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Recent advances in multi-atlas based algorithms address many of the previous limitations in model-based and probabilistic segmentation methods. However, at the label fusion stage, a majority of algorithms focus primarily on optimizing weight-maps associated with the atlas library based on a theoretical objective function that approximates the segmentation error. In contrast, we propose a novel method—Autocorrecting Walks over Localized Markov Random Fields (AWoL-MRF)—that aims at mimicking the sequential process of manual segmentation, which is the gold-standard for virtually all the segmentation methods. AWoL-MRF begins with a set of candidate labels generated by a multi-atlas segmentation pipeline as an initial label distribution and refines low confidence regions based on a localized Markov random field (L-MRF) model using a novel sequential inference process (walks). We show that AWoL-MRF produces state-of-the-art results with superior accuracy and robustness with a small atlas library compared to existing methods. We validate the proposed approach by performing hippocampal segmentations on three independent datasets: (1) Alzheimer's Disease Neuroimaging Database (ADNI); (2) First Episode Psychosis patient cohort; and (3) A cohort of preterm neonates scanned early in life and at term-equivalent age. We assess the improvement in the performance qualitatively as well as quantitatively by comparing AWoL-MRF with majority vote, STAPLE, and Joint Label Fusion methods. AWoL-MRF reaches a maximum accuracy of 0.881 (dataset 1), 0.897 (dataset 2), and 0.807 (dataset 3) based on Dice similarity coefficient metric, offering significant performance improvements with a smaller atlas library (< 10) over compared methods. We also evaluate the diagnostic utility of AWoL-MRF by analyzing the volume differences per disease category in the ADNI1: Complete Screening dataset. We have made the source code for AWoL-MRF public at: https://github.com/CobraLab/AWoL-MRF.

The harms of youth homelessness are well described in the academic literature, but less is known about transitions into homelessness among at risk youth. Given the importance of preventing youth homelessness, and in particular, the first incidence of homelessness, quantitative and qualitative data from street involved youth in Vancouver were analyzed in order to determine significant factors associated with this transition and generate policy options for addressing this issue. Ultimately, this study recommends placing youth workers in secondary schools to support the academic and social development of at risk youth, as well as provide connections to appropriate community supports such as housing. This is the first known study to directly ask youth for their thoughts on how to prevent the first incidence of homelessness, and the results from this Capstone provides policy makers with opportunities for targeted interventions to address youth homelessness in Vancouver.

Osteoarthritis (OA) of the knee affects between 5.4% and 38% of older adults and this prevalence is increasing as the population ages and becomes more obese. As health costs rise, it is important to have accurate and cost-effective methods to assess knee OA and the risk for OA. One risk factor for progression of knee OA is lower extremity (LE) frontal-plane malalignment. The first goal of this thesis was to assess the suitability of knee radiographs and LE photographs for the estimation of frontal-plane LE alignment. In the first study, several versions of the femoral shaft-tibial shaft (FS-TS) angle, assessed from knee radiographs, were compared to the hip-knee-ankle (HKA) angle, assessed from full-length radiographs. We concluded that the FS-TS angle is not a recommended substitute for the HKA angle, because the association between the two measures differs depending on alignment, OA severity and the method of determining the FS-TS angle. In the second study, the hip-knee-ankle angle determined from a pelvis-to-ankle photograph (HKA-P) was assessed for its ability to estimate the HKA angle. The HKA-P angle was reliable and highly correlated to the HKA. It therefore shows promise as an accurate and cost-effective assessment tool for the estimation of LE alignment. Commonly-used grading scales for the severity of knee OA seen on a radiograph emphasize just one feature of OA; therefore the second goal of this thesis was to assess the psychometric properties of the unicompartmental osteoarthritis grade (UCOAG), a composite scale which grades several features of OA in the tibiofemoral (TF) compartment. In the third and fourth studies, the reliability, validity and sensitivity to change of the UCOAG scale was assessed and compared to two commonly-used scales (Kellgren-Lawrence and Osteoarthritis Research Society International joint space narrowing). The UCOAG scale showed moderate to excellent reliability. All three scales demonstrated comparable validity and sensitivity to change. The UCOAG is therefore recommended for the assessment of OA severity and change over time. This research provides evidence for the use of accurate and cost-effective measures to assess LE alignment using photographs, and TF OA severity using radiographs, for clinical assessment and research purposes.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10^−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Children and youth exposed to the child welfare system represent one of society’s most vulnerable populations. Compared to their peer group, too many youth exposed to the child welfare system in British Columbia experience elevated rates of homelessness, substance use, incarceration, unplanned pregnancies, poverty and underemployment, and both mental and physical health issues in early adulthood. Given these disparities, child welfare policy reform is needed to better assist youth in care, rectify lagging outcomes and facilitate successful transitions to independence throughout the province. This study employed a mixed methodology using quantitative data from a prospective cohort of illicit substance-using street youth, semi-structured qualitative interviews and a literature review. Findings from the quantitative analysis found that youth with a history of being in care were more likely to: be of Aboriginal ancestry; have been physically abused; have a parent that drank heavily or used illicit substances; not have completed high school; and have initiated hard drug-use at an earlier age. A range of policy options were developed and informed by various stakeholder groups and evaluated against a set of criteria. The outcome of these evaluations indicate that a portfolio of policies, including the provision of greater resources to kinship caregivers and extending foster care to 21 years old will have the greatest impact on improving outcomes for former government care youth. Moving towards expanding and extending independent living programs was also identified as a promising policy approach to improve outcomes for youth transitioning out of care.

