Background Respiratory viruses are a leading cause of acute lower respiratory infections (ALRI) in young children. The role of seasonal influenza virus in childhood ALRI is generally underappreciated. This is because the global burden of disease due to ALRI attributable to seasonal influenza virus in children is unknown. This thesis aims to estimate the global and regional hospital admissions for seasonal influenzaassociated ALRI and the possible boundaries for influenza-associated ALRI mortality in children younger than five years. The WHO has developed guidelines for influenza surveillance using severe acute respiratory infections (SARI) sentinel surveillance network. However, data from sentinel surveillance are not routinely used in estimating disease burden in a population. This thesis also aims to provide tools for estimating influenza disease burden using data from SARI sentinel surveillance in developing country settings. Methods Incidence data for influenza-associated ALRI (from passive, hospital-based studies) were collected using a systematic review of studies published between January 1, 1995 and October 31, 2010. These data were supplemented by unpublished data from 15 population-based studies that were obtained by forming a consortium of researchers (Influenza Study Group) working in developing countries. The incidence meta-estimates were applied to global and regional population estimates for 2008 to calculate the estimated number of hospitalised influenza-associated ALRI cases that year. The possible bounds for influenza-associated mortality were estimated by combining incidence estimates with in-hospital case fatality ratios and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. The data to estimate the incidence of all-cause hospitalised ALRI were collected using a systematic literature review that was supplemented with unpublished data from 24 population-based studies that were obtained by collaborating with research sites in developing countries (Severe ALRI Working Group). The hospitalised ALRI incidence meta-estimates were applied to global and regional population estimates for 2008 to calculate the estimated number of all-cause hospitalised ALRI cases that year. Data on the proportion of hospitalised ALRI cases that were positive for influenza were collected using a systematic review of the studies published between January 1, 1995 and December 31, 2011. The meta-estimates of the proportion of hospitalised ALRI cases positive for influenza were applied to the estimated number of hospitalised ALRI cases in the year 2008 to estimate the number of hospitalised influenza-associated ALRI cases globally and for the six WHO regions using this alternative method. The tools for estimating influenza disease burden using surveillance data were developed after a literature review and a survey of 27 end-users (influenza epidemiologists) in 24 countries. Results Thirty nine studies (21 from developing and 18 from industrialised regions) satisfying the eligibility criteria, provided data on the incidence of influenza-associated hospitalised ALRI. The incidence is highest in infants in the first six months of life, both in developing as well as industrialised countries. It is estimated that the incidence of hospitalised influenza-associated ALRI in children under the age of five years was about 1.5 (95% CI 1.0 to 2.3) and 1.2 (95% CI 0.9 to 1.6) per 1000 children in developing and industrialised countries respectively. This translates to about 911,000 (95% CI 617,000 to 1.4 million) hospitalisations worldwide due to influenza-associated ALRI in children younger than five years in 2008, 93% of the cases occurring in developing countries (where 90% of the global under-5 population reside). An estimated 21,500 (based on 20 studies) to 115,000 deaths (based on only 1 study) in under-five children were attributable to influenza-associated ALRI in 2008. Incidence and mortality varied substantially from year to year in any one setting. Eighty five studies (61 from developing and 24 from industrialised) reported incidence of hospitalised ALRI in children aged 0 to 4 years. It is estimated that about 11.3 (95% CI 9.5 to 13.5) million episodes of ALRI resulting in hospitalisation occurred worldwide in children aged 0 to 4 years in 2008, 92% of these occurring in developing countries. Twenty three studies (19 from developing and 4 from industrialised) reported data on proportion of hospitalised ALRI cases testing positive for influenza using laboratory tests. The estimated proportion of influenza-positive hospitalised ALRI cases was about 5.0 (95% CI 3.6 to 7) percent and 8.4 (95% CI 4.2 to 16.7) percent in developing and industrialised countries respectively. This translates to about 772,000 (95% CI 343,000 to 1.8 million) cases of influenza-associated hospitalised ALRI in children younger than five years worldwide in the year 2008. A manual (targeted at developing countries) describing the methods to estimate the disease burden associated with seasonal influenza using the various surveillance data was developed after considering the results of the preliminary survey. An electronic tool (based on a spread sheet model) to help the end-users (epidemiologists at sentinel surveillance sites and Ministries of Health) to estimate the disease burden at local and national levels was developed as an adjunct to the manual. The manual along with the electronic tool were piloted at three different sites in two developing countries (India and Ghana) and feedback from the end-users was obtained to make the version more user-friendly. The final draft of the manual along with the tool has been submitted to the WHO for final clearance. The member states and the WHO Eastern Mediterranean Regional Office decided to adopt the manual and in the first instance estimate the influenza disease burden in 8 member states having the requisite data for undertaking disease burden estimation. Conclusions Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on hospital inpatient services worldwide. There are significant gaps in published data from developing countries (especially the African and Eastern Mediterranean regions of the WHO). Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not presently available. Effective use of sentinel surveillance data for disease burden estimation would greatly improve the quality and precision of disease burden estimates (especially those resulting in hospitalisation). Improved disease burden estimates (particularly at the national level) would inform policy makers and national governments in formulating immunization policies for vaccinating high-risk groups, and planning annual requirements for vaccines and anti-viral drugs against seasonal influenza.

