Melbourne School of Population and Global Health - Theses
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ItemVillage chicken production and the risk of avian influenza events in Indonesian villages( 2019)As of 2019, Highly Pathogenic Avian Influenza (HPAI) H5N1 is under control in Indonesia as a result of improved biosecurity and vaccination in large poultry enterprises. Nevertheless, the virus still circulates in less specialized village chicken production systems posing economic burden and public health risk. Past field research established that the trading activity associated with village chicken production is the primary pathway for HPAI-H5N1 release and spread in Indonesian villages; lamentably, the scarcity of data on village trading limits the exploration of risk frameworks to identify high-risk HPAI-H5N1 villages. This thesis investigates the village chicken productive landscape (that is, the collective of village chicken systems in a given village) as a determinant of the risk of HPAI-H5N1 events in Indonesian villages. Three core dimensions of these systems: type of village chicken system, village chicken productive dynamics, and risk mitigation strategies, are explored in relation to HPAI-H5N1 in four studies. First, a systematic review and meta-analysis that evaluates the efficacy of commercial vaccines against HPAI-H5N1 in Indonesia. Second, a Leslie matrix model to determine the underlying village chicken population dynamics and their effect on the maintenance of vaccine coverage. Third, an exploration and characterization of the Indonesian village chicken systems, along with the introduction of a deterministic age-structured model that simulates population dynamics and allows estimation of the presumed frequency of trading events to approximate the risk of HPAI-H5N1 release into villages. Fourth, a stochastic susceptible-exposed-infected age-structured model that allows exploration of transmission dynamics in different village chicken productive landscapes and evaluation of plausible risk mitigation strategies. The first study showed that viral drift reduces vaccine efficacy and that seed-homologous vaccine immunogenicity is not a good proxy for efficacy against wild isolates. The meta-analysis demonstrated that extra-label vaccination and the use of alternative seed homologous formulations are emerging sources of heterogeneous vaccine efficacy. The second study demonstrated that a mix of village chicken systems and not a "traditional scavenging" landscape, as suggested in the literature, drives the underlying village chicken population dynamics in Indonesia and these may quickly undermine perfect vaccine coverage. The third study demonstrated the limitations of the current classification of village chicken systems based on farming practice. The hierarchical clustering analysis in this study suggests that village chicken systems transitioned from traditional to semi-commercial modes of operation expressed as produce specialty (non-specialist, bird-specialist, or egg-specialists) and alternative trading strategies. The presumed frequency of trading events based on simulated productive dynamics suggests that the egg-specialists are heavily engaged in trading activities that increase the risk of HPAI-H5N1 release into villages. The fourth study shows that the type of village chicken landscape might not determine the probability of an epidemic event of HPAI-H5N1; however, outbreaks in landscapes that are abundant in bird-specialist and egg-specialist premises may persist longer. The simulations performed suggest that the extinction of the infected population seems invariably required to control these outbreaks. This thesis provides evidence that the Indonesian village chicken productive landscapes may determine the risk of HPAI-H5N1 events in Indonesian villages. This research suggests that a transition from traditional modes towards semi-commercial modes of operation that leads to a more significant presence of egg-specialists in the village results in a higher risk of viral release and likely more persistent epidemic events. The exploration of mitigation strategies which are plausible at the local level revealed challenges of controlling outbreaks in villages. These results emphasize the importance of identifying high-risk villages to enable adequate surveillance that reduces the need for mitigation strategies based on culling. In conclusion, this thesis suggests that an adequate characterization of the village chicken productive landscape may help, or even suffice, to identify villages at high risk of HPAI-H5N1 events, guiding surveillance, education, and future control efforts.
