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Early-onset myopathies are genetically heterogeneous mendelian diseases. We have performed solo or trio whole exome sequencing (WES) in a cohort of 24 individuals with genetically undiagnosed early-onset myopathies from 21 families. We have identified single nucleotide variant (SNV) or copy number variants (CNV) in known genes in 52% of the patients. We contributed to the expansion of the phenotypic spectrum for two genes (TTN, TRIP4). In particular, through international collaborative efforts, we described the severe end of the phenotypic spectrum of congenital titinopathy. Fifteen cases, with biallelic TTN truncating or canonical splice site mutations, presented with severe in utero features and/or severe weakness and respiratory compromise at birth, leading to termination of pregnancy, neonatal death or survival with long term respiratory support. The presence of multiple congenital limb contractures, congenital long bone fracture and/or complete absence of muscle groups can be diagnostic clues. All severely affected patients that survived until birth had at least one mutation predicted to result in the production of at least some near-normal-length titin, a finding that seems to be essential for human in utero survival.WES also allowed us to identify three novel candidate genes (JAG2, R. U.). Through Matchmaker Exchange, we assembled a cohort of 23 individuals with undiagnosed muscular dystrophy from 13 unrelated families with rare homozygous or compound heterozygous variants in JAG2. Individuals with JAG2 variants had a wide spectrum of phenotypes and disease severity but the muscle MRI findings appear to be the unifying feature that helps to identify these patients. Transcriptome analysis in the muscle of two affected individuals suggests satellite cell depletion, a finding that is also present in other muscular dystrophies linked to the Notch pathway like POGLUT1 or MEGF10 related muscular dystrophies. If the implication of our three novel candidate genes is confirmed, the diagnostic yield in the cohort would increase to 67%. The zebrafish has been widely used to validate the implication of novel genes of myopathy, mostly with morpholino or mutated mRNA injections. As the specificity of morpholinos and mutated mRNA injections had been questioned, we have decided to use CRISPR-Cas9 to model loss-of-function or gain-of-function by creating knockout or knockin lines. We generated a knockout line for mtm1 and a knockin line for the S619L gain-of-function mutation in dnm2a because these mutations were associated with severe myopathic phenotypes in humans and had already been modeled in zebrafish with morpholino or mutated mRNA injections. In contrast to the severe phenotype of morpholino/mRNA injected fish, we did not observe any structural or functional defect in the muscle of mtm1 mutants and dnm2a mutants. Off-target effects of morpholino or mRNA injections as well as genetic compensation mechanisms in mutant lines are possible mechanisms explaining these discrepancies. The absence of phenotype in a zebrafish mutant line is not sufficient to rule out the implication of a gene in a human phenotype. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

A probability distribution is a statistical function that describes the probability of possible outcomes in an experiment or occurrence. There are many different probability distributions that give the probability of an event happening, given some sample size n. An important question in statistics is to determine the distribution of the sum of independent random variables when the sample size n is fixed. For example, it is known that the sum of n independent Bernoulli random variables with success probability p is a Binomial distribution with parameters n and p: However, this is not true when the sample size is not fixed but a random variable. The goal of this thesis is to determine the distribution of the sum of independent random variables when the sample size is randomly distributed as a Poisson distribution. We will also discuss the mean and the variance of this unconditional distribution.

A main objective of Departments of Transportation is to improve the safety of the roadways over which they have jurisdiction. Safety projects, such as cable barriers and raised medians, are utilized to reduce both crash frequency and crash severity. The efficacy of these projects must be evaluated in order to use resources in the best way possible. Five models are proposed for the evaluation of traffic projects: (1) a Bayesian Poisson regression model; (2) a hierarchical Poisson regression model building on model (1) by adding hyperpriors; (3) a similar model correcting for overdispersion; (4) a dynamic linear model; and (5) a traditional before-after study model. Evaluation of these models is discussed using various metrics including DIC. Using the models selected for analysis, it was determined that cable barriers are quite effective at reducing severe crashes and cross-median crashes on Utah highways. Raised medians are also largely effective at reducing severe crashes. The results of before and after analyses are highly valuable to Departments of Transportation in identifying effective projects and in determining which roadway segments will benefit most from their implementation.

It is estimated that one third of the world's population is infected with tuberculosis. Though once thought a "dead" disease, tuberculosis is very much alive. The rise of drug resistant strains of tuberculosis, and TB-HIV coinfection have made tuberculosis an even greater worldwide threat. While HIV, poverty, and public health infrastructure are historically assumed to affect the burden of tuberculosis, recent research has been done to implicate smoking in this list. This analysis involves combining data from multiple sources in order determine if smoking is a statistically significant factor in predicting the number of incident tuberculosis cases in a country. Quasi-Poisson generalized linear models and negative binomial regression will be used to analyze the effect of smoking, as well as the other factors, on tuberculosis incidence. This work will enhance tuberculosis control efforts by helping to identify new hypotheses that can be tested in future studies. One of the main hypotheses is whether or not smoking increases the number of tuberculosis cases above and beyond the effects of other factors that are known to influence tuberculosis incidence. These known factors include TB-HIV coinfection, poverty and public health infrastructure represented by treatment outcomes.