This thesis investigates the epidemiology of hepatitis B virus infection (HBV) and estimates HBV-related liver disease burden in Vietnam and Australia using a cross-sectional study design and mathematical modelling. A population-based seroprevalence survey was undertaken in rural Northern Vietnam. In a sample of 870 study participants, prevalence of anti-HBV core antibody (anti-HBc) and hepatitis B virus surface antigen (HBsAg) was 68.2% and 19.0%, respectively, and hepatitis B e antigen (HBeAg) was detected in 16.4% of the HBsAg-positive group. Factors associated with HBV infection (anti-HBc and/or HBsAg-positive) were age 60 years or older (adjusted odds ratio (AOR), 3.82; 95% CI, 1.35??10.80; P = 0.01), residence in Vu Thu district (AOR, 3.00; 95% CI, 2.16??4.17; P <0.001), hospital admission (AOR, 2.34; 95% CI, 1.33??4.13; P = 0.003) and history of acupuncture (AOR, 2.01; 95% CI, 1.29??3.13; P = 0.002). Household contact with a person with liver disease (AOR, 2.13; 95% CI, 1.29??3.52; P = 0.003), reuse of syringes (AOR, 1.81; 95% CI, 1.25??2.62; P = 0.002) and sharing of razors (AOR, 1.69; 95% CI, 1.03??2.79; P = 0.04) were independent predictors of HBsAg positivity. Alanine aminotransferase (ALT) level was elevated (>40 IU/L) in 43% of the HBsAg-positive group; the proportion of elevated ALT was higher in HBeAg-positive (65%) compared with HBeAg-negative (39%) (P = 0.02). Based on data from the seroprevalence study, other prevalence estimates and HBV natural history parameters, a mathematical model was used to estimate HBV-related liver disease burden in Vietnam. Estimated chronic HBV prevalence increased from 6.4 million cases in 1990 to around 8.4 million cases in 2005 and was projected to decrease to 8.0 million by 2025. Estimated HBV-related liver cirrhosis and hepatocellular carcinoma (HCC) incidence increased linearly from 21 900 and 9400 in 1990 to 58 650 and 25 000 in 2025. Estimated HBV-related mortality increased from 12 600 in 1990 to 40 000 in 2025. To estimate HBV-related HCC incidence among Australians born in the Asia-Pacific region (APR), a mathematical modelling was developed utilising HBV natural history parameters, HBV prevalence estimates in APR countries and immigration data. Chronic HBV cases among the APR-born population increased rapidly from the late 1970s, reaching a peak of 4182 in 1990. Chronic HBV prevalence increased to more than 53 000 in 2005. Estimates of HBV-related HCC increased linearly from one in 1960 to 140 in 2005, with a projected increase to 250 in 2025. Universal HBV vaccination programs in countries of origin had limited impact on projected HBV-related HCC to 2025. HBV-related HCC survival was analysed in a population-based linkage study in New South Wales (NSW), Australia. Between 1994 and 2002, 278 HCC cases notified to the NSW Cancer Registry were linked to chronic HBV infection notifications to the NSW Health Department. The majority of cases were male (83.5%) and overseas born (93.6%); Asian-born cases accounted for 72.1%. Median survival following HCC diagnosis was 15 months. HCC survival was poorer among older age groups (P <0.001), and among cases with regional spread (HR 3.23; 95% CI, 1.83??5.69; P <0.001) and distant metastases (HR 3.85; 95% CI, 2.44??6.08; P <0.001). Sex, region of birth, and study period (1994??1997 versus 1998??2002) were not associated with HCC survival. The results of these studies show that HBV infection remains a major public health challenge in highly endemic countries such as Vietnam. HBV-related liver disease burden in Vietnam was estimated to increase for at least two decades despite the introduction of a universal infant HBV-vaccination program. Similarly, HBV-related HCC among Australians born in the APR was estimated to continue to increase over the next two decades. Survival for HBV-related HCC even in settings such as Australia continues to be extremely poor. Strategies are required to expand HBV treatment to individuals with chronic HBV infection who are at greatest risk of progression to advanced liver disease.

