Computational genomics is at the intersection of computational applied physics, math, statistics, computer science and biology. With the advances in sequencing technology, large amounts of comprehensive genomic data are generated every year. However, the nature of genomic data is messy, complex and unstructured; it becomes extremely challenging to explore, analyze and understand the data based on traditional methods. The needs to develop new quantitative methods to analyze large-scale genomics datasets are urgent. By collecting, processing and organizing clean genomics datasets and using these datasets to extract insights and relevant information, we are able to develop novel methods and strategies to address specific genetics questions using the tools of applied mathematics, statistics, and human genetics. This thesis describes genetic and bioinformatics studies focused on utilizing and developing state-of-the-art computational methods and strategies in order to identify and interpret de novo mutations that are likely causing developmental disorders. We performed whole exome sequencing as well as whole genome sequencing on congenital diaphragmatic hernia parents-child trios and identified a new candidate risk gene MYRF. Additionally, we found male and female patients carry a different burden of likely-gene- disrupting mutations, and isolated and complex patients carry different gene expression levels in early development of diaphragm tissues for likely-gene-disrupting mutations. To increase the power to detect risk genes and risk variants, we developed a deep neural network classifier called MVP to accurately predict the pathogenicity of missense variants. MVP implemented an advanced structure of ResNet model and based on two independent data sets, MVP achieved clearly better results in prioritizing pathogenic variants than other methods. Additionally, we studied the genetic connection between developmental disorders and cancer. We found that in developmental disorder patients predicted deleterious de novo mutations are more enriched in cancer driver genes than non cancer driver genes. A Hidden Markov Model was implemented to discover cancer somatic missense mutation hotspots and we demonstrated many cancer driver genes shared a similar mode of action in developmental disorders and caner. By improving ability to interpret missense mutations and leveraging cancer genomics data, we can improve risk gene inference in developmental disorders.

The purpose of this thesis is to determine assistive technology-based instructions in the area of Living for postsecondary education students with autism spectrum disorder and/ or intellectual and developmental disabilities for investigating the types of AT support in improving independent living skills. An electronic search was conducted using the following databases: ERIC (Education Source version), ERIC (EBSCO host version), ERIC (ProQuest version), PsycINFO, and Google Scholar. Seven peer-reviewed journals were searched between 2008 and 2018. The references identified and relevant articles were scanned to find additional relevant literature. Papers referring to an assistive-technology based intervention that targets the area of independent living and be taught within the postsecondary program were included. Participants were diagnosed with ASD and/ or IDD and were enrolled in a postsecondary program designed for individuals with developmental disabilities. Only single-case studies or experimental/quasi- experimental designed studies were included. A total of 155 articles were found. The references and abstracts were saved in Endnote reference manager software for the selection process. First, 19 duplicates were found and excluded. A selection process was then carried out with the remaining 136 articles. The articles were screened by title and abstract, and 32 articles were excluded. Subsequently, full-text screening was conducted, and eight peer-reviewed articles and two dissertations were left. To conclude, the types of assistive technology while teaching independent living skills to postsecondary students with disabilities were reported. The skills were taught by using assistive technology were diverse. Results indicated the positive effectiveness of using assistive technology-based instructional practices in teaching independent living skills.

Autism Spectrum Disorder is a developmental disability characterized by social, behavioral, and communicative impairments. A primary characteristic of Autism includes impairment in social skills. Along the same lines, praise, defined as approval or admiration, does not always function as a reinforcer for this population. One way to address the absence of a reinforcement effect for praise is to condition praise as a reinforcer. The literature on conditioned reinforcement encompasses many procedural variations that have been shown to increase the reinforcing value of neutral stimuli. One such variation relatively new to the conditioned reinforcement literature includes observational conditioning. With observational conditioning, initially neutral stimulus are established as reinforcers through observation of others receiving an initially neural stimulus, contingent on some response, while the same neutral stimulus is restricted to the observer for engagement the same response. Few component analyses of observational conditioning procedures have been conducted. Identification of its key aspects and further clarification of its generality will improve understanding of the effect and lead to more reliable clinical endpoints. Given this, and the need for procedures focused on conditioning praise as a reinforcer for individuals with Autism, the purpose of the current proposal was twofold. The purpose of Study 1 was to compare the effects of the observational conditioning procedure to observational conditioning plus response restriction in children diagnosed with Autism. The purpose of Study 2 was to assess the effects of observational conditioning plus response restriction to condition praise as a reinforcer in children diagnosed with Autism.

