Characterizing Genetic Drivers of Lymphoma through High-Throughput Sequencing

The advent of next-generation sequencing, now nearing a decade in age, has enabled, among other capabilities, measurement of genome-wide sequence features at unprecedented scale and resolution.

In this dissertation, I describe work to understand the genetic underpinnings of non-Hodgkin’s lymphoma through exploration of the epigenetics of its cell of origin, initial characterization and interpretation of driver mutations, and finally, a larger-scale, population-level study that incorporates mutation interpretation with clinical outcome.

In the first research chapter, I describe genomic characteristics of lymphomas through the lens of their cells of origin. Just as many other cancers, such as breast cancer or lung cancer, are categorized based on their cell of origin, lymphoma subtypes can be examined through the context of their normal B Cells of origin, Naïve, Germinal Center, and post-Germinal Center. By applying integrative analysis of the epigenetics of normal B Cells of origin through chromatin-immunoprecipitation sequencing, we find that differences in normal B Cell subtypes are reflected in the mutational landscapes of the cancers that arise from them, namely Mantle Cell, Burkitt, and Diffuse Large B-Cell Lymphoma.

In the next research chapter, I describe our first endeavor into understanding the genetic heterogeneity of Diffuse Large B Cell Lymphoma, the most common form of non-Hodgkin’s lymphoma, which affects 100,000 patients in the world. Through whole-genome sequencing of 1 case as well as whole-exome sequencing of 94 cases, we characterize the most recurrent genetic features of DLBCL and lay the groundwork for a larger study.

In the last research chapter, I describe work to characterize and interpret the whole exomes of 1001 cases of DLBCL in the largest single-cancer study to date. This highly-powered study enabled sub-gene, gene-level, and gene-network level understanding of driver mutations within DLBCL. Moreover, matched genomic and clinical data enabled the connection of these driver mutations to clinical features such as treatment response or overall survival. As sequencing costs continue to drop, whole-exome sequencing will become a routine clinical assay, and another diagnostic dimension in addition to existing methods such as histology. However, to unlock the full utility of sequencing data, we must be able to interpret it. This study undertakes a first step in developing the understanding necessary to uncover the genomic signals of DLBCL hidden within its exomes. However, beyond the scope of this one disease, the experimental and analytical methods can be readily applied to other cancer sequencing studies.

Thus, this dissertation leverages next-generation sequencing analysis to understand the genetic underpinnings of lymphoma, both by examining its normal cells of origin as well as through a large-scale study to sensitively identify recurrently mutated genes and their relationship to clinical outcome.

Les IgG et les IgE spécifiques aux isocyanates chez les apprentis en carrosserie automobile à risque de développer de l'asthme professionnel

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

AUTO-RUINS. Thinks about automobile into the contemporary landscape

The article analyses the evolution of the representation of the automobile inserted in the natural and urban environment in the Contemporary Art, from the appearance of the first cars in the beginning of the 20th century until the present day. The text compares the diverse attitudes and analysis of some representative artists who have used the image of the machine in general and the car in particular in their aesthetic discourse, using as a conductive thread the metaphor of the life cycle (birth, growth, feeding, reproduction and death). It deals with the discovery, the development and the coexistence between human and the automobile and its interpretation as a basic element of the artistic work. The text connects the image of the automobile located in the contemporary industrial landscape utilizing the artist references who have integrated the car in their work inside the natural or artificial environment characteristic of each moment. At the same time, the article goes deeply into the relationship of romantic ruin and natural landscape and the evolution of the industrial and architectural modern environment, through the work of the artists who has used the car as an inhabitant of the landscape.