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ItemEpidemiology of obstructive sleep apnoea: diagnosis, prevalence, comorbiditis, and risk factors( 2019)Obstructive sleep apnoea (OSA) occurs due to repetitive partial or complete upper airway obstruction during sleep and may lead to generalised hypoxia and/or arousals from sleep. OSA has both direct and indirect health and economic costs. However, design of public health interventions to control OSA is constrained by some critical gaps in knowledge. OSA is widely regarded to be highly prevalent but the reported prevalence estimates vary widely. The last population prevalence study in Australia was performed nearly twenty-five years ago. New estimates on population prevalence and the comorbidities associated with OSA would help better understand the burden of disease. Several OSA-screening questionnaires have been recommended for use in primary care settings in Australia, but these questionnaires have not been validated in the Australian primary-care population. Although OSA is seemingly associated with some chronic disorders such as cardiovascular and cerebrovascular disorders, metabolic disorders, respiratory disorders and psychiatric disorders, evidence for some associations are limited. Furthermore, the currently known modifiable risk factors for OSA are limited and rarely based on longitudinal evidence. No childhood risk factors are known for OSA. Given these knowledge gaps, during my doctoral work I aimed (1) to determine the validity of commonly known OSA-screening-questionnaires, (2) to describe the prevalence of OSA and its co-morbidities in the general population, and (3) to describe some potential early-life and lifetime risk factors for OSA. My specific objectives were (a) to systematically summarise the current evidence on the validity of the common OSA questionnaires for which such systematically synthesised evidence was unavailable, (b) to determine the validity of some common OSA-screening-questionnaires to detect OSA among middle-aged Australian adults, (c) to systematically summarise the available evidence on the prevalence of OSA in the adult general population including in age and sex- specific subgroups, (d) to describe the prevalence and associated chronic co-morbidities of OSA in middle-aged Australian adults, (e) to determine the role of lifetime lung function trajectories on OSA in adult life, and (f) to determine the role of childhood respiratory risk factors on OSA in adult life. To achieve the first aim, I systematically synthesised the literature on the validity of the Berlin questionnaire (Chapter 3). The evidence on the validity of the other questionnaires were already synthesised at the time I commenced this work. The included studies reported varied sensitivity and specificity based on the OSA assessment method used. I then used the data from the Tasmanian Longitudinal Health Study (TAHS) to validate the Berlin (BQ), STOP-Bang and OSA-50 questionnaires against type-4 sleep studies (Chapter 6). To determine if the flow-based AHI or ODI is more suitable as the reference standard, I investigated their agreement in detecting and classifying OSA (Chapter 6 [6.1]). I found that ODI identified more clinically significant OSA than flow-based AHI. Unlike in the previous studies that relied only on conventional AHI/ respiratory disturbance index (RDI)/oxygen desaturation index (ODI) cut-off levels for the reference test, I derived and used a new reference standard, namely, ‘clinically-relevant OSA’ that included moderate-severe OSA (ODI≥15) and mild (ODI≥5) OSA with symptoms as a combined group, as this is the group that needs to be captured for clinical management. I found that all three questionnaires were not clinically useful on their own (sub-optimal sensitivity and specificity) in a simulated primary-care sample but could be used to rule-in OSA (high specificity) when combined with Epworth sleepiness scale (Chapter 6 [6.2]). I also found that OSA-50 and STOP-Bang had a moderate sensitivity and low specificity and BQ had low sensitivity and moderate specificity, at the recommended thresholds, in the general population (Chapter 6 [6.3]). The trade-off between sensitivity and specificity remain a limitation of their practical use. To achieve the second aim, I systematically synthesised the literature on the prevalence of OSA (Chapter 4). I found that the prevalence of OSA varied between population subgroups and the OSA assessment methods. I then used the data from the Ten to Men study to determine the prevalence of doctor diagnosed OSA in Australian men and its co-morbidities (Chapter 7 [7.1]). I found that the prevalence increased from 2% in younger adults to 8% in the middle-age and that OSA was associated with several chronic cardiovascular, metabolic, respiratory and psychiatric disorders. Using data from the TAHS, I found the prevalence of medically-confirmed OSA to be 5% and probable OSA as determined by the STOP-Bang questionnaire to be 15% (Chapter 7 [7.2]). Medically-confirmed OSA as well as probable OSA were associated with several co-morbidities as seen in the Ten to Men study. Furthermore, I investigated how nocturnal-asthma-like symptoms and bronchial hyper-reactivity (BHR) contribute to the association between OSA-risk and current-asthma using the data from TAHS. I found no evidence for any role of BHR in this association but found some evidence for some nocturnal asthma symptoms to be suggestive of undiagnosed OSA. To achieve the third aim, I investigated how OSA is related to lifetime lung function trajectories and childhood respiratory