This thesis investigates the epidemiology of hepatitis B virus infection (HBV) and estimates HBV-related liver disease burden in Vietnam and Australia using a cross-sectional study design and mathematical modelling. A population-based seroprevalence survey was undertaken in rural Northern Vietnam. In a sample of 870 study participants, prevalence of anti-HBV core antibody (anti-HBc) and hepatitis B virus surface antigen (HBsAg) was 68.2% and 19.0%, respectively, and hepatitis B e antigen (HBeAg) was detected in 16.4% of the HBsAg-positive group. Factors associated with HBV infection (anti-HBc and/or HBsAg-positive) were age 60 years or older (adjusted odds ratio (AOR), 3.82; 95% CI, 1.35??10.80; P = 0.01), residence in Vu Thu district (AOR, 3.00; 95% CI, 2.16??4.17; P <0.001), hospital admission (AOR, 2.34; 95% CI, 1.33??4.13; P = 0.003) and history of acupuncture (AOR, 2.01; 95% CI, 1.29??3.13; P = 0.002). Household contact with a person with liver disease (AOR, 2.13; 95% CI, 1.29??3.52; P = 0.003), reuse of syringes (AOR, 1.81; 95% CI, 1.25??2.62; P = 0.002) and sharing of razors (AOR, 1.69; 95% CI, 1.03??2.79; P = 0.04) were independent predictors of HBsAg positivity. Alanine aminotransferase (ALT) level was elevated (>40 IU/L) in 43% of the HBsAg-positive group; the proportion of elevated ALT was higher in HBeAg-positive (65%) compared with HBeAg-negative (39%) (P = 0.02). Based on data from the seroprevalence study, other prevalence estimates and HBV natural history parameters, a mathematical model was used to estimate HBV-related liver disease burden in Vietnam. Estimated chronic HBV prevalence increased from 6.4 million cases in 1990 to around 8.4 million cases in 2005 and was projected to decrease to 8.0 million by 2025. Estimated HBV-related liver cirrhosis and hepatocellular carcinoma (HCC) incidence increased linearly from 21 900 and 9400 in 1990 to 58 650 and 25 000 in 2025. Estimated HBV-related mortality increased from 12 600 in 1990 to 40 000 in 2025. To estimate HBV-related HCC incidence among Australians born in the Asia-Pacific region (APR), a mathematical modelling was developed utilising HBV natural history parameters, HBV prevalence estimates in APR countries and immigration data. Chronic HBV cases among the APR-born population increased rapidly from the late 1970s, reaching a peak of 4182 in 1990. Chronic HBV prevalence increased to more than 53 000 in 2005. Estimates of HBV-related HCC increased linearly from one in 1960 to 140 in 2005, with a projected increase to 250 in 2025. Universal HBV vaccination programs in countries of origin had limited impact on projected HBV-related HCC to 2025. HBV-related HCC survival was analysed in a population-based linkage study in New South Wales (NSW), Australia. Between 1994 and 2002, 278 HCC cases notified to the NSW Cancer Registry were linked to chronic HBV infection notifications to the NSW Health Department. The majority of cases were male (83.5%) and overseas born (93.6%); Asian-born cases accounted for 72.1%. Median survival following HCC diagnosis was 15 months. HCC survival was poorer among older age groups (P <0.001), and among cases with regional spread (HR 3.23; 95% CI, 1.83??5.69; P <0.001) and distant metastases (HR 3.85; 95% CI, 2.44??6.08; P <0.001). Sex, region of birth, and study period (1994??1997 versus 1998??2002) were not associated with HCC survival. The results of these studies show that HBV infection remains a major public health challenge in highly endemic countries such as Vietnam. HBV-related liver disease burden in Vietnam was estimated to increase for at least two decades despite the introduction of a universal infant HBV-vaccination program. Similarly, HBV-related HCC among Australians born in the APR was estimated to continue to increase over the next two decades. Survival for HBV-related HCC even in settings such as Australia continues to be extremely poor. Strategies are required to expand HBV treatment to individuals with chronic HBV infection who are at greatest risk of progression to advanced liver disease.

