Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.

Systemic Lupus Erythematosus (SLE), a prototypic multi-organ autoimmune disease, is associated with a dramatically increased risk of coronary artery disease (CAD) manifesting as angina, myocardial infarction and sudden cardiac death. Traditional cardiac risk factors such as hypertension and hypercholesterolemia, measured at baseline in accordance with the Framingham model, only partially account for the increased risk of CAD in SLE. In this thesis, I have shown that blood pressure (BP), lipids and novel risk factors such as the inflammatory marker high-sensitivity C-reactive protein (hsCRP), take a dynamic course in SLE, with more than half of the variance in serial measurements over time occurring within rather than between individuals. This variability is due to changes in disease activity, treatment, accrual of other cardiac risk factors, and complications such as infection. I have demonstrated that by capturing cumulative exposure over time, ‘summary measures’ such as arithmetic mean and time-adjusted mean (AM) are better able to quantify CAD risk in patients with SLE than single-point-in-time measurements of risk factors. By incorporating ‘summary measures’ such as mean and AM into time-dependent covariate survival analysis models, I was able to quantify the magnitude of increase in CAD risk associated with increments in systolic and diastolic BP, and to demonstrate and quantify the association between several lipids / lipoproteins and CAD risk in SLE. Using this methodology, I was also able to demonstrate that despite marked variability over time, ‘summary measures’ of hsCRP are independently predictive of CAD risk among patients with SLE, highlighting the pivotal role of inflammation in atherosclerosis. Furthermore, I was able to determine lipid and hsCRP ‘cut-points’ that will aid clinicians in identifying a subgroup of patients with SLE who are at significantly increased cardiac risk.

Biomarkers measured in the blood can provide information about disease pathophysiology, diagnosis and prognosis. Pronounced proinflammatory responses are characteristic of severe malaria, and excessive activation of the immune system is central to the pathophysiology of both cerebral malaria and placental malaria. Severe malaria is characterized by cytoadherence of parasitized erythrocytes to the microvasculature; impaired tissue perfusion; dysregulated inflammatory responses; and activation of the complement system, mononuclear cells, and endothelium. Despite the availability of effective antimalarial drugs, the mortality rate in severe malaria remains unacceptably high. To glean further insight into malaria pathophysiology, we investigated host biomarkers of immune activation in the blood of subjects with different manifestations of severe disease. C5 has been identified as being necessary and sufficient for the development of experimental cerebral malaria. We hypothesized that C5a (a terminal component of the complement cascade with potent inflammatory properties) may mediate its action by inducing and exacerbating inflammatory processes in severe malaria, leading to endothelial activation and dysregulated angiogenesis. I tested this hypothesis in vitro, and found that C5a interacted with malaria toxin PfGPI to drive deleterious inflammatory and anti-angiogenic responses. As C5a and anti-angiogenic factor sFlt-1 have been implicated in models of pathologic pregnancies, we asked whether increased levels of C5a in subjects with placental malaria were associated with altered angiogenesis and poor birth outcomes. Our results suggest that C5a impairs angiogenic remodelling in placental malaria leading to vascular insufficiency and fetal growth restriction. Further, altered profiles of inflammatory and angiogenic biomarkers in the periphery may identify occult placental malaria infections. We extended these observations to cerebral malaria where similar pathogenic pathways contribute to disease pathophysiology. In adults and children with cerebral malaria, altered profiles of angiogenic proteins were associated with disease severity and mortality and represent putative diagnostic and prognostic biomarkers in severe malaria.

Aisha Kamilah O. Lofters Cervical Cancer Screening Among Ontario’s Urban Immigrants Doctor of Philosophy, 2012 Institute of Health Policy, Management and Evaluation University of Toronto Background: The majority of cervical cancers can be prevented because of the highly effective screening tool, the Papanicolaou (Pap) test. Relevant guidelines recommend routine screening for nearly all adult women. However, inequities in screening exist in Ontario. This dissertation, consisting of three studies, uses administrative data to advance knowledge on barriers to cervical cancer screening for Ontario’s urban immigrant population. Methods: First, we developed and validated a billing code-based algorithm for cervical cancer screening. We then implemented this algorithm to examine screening rates in Ontario among women with various sociodemographic characteristics for 2003-2005. Second, we compared the prevalence of appropriate cervical cancer screening in Ontario in 2006-2008 among immigrant women from all major geographic regions of the world and Canadian-born women. Third, we used a stratified multivariate analysis to determine if the independent effects of various factors that could serve as screening barriers were modified by region of origin for immigrant women for 2006-2008. Results: Our first study showed that our algorithm was 99.5% sensitive and 85.7% specific, and that screening inequities in Ontario’s urban areas are largest among women 50 years and older, living in the lowest-income neighbourhoods and new to the province. In our second study, we determined that immigrant women had significantly lower screening rates than their peers, with the most pronounced differences seen for South Asian women aged 50 years and above. In the final study, we demonstrated that living in the lowest-income neighbourhoods, being younger than 35 years or older than 49 years, not being enrolled in a primary care enrolment model, having a male provider, and having a provider from the same region of the world each significantly influenced screening for immigrant women regardless of region of origin. Conclusion: These results add to the literature on health equity in cancer screening. Our findings demonstrate that Ontario’s urban immigrant women experience significant inequities in cervical cancer screening, and may offer guidance toward targeted patient and physician interventions to decrease screening gaps.