Status, trends and drivers of kelp forests in Europe: an expert assessment

A comprehensive expert consultation was conducted in order to assess the status, trends and the most important drivers of change in the abundance and geographical distribution of kelp forests in European waters. This consultation included an on-line questionnaire, results from a workshop and data provided by a selected group of experts working on kelp forest mapping and eco-evolutionary research. Differences in status and trends according to geographical areas, species identity and small-scale variations within the same habitat where shown by assembling and mapping kelp distribution and trend data. Significant data gaps for some geographical regions, like the Mediterranean and the southern Iberian Peninsula, were also identified. The data used for this study confirmed a general trend with decreasing abundance of some native kelp species at their southern distributional range limits and increasing abundance in other parts of their distribution (Saccharina latissima and Saccorhiza polyschides). The expansion of the introduced species Undaria pinnatifida was also registered. Drivers of observed changes in kelp forests distribution and abundance were assessed using experts’ opinions. Multiple possible drivers were identified, including global warming, sea urchin grazing, harvesting, pollutionand fishing pressure, and their impact varied between geographical areas. Overall, the results highlight major threats for these ecosystems but also opportunities for conservation. Major requirements to ensure adequate protection of coastal kelp ecosystems along European coastlines are discussed, based on the local to regional gaps detected in the study.

Status, trends and drivers of kelp forests in Europe: an expert assessment

A comprehensive expert consultation was conducted in order to assess the status, trends and the most important drivers of change in the abundance and geographical distribution of kelp forests in European waters. This consultation included an on-line questionnaire, results from a workshop and data provided by a selected group of experts working on kelp forest mapping and eco-evolutionary research. Differences in status and trends according to geographical areas, species identity and small-scale variations within the same habitat where shown by assembling and mapping kelp distribution and trend data. Significant data gaps for some geographical regions, like the Mediterranean and the southern Iberian Peninsula, were also identified. The data used for this study confirmed a general trend with decreasing abundance of some native kelp species at their southern distributional range limits and increasing abundance in other parts of their distribution (Saccharina latissima and Saccorhiza polyschides). The expansion of the introduced species Undaria pinnatifida was also registered. Drivers of observed changes in kelp forests distribution and abundance were assessed using experts’ opinions. Multiple possible drivers were identified, including global warming, sea urchin grazing, harvesting, pollutionand fishing pressure, and their impact varied between geographical areas. Overall, the results highlight major threats for these ecosystems but also opportunities for conservation. Major requirements to ensure adequate protection of coastal kelp ecosystems along European coastlines are discussed, based on the local to regional gaps detected in the study.

Historical comparisons reveal multiple drivers of decadal change of an ecosystem engineer at the range edge

Biogenic reefs are important for habitat provision and coastal protection. Long-term datasets on the distribution and abundance of Sabellaria alveolata (L.) are available from Britain. The aim of this study was to combine historical records and contemporary data to (1) describe spatiotemporal variation in winter temperatures, (2) document short-term and long-term changes in the distribution and abundance of S. alveolata and discuss these changes in relation to extreme weather events and recent warming, and (3) assess the potential for artificial coastal defense structures to function as habitat for S. alveolata. A semi-quantitative abundance scale (ACFOR) was used to compare broadscale, long-term and interannual abundance of S. alveolata near its range edge in NW Britain. S. alveolata disappeared from the North Wales and Wirral coastlines where it had been abundant prior to the cold winter of 1962/1963. Population declines were also observed following the recent cold winters of 2009/2010 and 2010/2011. Extensive surveys in 2004 and 2012 revealed that S. alveolata had recolonized locations from which it had previously disappeared. Furthermore, it had increased in abundance at many locations, possibly in response to recent warming. S. alveolata was recorded on the majority of artificial coastal defense structures surveyed, suggesting that the proliferation of artificial coastal defense structures along this stretch of coastline may have enabled S. alveolata to spread across stretches of unsuitable natural habitat. Long-term and broadscale contextual monitoring is essential for monitoring responses of organisms to climate change. Historical data and gray literature can be invaluable sources of information. Our results support the theory that Lusitanian species are responding positively to climate warming but also that short-term extreme weather events can have potentially devastating widespread and lasting effects on organisms. Furthermore, the proliferation of coastal defense structures has implications for phylogeography, population genetics, and connectivity of coastal populations.