The introduction of the polymerase chain reaction (PCR) into the diagnostic setting has provided unprecedented opportunities in the field of respiratory medicine, not only because pathogens need no longer be cultivable for detection but also through improved sensitivity, specificity and turnaround time compared with traditional methods. The recent discovery of several novel respiratory viruses, such as human metapneumovirus (HMPV), human bocavirus and human coronaviruses (HCoVs) NL63 and HKU1 has nevertheless created significant challenges in respiratory diagnostics, as identification of which pathogens should be tested for is increasingly difficult. The recent discovery of two novel respiratory coronaviruses (HCoV-HKU1 and HCoV-NL63) presented the opportunity to undertake large scale clinical and epidemiologic study of these alongside two previously known respiratory coronaviruses, HCoV-229E and HCoV-OC43. Over 12,000 samples collected over three years were screened using a novel four-way multiplex real-time reverse transcription-PCR (RTPCR). Clinically, coronaviruses were similar to viruses currently included in routine diagnostics, with the exception of HCoV-229E which was identified as an opportunistic pathogen in immunocompromised hosts. Variability in detection frequencies of HCoVHKU1 and HCoV-OC43 was evident. The low detection frequencies of HCoVs, comparable to those of parainfluenza viruses 1 and 2 (which are included in the routine diagnostic screening panel) indicate a borderline case for inclusion of these pathogens in routine respiratory diagnostics. To investigate the epidemiology and clinical correlates of HMPV in Edinburgh, large scale retrospective screening of over 7000 respiratory samples collected over two years was conducted. Nucleotide sequencing of HMPV-positive samples was undertaken to determine phylogenetic relationships of circulating HMPV strains. HMPV comprises two genotypes, A and B. Comparisons of the clinical presentations of the two genotypes revealed little difference, with only the observation that sub-genotype B2 was more frequently associated with infection of immunocompromised patients. Detection frequencies and symptomatology associated with HMPV infections were comparable to respiratory viruses currently included in the routine diagnostic panel, mandating its inclusion in future diagnostic screening. A switch of the predominantly circulating genotype of HMPV was observed between respiratory seasons. This is a phenomenon more widely reported for the closely related respiratory syncytial virus (HRSV), which also comprises two circulating groups. To further investigate subtype (HRSV)/ genotype (HMPV) switching, evolutionary analyses of nucleotide sequence data generated from isolates collected from geographically disparate referral centres was undertaken. The fusion and attachment (G) genes were targeted, as these encode major surface proteins and are immunogenic. Analyses were by MCMC analyses using Bayesian Evolutionary Analyses of Sampling Trees (BEAST) software. Identification of positively selected sites was performed using Phylogenetic Analysis Maximum Likelihood (PAML). Switching of the predominantly circulating lineage does not arise for either virus due to emergence of novel strains, but through fluctuating circulation frequencies of pre-existing lineages which have been circulating for several decades, indicated by the time since the most recent common ancestor. Two HRSV-A lineages comprising genotypes undergoing turnover and replacement were identified. This finding is agreeable with serologic studies of the 1970s which reported three HRSV serogroups, two within HRSV-A and one within HRSV-B. HMPV and HRSV have similar mutation rates. Positively selected sites identified within the HRSV G gene were incongruent with those identified in a previous study, generating the hypothesis that immune evasion occurs within linear epitopes rather than at specific sites. A great deal of clinical and epidemiologic data was generated through this work, parallel studies of other respiratory viruses and through diagnostic screening results. To provide a robust indication of where resources should be diverted in terms of diagnostics, therapeutics and vaccine development, and to inform infection control measures and public health policy planning, quantification of the relative disease burden attributable to the most commonly detected respiratory viruses was calculated using the World Health Organization- endorsed Disability Adjusted Life Year (DALY) model. Relative disease burden was calculated in an age stratified manner to reflect the differences in sampling in different age groups. HRSV and influenza A were consistently one of the greatest causes of disease regardless of sampled population, although HRSV caused more disease in children under 5 than influenza A and B combined. Rhinoviruses and PIV-3 were significant pathogens in all groups except those aged 16-64 years; rhinoviruses were the leading cause of disease in the immunocompromised patient group. The potential for patient-specific diagnostic screening and guidance of interventions such as patient cohorting were clear.

