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While data generation has been, and will remain crucial to making scientific discoveries, our ability to analyze data has not been at par with data generation. Therefore, it is important to direct our efforts towards making sense of the data already produced. In this thesis, the harmonization of single nucleotide polymorphism (SNP) identifiers is investigated. Harmonization of SNP identifiers means having the same identifier for a SNP every time it occurs. Harmonizing SNP identifiers would allow the genetic data from different datasets to become comparable, which would allow re-purposing of existing datasets in public repositories. Genetic data helps in associating genetic alterations with disease and health. Genetic data is being generated at a rate faster than Moore’s law. With the intention of making generated data available to all researchers in the world, public repositories like the UK Biobank, European Genome-phenome archive (EGA), and database of Genotypes and Phenotypes (dbGaP) have been set up to host public data and disseminate it according to protocols established. The data in these repositories is from different time points, is generated using different genotyping arrays, and is submitted by researchers all over the world. This leads to a large degree of heterogeneity in the data. In order to make the most of the data, they need to be harmonized. The greater the overlap between two datasets, the easier it is to harmonize them. Thus, in order to assess the extent to which datasets can be harmonized, it is important to perform an overlap between them. SNPs are of most interest in genetic datasets. Because of the numerous kinds of identifiers a SNP may have, determining the number and identity of overlapping SNPs between datasets is challenging and increases in complexity with the number of comparisons (SNPs and datasets). There is no tool available to perform on-the-fly harmonization of SNP identifiers. The SNP Overlap Tool (SPOT) was designed to harmonize SNP identifiers using the SNP chromosomal locations, and subsequently calculate the overlap of SNPs between two datasets. It is a web-based tool, coded in Java programming language.

© 2014 WILEY PERIODICALS INC. Methylmalonyl CoA mutase (MUT) is an essential enzyme in propionate catabolism that requires adenosylcobalamin as a cofactor. Almost 250 inherited mutations in the MUT gene are known to cause the devastating disorder methylmalonic aciduria; however the mechanism of dysfunction of these mutations more than half of which are missense changes has not been thoroughly investigated. Here we examined 23 patient missense mutations covering a spectrum of exonic/structural regions clinical phenotypes and ethnic populations in order to determine their influence on protein stability using two recombinant expression systems and a thermostability assay and enzymatic function by measuring MUT activity and affinity for its cofactor and substrate. Our data stratify MUT missense mutations into categories of biochemical defects including (1) reduced protein level due to misfolding (2) increased thermolability (3) impaired enzyme activity and (4) reduced cofactor response in substrate turnover. We further demonstrate the stabilization of wild type and thermolabile mutants by chemical chaperones in vitro and in bacterial cells. This in depth mutation study illustrates the tools available for MUT enzyme characterization guides future categorization of further missense mutations and supports the development of alternative chaperone based therapy for patients not responding to current treatment.

Cell migration requires the coordination of adhesion site assembly and turnover. Canonical models for nascent adhesion formation postulate that integrin binding to extracellular matrix (ECM) proteins results in the rapid recruitment of cytoskeletal proteins such as talin and paxillin to integrin cytoplasmic domains. It is thought that integrin-talin clusters recruit and activate tyrosine kinases such as focal adhesion kinase (FAK). However, the molecular connections of this linkage remain unresolved. Our recent findings support an alternative model whereby FAK recruits talin to new sites of β1 integrin-mediated adhesion in mouse embryonic fibroblasts and human ovarian carcinoma cells. This is dependent on a direct binding interaction between FAK and talin and occurs independently of direct talin binding to β1 integrin. Herein, we discuss differences between nascent and mature adhesions, interactions between FAK, talin and paxillin, possible mechanisms of FAK activation and how this FAK-talin complex may function to promote cell motility through increased adhesion turnover.

Abstract There is increasing evidence showing that the accumulation of the amyloid-β (Aβ) peptide into extracellular plaques is a central event in Alzheimer's disease (AD). These abnormalities can be detected as lowered levels of Aβ42 in the cerebrospinal fluid (CSF) and are followed by increased amyloid burden on positron emission tomography (PET) several years before the onset of dementia. The aim of this study was to assess amyloid network topology in nondemented individuals with early stage Aβ accumulation, defined as abnormal CSF Aβ42 levels and normal Florbetapir PET (CSF+/PET−), and more advanced Aβ accumulation, defined as both abnormal CSF Aβ42 and Florbetapir PET (CSF+/PET+). The amyloid networks were built using correlations in the mean 18F-florbetapir PET values between 72 brain regions and analyzed using graph theory analyses. Our findings showed an association between early amyloid stages and increased covariance as well as shorter paths between several brain areas that overlapped with the default-mode network (DMN). Moreover, we found that individuals with more advanced amyloid accumulation showed more widespread changes in brain regions both within and outside the DMN. These findings suggest that amyloid network topology could potentially be used to assess disease progression in the predementia stages of AD.

