction between disabled people and mobile devices takes on an embodied and social characteristic. This research concludes that both on an individual level and collectively, disabled people are engaging with digital artifacts in ways that promote agency and independence as well as reshaping how disability is experienced and perceived in the digital age.