Objectif: Le syndrome d'apnée obstructive du sommeil (SAOS) est de plus en plus présent en Amérique du Nord et a été associé avec certaines maladies chroniques, particulièrement les maladies cardiaques. En première ligne, là où la prévalence de cooccurrence de maladies chroniques est très élevée, l'association potentielle avec l'apnée du sommeil est inconnue. L'objectif de cette étude était d'explorer l'association entre l'apnée obstructive du sommeil et 1) la présence et la gravité de la multimorbidité (cooccurrence de plusieurs maladies chroniques), et 2) des sous-catégories de multimorbidité. Méthode La technique d'échantillonnage en grappe a été utilisée pour recruter 120 patients atteints de SAOS à différents niveaux de gravité et ce, à partir de la base de données d'un laboratoire de sommeil. La gravité de la maladie a été établie grâce aux résultats de la polysomnographie. Les patients, qui furent invités à participer, ont reçu, par la poste, un questionnaire de renseignements sociodémographiques et le questionnaire auto-rapporté Disease Burden Morbidity Assessment (DBMA). L'envoi incluait un formulaire de consentement permettant l'accès au dossier médical afin d'obtenir plusieurs autres informations essentielles. Le DBMA a été utilisé pour avoir un score global de multimorbidité et des sous-scores de maladies qui affectent divers systèmes. Résultats Les analyses bivariées n'ont pas permis de démontrer une association entre l'apnée obstructive du sommeil et la multimorbidité (r = 0,117; p = 0,205). Par contre, le SAOS grave a été associé à la multimorbidité (odds ratio ajustés = 7,3 [1,7-32,2] ; p = 0,05). Le SAOS est modérément corrélé avec des sous-scores de multimorbidité vasculaire (r = 0,26 ; p = 0,01) et de syndrome métabolique (r = 0,26 ; p = 0,01). Conclusion Cette étude démontre que la gravité du SAOS est associée à la gravité de la multimorbidité et à des sous-scores de multimorbidité. Cette recherche ne permet pas d'établir un lien de causalité, d'autres recherches s'imposent pour confirmer ces associations. Toutefois, les intervenants de santé en première ligne devraient être au fait de cette association potentielle et devraient investiguer la présence de l'apnée du sommeil quand cela leur semble approprié.

There is documented evidence of high genetic diversity amongst African populations, but there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA genes are highly polymorphic, and encode for proteins that are part of the host defence mechanism mediated through antigen presentation to immune system effector cells. The highly polymorphic nature of HLA genes facilitates the presentation of a wide range of antigenic peptides to the immune system leading to an immune response. With the high disease burden in Africa, it is important to fully understand HLA diversity in these populations, to establish HLA-disease associations, and potentially use this data for the informed design of population-specific vaccines against the many diseases, and to improve on donor-recipient matching. The aim of this thesis is to understand HLA diversity in South African populations to support transplantation programs, add knowledge on human diversity and build a potential future resource for disease association and population studies. There is generally limited HLA data from southern African populations (Chapter 2) to support disease association studies, provide guidance in vaccine design and donor recruitment for transplantation programs. Despite being the only active bone marrow donor registry in Africa supporting transplantation programs, HLA diversity in volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR) is largely undocumented. This study documents HLA -A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies from a subset of 237 SABMR registered donors with the objective of highlighting HLA diversity in South Africans (Chapter 3). Additionally, mixed resolution HLA data from the National Health Laboratory Services (NHLS) and the South African National Blood Transfusion Service (SANBS) are reported (Chapter 4). A comparison of South African HLA data (NHLS and SANBS) with other global populations including sub Saharan Africans confirm the genetic diversity of South Africans. To counter the paucity of HLA data, in silico HLA imputation tools may be used to determine HLA alleles from existing whole genome sequencing (WGS) data. HLA imputation is an economically feasible typing option for resource limited settings. To support the feasibility of HLA imputation, this study describes high resolution (up to 8 digit typing) HLA alleles determined by in silico HLA imputation tools from 24 WGS of South African individuals (chapter 5). Generally, HLA diversity of South African populations is described in detail through literature meta-analysis, documentation of previously typed individuals (SANBS, NHLS and SABMR) and HLA imputation from existing next generation sequencing (NGS) data. Although results