OBJECTIVES: To describe all published articles that have conducted comparisons of model-based effectiveness and cost-effectiveness results in the field of vaccination. Specific objectives were to 1) describe the methodologies used and 2) identify the strengths and limitations of the studies. METHODS: We systematically searched MEDLINE and Embase databases for studies that compared predictions of effectiveness and cost-effectiveness of vaccination of two or more mathematical models. We categorized studies into two groups on the basis of their data source for comparison (previously published results or new simulation results) and performed a qualitative synthesis of study conclusions. RESULTS: We identified 115 eligible articles (only 5% generated new simulations from the reviewed models) examining the effectiveness and cost-effectiveness of vaccination against 14 pathogens (69% of studies examined human papillomavirus, influenza, and/or pneumococcal vaccines). The goal of most of studies was to summarize evidence for vaccination policy decisions, and cost-effectiveness was the most frequent outcome examined. Only 33%, 25%, and 3% of studies followed a systematic approach to identify eligible studies, assessed the quality of studies, and performed a quantitative synthesis of results, respectively. A greater proportion of model comparisons using published studies followed a systematic approach to identify eligible studies and to assess their quality, whereas more studies using new simulations performed quantitative synthesis of results and identified drivers of model conclusions. Most comparative modeling studies concluded that vaccination was cost-effective. CONCLUSIONS: Given the variability in methods used to conduct/report comparative modeling studies, guidelines are required to enhance their quality and transparency and to provide better tools for decision making.

Congenital amusia in its most common form is a disorder characterized by a musical pitch processing deficit. Although pitch is involved in conveying emotion in music, the implications for pitch deficits on musical emotion judgements is still under debate. Relatedly, both limited and spared musical emotion recognition was reported in amusia in conditions where emotion cues were not determined by musical mode or dissonance. Additionally, assumed links between musical abilities and visuo-spatial attention processes need further investigation in congenital amusics. Hence, we here test to what extent musical emotions can influence attentional performance. Fifteen congenital amusic adults and fifteen healthy controls matched for age and education were assessed in three attentional conditions: executive control (distractor inhibition), alerting, and orienting (spatial shift) while music expressing either joy, tenderness, sadness, or tension was presented. Visual target detection was in the normal range for both accuracy and response times in the amusic relative to the control participants. Moreover, in both groups, music exposure produced facilitating effects on selective attention that appeared to be driven by the arousal dimension of musical emotional content, with faster correct target detection during joyful compared to sad music. These findings corroborate the idea that pitch processing deficits related to congenital amusia do not impede other cognitive domains, particularly visual attention. Furthermore, our study uncovers an intact influence of music and its emotional content on the attentional abilities of amusic individuals. The results highlight the domain-selectivity of the pitch disorder in congenital amusia, which largely spares the development of visual attention and affective systems.

Due to scientific and technological advancements, investigations in modern medicine are producing more measurement data than ever before. Since a large amount of information exists, and it is also being produced at ever-increasing rates, no single person can digest all current knowledge of diseases. Data collected from large patient cohorts may contain valuable knowledge of diseases, which could be useful to clinicians when making diagnoses or choosing treatments. Making use of the large volumes of data in clinical decision-making requires ancillary help from information technologies, but such systems have not yet become widely available. This thesis addresses the challenge by proposing a computer-based decision support method that is suited to clinical use. This thesis presents the Disease State Index (DSI), a supervised machine learning method intended for the analysis of patient data. The DSI comprehensively compares patient data with previously diagnosed cases with or without a disease. Based on this comparison, the method provides an estimate of the state of disease progression in the patient. Interpreting the DSI is made possible by its visual counterpart, the Disease State Fingerprint (DSF), which allows domain experts to gain a comprehensive view of patient data and the state of the disease at a quick glance. In the design and development of these methods, both performance and applicability in clinical use were taken into account equally. Alzheimer's disease (AD) is a slowly progressing neurodegenerative disease and one of the largest social and economic burdens in the world today, and it will continue to be so in the future. Studies with large patient cohorts have significantly improved our knowledge of AD during the last decade. This information should be made extensively available at memory clinics to maximize the benefits for diagnostics and treatment of the disease. The DSI and DSF methods proposed in this thesis were studied in the early diagnosis of AD and as a measure of disease progression in six original publications. The methods themselves and their implementation within a clinical decision support system, the PredictAD tool, were quantitatively evaluated with regard to their performance and potential benefits in clinical use. The results show that the methods and clinical decision support tool based on these methods can be used to follow disease progression objectively and provide earlier diagnoses of AD. These, in turn, could improve treatment efficacy due to earlier interventions and make drug trials more efficient by allowing better patient selection.