 Background and Objectives: ‘Neurodevelopmental disorders’ is often synonymously used with childhood developmental disorders such as autism spectrum disorder (ASD), however, increasingly new lines of evidence from genetics and epidemiology suggests having schizophrenia and bipolar disorder to be included as well. For example, there is a strong tendency for schizophrenia and bipolar disorder to occur in people with ASD and shared aetiological factors such as prenatal infection and maternal vitamin D deficiency during pregnancy have all been linked with increased risks in all three conditions. To investigate into this, I have turned to brain imaging, a technique which has opened up a new horizon for neurobiologists. Typically, neuroimaging studies focus on one disorder, matching patients with healthy volunteers and compare their brain structures volumetric differences. On the other hand, such studies are limited by various factors including small ample size, low power, no psychiatric control group, and sample or design heterogeneity. Methods: To summarize all the data into a more meaningful biological representation, Anatomical Likelihood Estimation (ALE), a cutting edge meta-analytic approach was applied. The rationale behind ALE is that it identifies brain differences most consistently reported across studies, while filtering away differences that are least documented. In this thesis, a novel application of ALE known as “dual disorder ALE” is introduced, which serves to estimate the extent of brain regional differences implicated in either disorder – in other words, a method to quantify which areas of the brain are more likely to be affected by ASD, schizophrenia or bipolar disorder. Findings: The analysis is separated into two parts. First, dual disorder ALE technique was applied to investigate the relationship between ASD and first-episode schizophrenia. Data from 25 MRI studies was extracted comprising 660 participants (308 ASD, 352 schizophrenia) and 801 healthy controls. In ASD and FE schizophrenia, there were similar brain differences near the limbic-striato-thalamic circuitry, and distinctive brain differences including amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for ASD. In the second part comparing bipolar disorder and schizophrenia, data from 651 schizophrenic patients, 540 bipolar patients, and 1438 healthy controls was used, and matched one-to-one by pairing up bipolar disorder studies with corresponding schizophrenia studies to minimize confounders. The ALE result indicated that there are substantial overlaps across the two disorders, with schizophrenia having more extensive brain differences than bipolar disorder. Conclusions: Both parts of the analysis suggest that there are similar aetiological pressures affecting neurodevelopmental disorders including ASD, schizophrenia and bipolar disorder. / published_or_final_version / Psychiatry / Master / Master of Philosophy

The purpose of the current study was to evaluate the conditions under which resurgence of appropriate communicative responses (mands) would occur with children with developmental disabilities. The experimental preparation consisted of a sequence of conditions that included (a) the reinforcement of one mand (i.e., microswitch activation or card exchange) on a FR 1 schedule, (b) an extinction condition in which the mand was no longer reinforced, (c) the reinforcement of a second mand (i.e., microswitch activation or card exchange) on a FR 1 schedule, and (d) a test for resurgence of the first mand which consisted of placing the second mand on extinction. The results demonstrated resurgence of mands during 2 out of 3 tests for resurgence for one participant. Resurgence of mands was demonstrated during all three tests for resurgence with the second participant. / text

When assessing preferences of individuals with developmental disabilities, choices can be described vocally or presented using objects or pictures in preference assessments. For individuals who are unable to perform auditory-visual discriminations and visual identity matching, objects instead of pictures or vocalizations need to be used for preference assessments to be effective. Considering the practical advantages of using pictures over objects, recent research has begun to focus on identifying and teaching skills needed for picture preference assessments. Although object-to-picture, picture-to-object, and generalized matching have been implicated as possible skills needed for picture preference assessments, further systematic studies are needed. The present study examined the relation between preference assessments (object vs. picture groups) and 5 discrimination skills. Based on direct paired-stimulus preference assessments completed at the beginning of the study, participants who could indicate their preferences with objects, but not with picture or vocal presentation, were assigned to the Object Group (n = 11); and participants who could indicate their preferences with both objects and pictures, but not vocal presentation, were assigned to the Picture Group (n = 9). The 5 discrimination tasks included: (a) object-picture matching and (b) its symmetry, picture-object matching; (c) generalized object-picture matching and (d) its symmetry, generalized picture-object matching; and (e) generalized identity picture-picture matching. All task stimuli were parts from everyday objects. Independent sample t-tests with Bonferroni correction showed that the percentages of correct responses were significantly higher in the Picture Group than in the Object Group on 4 of the 5 tasks (p < .01). Individual data showed that 8 of the 9 Picture Group participants met the pass criterion (80% or higher correct responses) on at least 1 discrimination task, with 6 participants passing 2 or more tasks. In contrast, only 1 of the 11 Object Group participants met the pass criterion on 1 discrimination task. The findings suggest that the effectiveness of picture preference assessments is not dependent on one specific discrimination, but possibly the ability to perform generalized matching.