reported here are from a small subset of 237 SABMR registered donors (chapter 3), 24 WGS (chapter 5) and mixed resolution typing NHLS and SANBS data (chapter 4), allele and haplotype frequencies generated could be a useful resource for future anthropological and population genetics studies. Furthermore, these findings may better inform donor recruitment strategies for the SABMR, and disease association studies. Future study recommendations include development of an HLA diversity resource for African populations, a comparison of large SABMR dataset with other global registries, and using more robust assembly based computational tools to fully understand the HLA diversity in South Africans. / Thesis (PhD)--University of Pretoria, 2018. / South African Medical Research Council (SAMRC) in terms of the MRC’s Flagships Awards Project (SAMRC-RFA-UFSP-01-2013/STEM CELLS), the SAMRC Extramural Unit for stem cell Research and Therapy, the Institute for Cellular and Molecular Medicine of the University of Pretoria, and the National Research Foundation of South Africa. / Immunology / PhD Medical Immunology / Unrestricted

What is the impact of disease burden on democracy in sub-Saharan Africa? Despite increasing interest in the implications of health crises for state stability, there has been a dearth of literature exploring the relationship between disease burden more generally and democracy specifically. This thesis takes a comprehensive approach to bridge this gap in the literature. Using quantitative and qualitative methods, it draws on data from the Global Burden of Disease database and the Varieties of Democracy (V-Dem) dataset to analyze this relationship. The diseases studied are categorized as long-wave (e.g., HIV/AIDS and tuberculosis), short-wave (e.g., Ebola and lower respiratory infections), or endemic (e.g., malaria and an aggregate of other infectious diseases). In terms of democracy, this thesis focuses on civil liberties and civil society. Having utilized a linear regression, controlling for economic variables, this study found a positive and significant relationship between long-wave diseases and both civil liberties and civil society; a negative and significant relationship between Ebola and both civil liberties and civil society; a positive and significant relationship between lower respiratory infections and both civil liberties and civil society; and, finally, a positive and significant relationship between the other infectious disease aggregate and civil society. Ultimately, there was no significant relationship between the other diseases studied and the democratic variables. By identifying past relationships between particular kinds of diseases and manifestations of democracy, we can establish a baseline from which to project our expectations about how emerging diseases like COVID-19 will impact the practice of democracy.

Aims: To investigate the natural history of CHC, estimate the disease burden of CHC, and assess the cost-effectiveness of screening for CHC among immigrants living in Canada. Methods: A retrospective cohort study compared the prognosis of CHC between immigrant patients and native-born patients who had advanced fibrosis. A cross-sectional study assessed the association between obesity and hepatitis C viremia. The disease burden of CHC among immigrants was estimated through Markov cohort model. The cost-effectiveness of screening for CHC was assessed among immigrants. Results: The retrospective cohort study including 318 patients demonstrated that immigrant patients had significantly higher risk of hepatocellular carcinoma than Canadian-born patients (p=0.005). The hazard ratio associated with ‘immigrant’ for hepatocellular carcinoma in multivariate Cox proportional-hazards analyses reduced to the least and non-significant (p=0.318) after adjusting age and type 2 diabetes. The prevalence of obesity in 1118 individuals tested positive for hepatitis C antibody was 28.8%. Multiple regression analyses and propensity score methods suggested a significant association between obesity and hepatitis C viremia. The disease burden study estimated that immigrants with CHC had much shorter average life years (26.9 years vs. 39.1 years) and quality adjusted life years (20.6 years vs. 32.4 years) than the age matched immigrants without CHC. The cost-effectiveness study indicated that screening for CHC among immigrants from 183 countries (72.1% of immigrant population in Canada) had an incremental cost-effectiveness ratio less than $50,000 per quality adjusted life year gained. Conclusion: Immigrant patients with CHC could have a higher risk of HCC than native-born patients. The significant association between obesity and hepatitis C viremia could explain the observed high prevalence of type 2 diabetes in patients with CHC. CHC reduces the average life expectancy of immigrants with CHC more than 10 years. Screening for CHC is cost-effective among over 70% of immigrants living in Canada.