Rationale: Critical illness survivors often experience permanent functional disability due to intensive care unit (ICU)-acquired weakness. The mechanisms responsible for long-term weakness persistence versus resolution are unknown. Objectives: To delineate cellular mechanisms underlying long-term weakness persistence in ICU survivors. Methods: We conducted a nested, prospective study of critically ill patients mechanically ventilated for 7 days or longer. The patients were recruited from the RECOVER program and serially assessed over 6 months after ICU discharge. Twenty-seven of 82 patients consented to participate; 15 and 11 patients were assessed at 7 days and 6 months after ICU discharge, respectively. Measurements and Main Results: We assessed motor functional capacity, quadriceps size, strength, and voluntary contractile capacity and performed electromyography, nerve conduction studies, and vastus lateralis biopsies for histologic, cellular, and molecular analyses. Strength and quadriceps cross-sectional areas were decreased 7 days after ICU discharge. Weakness persisted to 6 months and correlated with decreased function. Quadriceps atrophy resolved in 27% patients at 6 months. Muscle mass reconstitution did not correlate with resolution of weakness, owing to persistent impaired voluntary contractile capacity. Compared with Day 7, increased ubiquitin proteasome system mediated muscle proteolysis, inflammation, and decreased mitochondrial content all normalized at 6 months. Autophagy markers were normal at 6 months. Patients with sustained atrophy had decreased muscle progenitor (satellite) cell content. Conclusions: Long-term weakness in ICU survivors results from heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity. These findings are not explained by ongoing muscle proteolysis, inflammation, or diminished mitochondrial content. Sustained muscle atrophy is associated with decreased satellite cell content and compromised muscle regrowth, suggesting impaired regenerative capacity.

Lyne Lalonde,1–4 Manon Choinière,3,5 Elisabeth Martin,3 Lise Lévesque,3 Éveline Hudon,2,3,6 Danielle Bélanger,2 Sylvie Perreault,1,7 Anaïs Lacasse,8 Marie-Claude Laliberté1,9 1Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada; 2Équipe de recherche en soins de première ligne, Centre de santé et de services sociaux de Laval, Laval, QC, Canada; 3Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; 4Sanofi Aventis Endowment Chair in Ambulatory Pharmaceutical Care, Faculty of Pharmacy, Université de Montréal and Centre de santé et de services sociaux de Laval, QC, Canada; 5Department of Anesthesiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; 6Department of Family Medicine and Emergency, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; 7Sanofi Aventis Endowment Chair in Drug Utilization, Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada; 8Département des sciences de la santé, Université du Québec en Abitibi-Témiscamingue, Rouyn-Noranda, QC, Canada; 9AbbVie Corporation, St-Laurent, QC, Canada Purpose: There is evidence that the management of chronic non-cancer pain (CNCP) in primary care is far from being optimal. A 1-day workshop was held to explore the perceptions of key actors regarding the challenges and priority interventions to improve CNCP management in primary care. Methods: Using the Chronic Care Model as a conceptual framework, physicians (n=6), pharmacists (n=6), nurses (n=6), physiotherapists (n=6), psychologists (n=6), pain specialists (n=6), patients (n=3), family members (n=3), decision makers and managers (n=4), and pain researchers (n=7) took part in seven focus groups and five nominal groups. Results: Challenges identified in focus group discussions were related to five dimensions: knowledge gap, “work in silos”, lack of awareness that CNCP represents an important clinical problem, difficulties in access to health professionals and services, and patient empowerment needs. Based on the nominal group discussions, the following priority interventions were identified: interdisciplinary continuing education, interdisciplinary treatment approach, regional expert leadership, creation and definition of care paths, and patient education programs. Conclusion: Barriers to optimal management of CNCP in primary care are numerous. Improving its management cannot be envisioned without considering multifaceted interventions targeting several dimensions of the Chronic Care Model and focusing on both clinicians and patients. Keywords: chronic pain, community-based participatory research, health service accessibility, patient-centered care, primary health care

Abstract Background When organismal phylogenies based on sequences of single marker genes are poorly resolved, a logical approach is to add more markers, on the assumption that weak but congruent phylogenetic signal will be reinforced in such multigene trees. Such approaches are valid only when the several markers indeed have identical phylogenies, an issue which many multigene methods (such as the use of concatenated gene sequences or the assembly of supertrees) do not directly address. Indeed, even when the true history is a mixture of vertical descent for some genes and lateral gene transfer (LGT) for others, such methods produce unique topologies. Results We have developed software that aims to extract evidence for vertical and lateral inheritance from a set of gene trees compared against an arbitrary reference tree. This evidence is then displayed as a synthesis showing support over the tree for vertical inheritance, overlaid with explicit lateral gene transfer (LGT) events inferred to have occurred over the history of the tree. Like splits-tree methods, one can thus identify nodes at which conflict occurs. Additionally one can make reasonable inferences about vertical and lateral signal, assigning putative donors and recipients. Conclusion A tool such as ours can serve to explore the reticulated dimensionality of molecular evolution, by dissecting vertical and lateral inheritance at high resolution. By this, we mean that individual nodes can be examined not only for congruence, but also for coherence in light of LGT. We assert that our tools will facilitate the comparison of phylogenetic trees, and the interpretation of conflicting data.