Parents of children with developmental disabilities have been reported to experience higher levels of stress than parents of typically developing children. This stress has been found to lead to adverse effects for both parents and children. Respite has been found to be a buffer of stress in the short term. The objective of this study was to: determine the types of respite Saskatchewan parents are using; and examine the correlational relationship between formal and informal respite use and child behaviour concerns, child adaptive skills, and parental stress. Open-ended questions related to additional influences on respite use were also analyzed. The current study examined respite use in 26 parents in Saskatchewan who have children between the ages of 6 and 18 with a diagnosed developmental disability. The Respite Information Questionnaire (adapted from Preece & Jordon, 2007) was used to explore the types and hours of respite use, child behaviour concerns, and child adaptive needs. Parental stress levels were measured with the Parental Stress Scale (Berry & Jones, 1995). Descriptive statistics, correlations and Mann-Whitney U statistical tests were used to analyze data gathered from the questionnaire and Parental Stress Scale. Results from this research showed that Saskatchewan parents used a range of formal (e.g., care homes, trained individual respite providers) and informal respite (e.g., siblings, grandparents) both in type and hours of use. No relationship was found between formal and informal respite use and child adaptive skills or parental stress. A preliminary relationship between child behavioural concerns and stress was found, indicating that as child behavioural concerns increase so does formal respite use. However, a basic thematic analysis of open-ended questions showed that parents felt respite services were limited as a result of their child`s behavioral concerns. This suggests child behavioural concerns should be considered in respite policy and program development.

Background According to the Americans with Disabilities Act, an individual with a disability has a physical or mental impairment that substantially limits one or more major life activities (ADA, 2014). A large body of literature indicates a strong relationship between disability and poor health. Adults with disabilities are more likely to suffer from chronic conditions than adults with no limitations. Thus, this vulnerable population with disabilities should be targeted for health promotion efforts. Healthy People 2020 calls for the inclusion of people with disabilities in U.S. health promotion efforts (Dixon, 2014). According to the Center for Disease Control and Prevention (CDC), individuals with disabilities that begin during the developmental period and last throughout their lifetime causing impairment in physical, learning, language, or behavior areas, are defined as having developmental disabilities (DD) (CDC, 2014). Despite the increasing prevalence of DD in the US, there is little known about the association of DD and chronic health conditions such as obesity, cancer, hypertension and diabetes mellitus. Developmental disability can impact healthy eating habits and physical activity; thus, people living with DD are a vulnerable population at risk of becoming overweight and/or obese and developing a multitude of chronic diseases. Emerging research supports an association between childhood obesity and ASD, one type of DD, documenting that the problem of overweight/obesity in children with ASD is at least as common, if not higher, than in the general pediatric population (Curtin, Anderson, Must, & Bandini, 2010). Although there are some studies that document the association of chronic diseases and intellectual disability among adults (Bhaumik, Watson, Thorp, Tyrer, & McGrother, 2008; de Winter, Bastiaanse, Hilgenkamp, Evenhuis, & Echteld, 2012b; de Winter, Magilsen, van Alfen, Penning, & Evenhuis, 2009; Melville, Hamilton, Hankey, Miller, & Boyle, 2007; Morin, Merineau-Cote, Ouellette-Kuntz, Tasse, & Kerr, 2012; Reichard & Stolzle, 2011; Rimmer & Wang, 2005), limited research has examined whether adults diagnosed with DD are more likely to become obese or have other chronic diseases. This is increasingly important as most recent data suggest that approximately 1 in 6 children in the U.S. have been diagnosed with a DD, ranging from mild disabilities such as speech and language impairments to more pervasive DDs, such as intellectual disability, cerebral palsy, and autism spectrum disorder (ASD) (CDC, 2014). Based on the paucity of research examining the relationship between DDs, including ASD, and chronic diseases that emerge during adolescence and adulthood, the purpose of this study is to examine these relationships, and to provide information about the health status of children and adolescents with DDs as they transition into adulthood. In order to achieve this purpose, an evaluation project was adopted that examined a health promotion program for adults with DDs that aimed to improve or maintain current health status, increase knowledge about healthy food and exercise choices and improve overall health behavior of adults with DDs.