The Utah Department of Transportation (UDOT) Traffic and Safety Division continues to advance the safety of roadway sections throughout the state. To aid UDOT in meeting their goal the Department of Civil and Environmental Engineering at Brigham Young University (BYU) has worked with the Statistics Department in developing analysis tools for safety. The most recent of these tools has been the development of a hierarchical Bayesian Poisson Mixture Model (PMM) statistical model of traffic crashes and safety on UDOT roadways statewide and the integration of the results of this model in a Geographic Information System (GIS) framework. This research focuses on the enhancement of the framework for highway safety mitigation in Utah with its six primary steps: 1) network screening, 2) diagnosis, 3) countermeasure selection, 4) economic appraisal, 5) project prioritization, and 6) effectiveness evaluation. The framework was enhanced by developing a methodology for accomplishing the steps of network screening, diagnosis, and countermeasure selection. This methodology is titled, "Hot Spot Identification and Analysis." The hot spot identification and analysis methodology consists of the following seven steps: 1) identify problematic segments with safety concern, 2) identify problem spots within the segments, 3) micro analysis of problematic segments and spots, 4) defining the segment, 5) defining the problem, 6) evaluation of possible countermeasures, and 7) selection and recommendation of feasible countermeasures. The methodology is to help in the identification of hot spots with safety concerns so that they can be analyzed and countermeasures can be identified to mitigate the safety issues. Examples of how the methodology is to function are given with specific examples from Utah's state roadway network.

Företag förväntas idag ta ett större samhällsansvar jämfört med tidigare och utvecklingen går hela tiden framåt. Kraven från intressenterna ökar och hållbarhetsredovisning används som ett verktyg för att presentera hur företag arbetar med ekonomiska-, miljömässiga- och sociala aspekter. Hållbarhetsredovisning ett viktigt instrument för att skapa legitimitet gentemot intressenter, långsiktig lönsamhet och idag en lagstiftad nödvändighet för en väsentlig del av svenska företag. Det kom en ny lagstiftning gällande hållbarhetsredovisning 2017, men många svenska företag har frivilligt hållbarhetsredovisat tidigare än så. Med denna studie vill vi undersöka om en VD:s observerbara egenskaper och företags karakteristika kan ha en påverkan på när svenska företag frivilligt implementerat hållbarhetsredovisning. Utifrån ett valt referensår (år 2000) har tiden till implementering och antalet redovisade hållbarhetssidor studerats för att kunna förklara hur viktigt företag anser det vara att arbeta med hållbart företagande och redovisa resultatet för sina intressenter. Studien syftar till att skapa förståelse kring om det finns specifika företags karakteristika och observerbara egenskaper hos företagets VD som har påverkat hur lång tid det tagit innan de undersökta företagen implementerade hållbarhetsredovisning, samt hur mycket hållbarhetsinformation som redovisades. För att besvara studiens syfte har vi använt en kvantitativ metod och samlat in data från 63 svenska företag inom 15 olika branscher. Företagens årsredovisningar har studerats och data har samlats in rörande en VD:s observerbara egenskaper och företags karakteristika. De observerbara egenskaper som studien har avsett att undersöka är: kön, ålder, tid på posten och utbildning. Sedan har även avkastning på eget kapital, antalet anställda, omsättning och branschtillhörighet studerats, vilket utgör företags karakteristika i studien. I studien har en Poisson-regression använts och vi har funnit många intressanta samband mellan de undersökta variablerna. Det tar i genomsnitt fem år snabbare för ett företag med en manlig VD att implementera hållbarhetsredovisning gentemot företag med en kvinnlig VD, samt att det tar längre tid att implementera hållbarhetsredovisning om företaget har en VD som suttit längre tid på posten. Även antalet eftergymnasiala utbildningsår har visat sig ha en positiv inverkan på implementeringstiden och ett företag med en VD som har en längre utbildning har börjat hållbarhetsredovisa tidigare. Antal eftergymnasiala utbildningsår har även ett positivt samband med mängden hållbarhetsinformation som redovisats under företagens implementeringsår.Företag med en högre omsättning implementerade hållbarhetsredovisning tidigare än företag med en lägre omsättning och företag med en högre omsättning redovisar även fler antalet sidor under implementeringsåret. Även branschtillhörighet har visat sig ha en påverkan på både implementeringsåret samt antalet redovisade sidor det specifika året. Sammanfattningsvis kan det fastställas att både specifika observerbara egenskaper hos en VD och vissa företags karakteristika har en påverkan på både implementeringsåret och antalet redovisade sidor. Detta ger en tydlig indikering på hur viktigt olika företag i olika branscher tycker det är att arbeta med hållbart företagande och redovisa sina handlingar gentemot företagets intressenter.

In this Thesis we study two types of mechanical nonholonomic systems, namely systems with linear constraints and lagrangian with a linear term in the velocities, and nonholonomic systems with affine constraints and lagrangian without a linear term in the velocities. For the former type of systems we construct an almost-Poisson bracket using elements related to a riemannian metric induced by the kinetic energy, and we show that under certain conditions gauge momenta exist. For the latter type of systems, we focus on the ones possessing a \emph{Noether symmetry}. To everyone of these systems we associate an equivalent system of the former type, and we exhibit the procedure to relate them and their gauge momentum. As a test case for the theory, we analyze the system of a heavy ball rolling without slipping on a rotating surface of revolution: we elucidate that also in this framework the so-called Routh integrals are related to symmetries, we give conditions for boundedness of the motions. In the particular case the surface of revolution is an inverted cone we characterize the qualitative behavior of the motions.

Several truncated models for market weights are discussed. To summarize, the new truncated ordered stick breaking model introduced give restrictions on the ranks of the markets weights and show better fitting results for real data sets. / Thesis / Master of Science (MSc)

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