The nuclear pore complex (NPC) is the sole bidirectional gateway for nucleocytoplasmic transport. Despite recent progress in elucidating the NPC symmetric core architecture, the asymmetrically decorated cytoplasmic face, essential for mRNA export and a hotspot for nucleoporin-associated diseases, has remained elusive. Here, we report a composite structure of the entire human cytoplasmic face obtained by combining biochemical reconstitution, crystal structure determination, docking into cryo-electron tomographic reconstructions, and physiological validation, accounting for a third of the NPC’s mass. Whereas an evolutionarily conserved ∼540 kDa hetero-hexameric cytoplasmic filament nucleoporin complex is anchored by species-specific motifs above the central transport channel, attachment of the pentameric NUP358 bundles depends on the double-ring arrangement of the coat nucleoporin complex. Our results and the predictive power of our composite structure provide a rich foundation for elucidating the molecular basis of mRNA export and nucleoporin diseases.

Rising global temperatures over the last decades have increased heat exposure among populations worldwide. An accurate estimate of the resulting impacts on human health demands temporally explicit and spatially resolved monitoring of near-surface air temperature (Ta). Neither ground-based nor satellite-borne observations can achieve this individually, but the combination of the two provides synergistic opportunities. In this study, we propose a two-stage machine learning-based hybrid model to estimate 1 × 1 km2 gridded intra-daily Ta from surface skin temperature (Ts) across the complex terrain of Israel during 2004–2016. We first applied a random forest (RF) regression model to impute missing Ts from the Moderate Resolution Imaging Spectroradiometer (MODIS) Aqua and Terra satellites, integrating Ts from the geostationary Spinning Enhanced Visible and InfraRed Imager (SEVIRI) satellite and synoptic variables from European Centre for Medium-Range Weather Forecasts' (ECMWF) ERA5 reanalysis data sets. The imputed Ts are in turn fed into the Stage 2 RF-based model to estimate Ta at the satellite overpass hours of each day. We evaluated the model's performance applying out-of-sample fivefold cross validation. Both stages of the hybrid model perform very well with out-of-sample fivefold cross validated R2 of 0.99 and 0.96, MAE of 0.42°C and 1.12°C, and RMSE of 0.65°C and 1.58°C (Stage 1: imputation of Ts, and Stage 2: estimation of Ta from Ts, respectively). The newly proposed model provides excellent computationally efficient estimation of near-surface air temperature at high resolution in both space and time, which helps further minimize exposure misclassification in epidemiological studies.

Background. Hepatitis C virus (HCV) coinfection occurs in 20–30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Purpose. To update national standards for management of HCV-HIV coinfected adults in the Canadian context with evolving evidence for and accessibility of effective and tolerable DAA therapies. The document addresses patient workup and treatment preparation, antiviral recommendations overall and in specific populations, and drug-drug interactions. Methods. A standing working group with HIV-HCV expertise was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published HCV antiviral data and update Canadian HIV-HCV Coinfection Guidelines. Results. The gap in sustained virologic response between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All coinfected individuals should be assessed for interferon-free, Direct Acting Antiviral HCV therapy. Regimens vary in content, duration, and success based largely on genotype. Reimbursement restrictions forcing the use of pegylated interferon is not acceptable if optimal patient care is to be provided. Discussion. Recommendations may not supersede individual clinical judgement. Treatment advances published since December 2015 are not considered in this document.