Type 2 Diabetes Mellitus (T2DM) prevalence is increasing globally with roughly 2.4 million people currently living with this condition in Canada. T2DM occurs more commonly in non-European ethnoracial groups, however the distribution of risk by age, sex, ethnicity and immigration status in Canada are not completely understood. The purpose of this thesis is to investigate the epidemiology of diabetes in an immigrant, multi-ethnic population using linked immigration and health data for the province of Ontario. The ultimate goal of this work is to generate information that can be used to design appropriate and effective targeted programs for diabetes prevention, management and control in order to reduce inequities in health. The principal findings of this work indicate that: 1) South Asians had a three-fold higher risk for developing diabetes as compared with people of European ethnicity and this disparity in risk was evident at a very young age; 2) The young age at diabetes onset experienced by many of our high-risk ethnic groups, including South Asians and people of African and Middle Eastern descent, suggest that in order to capture an equivalent risk of disease, screening may be recommended up to 15 years earlier in these groups – which is not reflected in current screening guidelines; 3) Contrary to patterns seen in Western European populations, women belonging to many high–risk ethnicities had equivalent or, in some cases, higher risk than men; 4) Risk varied substantially across country and region of birth making broad definitions of race or ethnicity (eg. ‘Asian’ or ‘Black’) inappropriate. These findings emphasize the heterogeneity of risk experienced by different ethnoracial populations in Canada and suggest that targeted primary prevention programs aimed at young adults and adolescents belonging to high-risk ethnic groups may be warranted. In addition, screening guidelines may need to be updated to reflect the younger age at onset in these populations. Further research is necessary to identify culturally appropriate and effective programs to reduce diabetes risk and associated health problems in these populations.

Background: The causes of trends in asthma incidence are not fully understood. Objectives: This study examined trends in age and severity at asthma diagnosis for Ontario children. Methods: Multiple birth cohorts of Ontario children between 1992-2000 were created using health administrative data. Descriptive statistics and multivariable logistic regression examined changes in age and severity of asthma at diagnosis over time. Results: Age at asthma diagnosis decreased (p<0.0001) with a higher relative risk of asthma in children under age three (RR=1.5, 95% CI:1.47, 1.54). Predictors of asthma diagnosis before three included male sex, lower income quintile, and maternal asthma. ‘Severe onset asthma’ increased over time (p<0.0001), its predictors being male sex, lower income quintile, rural residence, comorbidity, low birth weight and age less than three. Conclusions: Observed trends in asthma incidence are not confined to mild disease and are secondary to variations in asthma rates in children under age three.

Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.

Biomarkers measured in the blood can provide information about disease pathophysiology, diagnosis and prognosis. Pronounced proinflammatory responses are characteristic of severe malaria, and excessive activation of the immune system is central to the pathophysiology of both cerebral malaria and placental malaria. Severe malaria is characterized by cytoadherence of parasitized erythrocytes to the microvasculature; impaired tissue perfusion; dysregulated inflammatory responses; and activation of the complement system, mononuclear cells, and endothelium. Despite the availability of effective antimalarial drugs, the mortality rate in severe malaria remains unacceptably high. To glean further insight into malaria pathophysiology, we investigated host biomarkers of immune activation in the blood of subjects with different manifestations of severe disease. C5 has been identified as being necessary and sufficient for the development of experimental cerebral malaria. We hypothesized that C5a (a terminal component of the complement cascade with potent inflammatory properties) may mediate its action by inducing and exacerbating inflammatory processes in severe malaria, leading to endothelial activation and dysregulated angiogenesis. I tested this hypothesis in vitro, and found that C5a interacted with malaria toxin PfGPI to drive deleterious inflammatory and anti-angiogenic responses. As C5a and anti-angiogenic factor sFlt-1 have been implicated in models of pathologic pregnancies, we asked whether increased levels of C5a in subjects with placental malaria were associated with altered angiogenesis and poor birth outcomes. Our results suggest that C5a impairs angiogenic remodelling in placental malaria leading to vascular insufficiency and fetal growth restriction. Further, altered profiles of inflammatory and angiogenic biomarkers in the periphery may identify occult placental malaria infections. We extended these observations to cerebral malaria where similar pathogenic pathways contribute to disease pathophysiology. In adults and children with cerebral malaria, altered profiles of angiogenic proteins were associated with disease severity and mortality and represent putative diagnostic and prognostic biomarkers in severe malaria.