A self-instructional training manual for conducting a multiple-stimulus without replacement (MSWO) preference assessment procedure was evaluated. The manual describes the MSWO procedure and how to summarize and interpret its results. Review questions that highlighted the key target behaviours were included at the end of each section of the manual, followed by an answer key. The manual was compared to a method description, adapted from the method sections of research articles published by DeLeon and Iwata (1996) and Roscoe, Fisher, Glover, and Volkert (2006). Eighteen undergraduate university students were assigned to two groups using a matched-pairs random assignment for the first 10 participants and random assignment for the next eight participants. Group 1 received the manual training first, followed by a crossover to the method description training if the pre-determined mastery criterion (85% correct or higher) was not met during simulated assessments. Group 2 received the training procedures in reverse order. The self-instructional manual was statistically significantly more effective than the method description in improving performance accuracy for conducting the MSWO procedure with an actor (a graduate student) simulating a person with an intellectual disability. Four out of nine participants in Group 1 met the mastery criterion after studying the manual only and one participant achieved mastery after the crossover. In contrast, none of the nine participants in Group 2 met the mastery criterion after studying the method description only and seven participants achieved mastery after the crossover. The remaining six participants all met the mastery criterion after observing a live demonstration of the procedure. Within each group, interventions were implemented in a modified multiple-baseline design across participants and the results showed that improvements occurred only after an intervention had been introduced. All participants who achieved mastery showed strong retention and generalization performances with novel actors and clients. On the social validity questionnaire, mean participant ratings showed that the manual was easier to follow and understand, and provided the necessary information for the assessment compared with the method description. The self-instructional manual has considerable potential as a low cost and effective tool to teach individuals to conduct the MSWO procedure.

When assessing preferences of individuals with developmental disabilities, choices can be described vocally or presented using objects or pictures in preference assessments. For individuals who are unable to perform auditory-visual discriminations and visual identity matching, objects instead of pictures or vocalizations need to be used for preference assessments to be effective. Considering the practical advantages of using pictures over objects, recent research has begun to focus on identifying and teaching skills needed for picture preference assessments. Although object-to-picture, picture-to-object, and generalized matching have been implicated as possible skills needed for picture preference assessments, further systematic studies are needed. The present study examined the relation between preference assessments (object vs. picture groups) and 5 discrimination skills. Based on direct paired-stimulus preference assessments completed at the beginning of the study, participants who could indicate their preferences with objects, but not with picture or vocal presentation, were assigned to the Object Group (n = 11); and participants who could indicate their preferences with both objects and pictures, but not vocal presentation, were assigned to the Picture Group (n = 9). The 5 discrimination tasks included: (a) object-picture matching and (b) its symmetry, picture-object matching; (c) generalized object-picture matching and (d) its symmetry, generalized picture-object matching; and (e) generalized identity picture-picture matching. All task stimuli were parts from everyday objects. Independent sample t-tests with Bonferroni correction showed that the percentages of correct responses were significantly higher in the Picture Group than in the Object Group on 4 of the 5 tasks (p < .01). Individual data showed that 8 of the 9 Picture Group participants met the pass criterion (80% or higher correct responses) on at least 1 discrimination task, with 6 participants passing 2 or more tasks. In contrast, only 1 of the 11 Object Group participants met the pass criterion on 1 discrimination task. The findings suggest that the effectiveness of picture preference assessments is not dependent on one specific discrimination, but possibly the ability to perform generalized matching.