Historical comparisons reveal multiple drivers of decadal change of an ecosystem engineer at the range edge

Biogenic reefs are important for habitat provision and coastal protection. Long-term datasets on the distribution and abundance of Sabellaria alveolata (L.) are available from Britain. The aim of this study was to combine historical records and contemporary data to (1) describe spatiotemporal variation in winter temperatures, (2) document short-term and long-term changes in the distribution and abundance of S. alveolata and discuss these changes in relation to extreme weather events and recent warming, and (3) assess the potential for artificial coastal defense structures to function as habitat for S. alveolata. A semi-quantitative abundance scale (ACFOR) was used to compare broadscale, long-term and interannual abundance of S. alveolata near its range edge in NW Britain. S. alveolata disappeared from the North Wales and Wirral coastlines where it had been abundant prior to the cold winter of 1962/1963. Population declines were also observed following the recent cold winters of 2009/2010 and 2010/2011. Extensive surveys in 2004 and 2012 revealed that S. alveolata had recolonized locations from which it had previously disappeared. Furthermore, it had increased in abundance at many locations, possibly in response to recent warming. S. alveolata was recorded on the majority of artificial coastal defense structures surveyed, suggesting that the proliferation of artificial coastal defense structures along this stretch of coastline may have enabled S. alveolata to spread across stretches of unsuitable natural habitat. Long-term and broadscale contextual monitoring is essential for monitoring responses of organisms to climate change. Historical data and gray literature can be invaluable sources of information. Our results support the theory that Lusitanian species are responding positively to climate warming but also that short-term extreme weather events can have potentially devastating widespread and lasting effects on organisms. Furthermore, the proliferation of coastal defense structures has implications for phylogeography, population genetics, and connectivity of coastal populations.

Mathematical Modeling to Assess the Drivers of the Recent Emergence of Typhoid Fever in Blantyre, Malawi

BACKGROUND: Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains.

METHODS: To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R0) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype.

RESULTS: Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data.

CONCLUSIONS: Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa.

Northern Ireland Policing Board Confidence in Policing Research: Key Drivers of Confidence

In January 2014, the Northern Ireland Policing Board (NIPB) commissioned the University of Ulster to conduct research into public confidence in policing to help inform the work of the Board and its oversight of police service delivery. More specifically, the research team were tasked with exploring ‘the key drivers of confidence in Northern Ireland’. To date, the subject of ‘confidence in policing’ within a Northern Ireland context has been relatively under researched, both in academic and policy terms. Thus, the present research is the first empirical research to be produced in the country to empirically assess confidence in policing from a cross section of society – including the key dynamics and drivers that underpin police confidence at a community level.

The report begins with a comprehensive review of academic literature, policy documents and contemporary events related to confidence in policing. The research then provides an overview of the methodology used to undertake the research, with the remainder of the report comprised of the findings from the survey. The report concludes with an overview of the central findings along with a series of recommendations.

Teenage motherhood: where you live is also important. A prospective cohort study of 14,000 women

The United Kingdom has among the highest rates of teenage motherhood (TM) in Western Europe. The relationship to individual social and material disadvantage is well established but the influence of area of residence is unclear. We tested for additional TM risks in deprived areas or in cities. The Northern Ireland Longitudinal Study was used to identify 14,055 nulliparous females (15-18). TM risk was measured using multilevel logistic regression, adjusting for health status, religion, family structure, socio-economic status, rurality and employment-based area deprivation. Most variation in TM was driven by individual, household and socioeconomic factors with the greatest proportion of mothers in low value or social rented accommodation. Living in an area with fewer employment opportunities was associated with elevated TM risk (most vs. least deprived, ORadj = 1.98 [1.49, 2.63]), as was urban dwelling (urban vs. intermediate, ORadj = 1.42 [1.13, 1.78]). We conclude that area of residence is a significant independent risk factor for TM. Interventions should be targeted towards the most deprived and urban areas and to those in the lowest value housing.

Licensed Iowa Drivers by County 2007-2015, January 29, 2016

Licensed Iowa drivers by county spreadsheet.

Iowa Crash History 2001 to 2015: Drivers Distracted by Use of Phone or Other Device, May 11, 2016

Iowa crash history of distracted drivers by use of phone or other devices.

Licensed Iowa Drivers by by Age Group & Sex - 2007 to 2015, January 29, 2016

Licensed Iowa drivers by age ground and sex spreadsheet.

Drivers' Behavior at Railroad Grade Crossings: Before and After Safety Campaign, HR-335, Survey Data Summaries, 1992

Summaries of the data gathered for this project.