Systemic Lupus Erythematosus (SLE), a prototypic multi-organ autoimmune disease, is associated with a dramatically increased risk of coronary artery disease (CAD) manifesting as angina, myocardial infarction and sudden cardiac death. Traditional cardiac risk factors such as hypertension and hypercholesterolemia, measured at baseline in accordance with the Framingham model, only partially account for the increased risk of CAD in SLE. In this thesis, I have shown that blood pressure (BP), lipids and novel risk factors such as the inflammatory marker high-sensitivity C-reactive protein (hsCRP), take a dynamic course in SLE, with more than half of the variance in serial measurements over time occurring within rather than between individuals. This variability is due to changes in disease activity, treatment, accrual of other cardiac risk factors, and complications such as infection. I have demonstrated that by capturing cumulative exposure over time, ‘summary measures’ such as arithmetic mean and time-adjusted mean (AM) are better able to quantify CAD risk in patients with SLE than single-point-in-time measurements of risk factors. By incorporating ‘summary measures’ such as mean and AM into time-dependent covariate survival analysis models, I was able to quantify the magnitude of increase in CAD risk associated with increments in systolic and diastolic BP, and to demonstrate and quantify the association between several lipids / lipoproteins and CAD risk in SLE. Using this methodology, I was also able to demonstrate that despite marked variability over time, ‘summary measures’ of hsCRP are independently predictive of CAD risk among patients with SLE, highlighting the pivotal role of inflammation in atherosclerosis. Furthermore, I was able to determine lipid and hsCRP ‘cut-points’ that will aid clinicians in identifying a subgroup of patients with SLE who are at significantly increased cardiac risk.

Aisha Kamilah O. Lofters Cervical Cancer Screening Among Ontario’s Urban Immigrants Doctor of Philosophy, 2012 Institute of Health Policy, Management and Evaluation University of Toronto Background: The majority of cervical cancers can be prevented because of the highly effective screening tool, the Papanicolaou (Pap) test. Relevant guidelines recommend routine screening for nearly all adult women. However, inequities in screening exist in Ontario. This dissertation, consisting of three studies, uses administrative data to advance knowledge on barriers to cervical cancer screening for Ontario’s urban immigrant population. Methods: First, we developed and validated a billing code-based algorithm for cervical cancer screening. We then implemented this algorithm to examine screening rates in Ontario among women with various sociodemographic characteristics for 2003-2005. Second, we compared the prevalence of appropriate cervical cancer screening in Ontario in 2006-2008 among immigrant women from all major geographic regions of the world and Canadian-born women. Third, we used a stratified multivariate analysis to determine if the independent effects of various factors that could serve as screening barriers were modified by region of origin for immigrant women for 2006-2008. Results: Our first study showed that our algorithm was 99.5% sensitive and 85.7% specific, and that screening inequities in Ontario’s urban areas are largest among women 50 years and older, living in the lowest-income neighbourhoods and new to the province. In our second study, we determined that immigrant women had significantly lower screening rates than their peers, with the most pronounced differences seen for South Asian women aged 50 years and above. In the final study, we demonstrated that living in the lowest-income neighbourhoods, being younger than 35 years or older than 49 years, not being enrolled in a primary care enrolment model, having a male provider, and having a provider from the same region of the world each significantly influenced screening for immigrant women regardless of region of origin. Conclusion: These results add to the literature on health equity in cancer screening. Our findings demonstrate that Ontario’s urban immigrant women experience significant inequities in cervical cancer screening, and may offer guidance toward targeted patient and physician interventions to decrease screening gaps.