Aims: To investigate the natural history of CHC, estimate the disease burden of CHC, and assess the cost-effectiveness of screening for CHC among immigrants living in Canada. Methods: A retrospective cohort study compared the prognosis of CHC between immigrant patients and native-born patients who had advanced fibrosis. A cross-sectional study assessed the association between obesity and hepatitis C viremia. The disease burden of CHC among immigrants was estimated through Markov cohort model. The cost-effectiveness of screening for CHC was assessed among immigrants. Results: The retrospective cohort study including 318 patients demonstrated that immigrant patients had significantly higher risk of hepatocellular carcinoma than Canadian-born patients (p=0.005). The hazard ratio associated with ‘immigrant’ for hepatocellular carcinoma in multivariate Cox proportional-hazards analyses reduced to the least and non-significant (p=0.318) after adjusting age and type 2 diabetes. The prevalence of obesity in 1118 individuals tested positive for hepatitis C antibody was 28.8%. Multiple regression analyses and propensity score methods suggested a significant association between obesity and hepatitis C viremia. The disease burden study estimated that immigrants with CHC had much shorter average life years (26.9 years vs. 39.1 years) and quality adjusted life years (20.6 years vs. 32.4 years) than the age matched immigrants without CHC. The cost-effectiveness study indicated that screening for CHC among immigrants from 183 countries (72.1% of immigrant population in Canada) had an incremental cost-effectiveness ratio less than $50,000 per quality adjusted life year gained. Conclusion: Immigrant patients with CHC could have a higher risk of HCC than native-born patients. The significant association between obesity and hepatitis C viremia could explain the observed high prevalence of type 2 diabetes in patients with CHC. CHC reduces the average life expectancy of immigrants with CHC more than 10 years. Screening for CHC is cost-effective among over 70% of immigrants living in Canada.

Regular physical activity reduces the risk of many chronic diseases. Consequently, the promotion of it and particular types (e.g. walking and cycling for travel), have become a priority for governments seeking to improve health and constrain rising demand on health services. Despite this many uncertainties persist. The aim of this thesis is to address two particular areas of uncertainty: a) the association of walking and cycling for travel with indices of health and well-being; b) and the extent to which increases in physical activity will reduce need for health and social care. The first part of my thesis consists of three studies that describe the health benefits associated with walking and cycling to work among working age adults. The first is a longitudinal study of the associations between maintenance of active commuting with sickness absence and well-being using the Commuting and Health in Cambridge dataset. The second, using the same dataset, describes the longitudinal associations between maintenance of active commuting and self-reported body mass index. Building on this, the third study using a large cohort study (the Fenland Study) with detailed characterisation of diet and physical activity (including objective measurement) describes the baseline associations between active commuting and objective measures of adiposity. The second part of my thesis describes the development of a combined microsimulation multi-state life table model that is used to characterise the effects of a population ‘shift’ in physical activity on the burden of six major diseases at the population-level. Specifically, it seeks to better describe the effect of increases in physical activity on healthcare need considering not just the effect of physical activity on disease incidence but also the effect on healthcare need arising from consequent survival to an older age (at which disease incidence is higher), and contrasts this with a method that does not make allowance for increased survival. The findings of this thesis provide evidence of the importance of walking or cycling to work in maintaining or improving the health and well-being of working age adults. It suggests that increases in physical activity, even after allowance for increased survival, are likely to reduce need for healthcare, although the reductions in need are less than might be assumed when allowance is not made for increased survival. Taken together this work provides a stronger empirical basis to inform public health practice. A stronger ‘health case’ for active travel can be made. The benefits of which should be communicated to individuals choosing how to travel as well as policy makers and others who can influence the determinants of active travel. It also provides a more realistic and nuanced understanding of how increases in physical activity may affect future healthcare need.