risk factors using longitudinal data from the TAHS. I found that three trajectories were associated with both probable OSA (defined using STOP-Bang questionnaire) and medically-confirmed OSA (Chapter 8 [8.1]). Frequent childhood lower respiratory tract infection, asthma and lung function trajectories were associated with probable OSA (Chapter 8 [8.2]). Overall, my findings have significant public health, clinical and research implications and significantly advanced the current knowledge in this area. My assessment between ODI and flow-based AHI is the first such evidence and suggest that ODI should be preferred in clinical practice. Current OSA screening-questionnaires could be useful in epidemiological research but not as clinical tools. This calls for development of better screening methods. My findings challenge the current recommendations for OSA screening at primary-care and I make suggestions as to how this process could be improved. The high prevalence of OSA in general, and in males and elderly, and its association with other priority chronic disorders provide public health foci for interventions. The demonstrated role of nocturnal respiratory symptoms in the OSA-asthma association suggests the need for clinical vigilance for undiagnosed OSA in patients with nocturnal symptoms. Furthermore, the evidence for association of lung function trajectories and childhood risk factors with OSA advances the current knowledge and provides platforms for future research to delineate the seemingly complex pathophysiology and natural history of OSA.
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ItemPre-existing mental disorders and health outcomes after release from prison: a case for continuity of care( 2018)Globally, there is good evidence that people in prison are distinguished by their poor health profile and by entrenched socio-economic disadvantage. Mental disorders, especially severe mental illness, are overrepresented among people in prison. People released from prison are at particularly high risk of poor health outcomes and this risk is higher among people with pre-existing mental disorders compared to those without mental disorders. However, beyond drug-related outcomes, infectious disease epidemiology, and mortality, substantial gaps in evidence exist, limiting the capacity to respond to the often multiple and complex needs of people with mental disorders released from prison. This thesis fills this internationally recognised gap in the literature. It comprises a review of the literature and six discrete studies. The studies included in this thesis generate previously unavailable evidence on gaps in transitional service provision for people with intellectual disability released from prison; patterns of health service utilisation, and health outcomes for people with and without pre-existing mental disorders released from prison; and the determinants of findings of unfitness and unsoundness for people with cognitive disability referred to a Mental Health Court in Australia. The findings reported in this thesis indicate that people with pre-existing mental disorders experience gaps in transitional service provision; and are at increased risk of poor health and related outcomes compared to those without a mental disorder after release from prison. Given their poor outcomes and inherent vulnerabilities in the criminal justice system, people with mental disorders should be considered for diversion from incarceration into therapeutic environments where appropriate. Furthermore, the findings in this thesis provide new evidence that injury is a key target for prevention among people released from prison, especially among those with co-occurring mental illness and substance use disorder. When taken together, the findings across the studies included in this thesis make a compelling case that increased integration between forensic and community healthcare providers would improve the continuity of care and prevent poor health outcomes experienced by people released from prison. Furthermore, these findings can be used to inform the development of interventions and service responses to improve the continuity of care for people with mental disorders released from prison.
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ItemRisk factors for and outcomes of lung function deficits throughout the lifespan( 2019)Good lung function is essential for general health and longevity. The lungs are responsible for providing oxygen to meet the metabolic demands of the body and expelling waste products of cellular respiration. They also play a critical role in maintaining acid-base balance. Impaired lung function imposes significant health issues. Chronic obstructive pulmonary disease (COPD) in late adulthood is responsible for the largest burden. Across the life course, lung function passes through different phases (development, growth, plateau, and decline). Lung function is influenced by multiple risk factors that act at different periods, which together form a complex web contributing to lifetime risk. Understanding how particular risk factors influence each phase as well as the lifetime trajectory of lung function and the consequences of these impairments is critical for evidence-based strategies to promote lung health and prevent lung diseases. However, such understanding is limited. Specifically, some major gaps in this literature include: how reduced lung development and growth in early life influence the risk of COPD and its phenotypes in later life; how multiple early life factors interact and predict long-term lung function deficits and COPD; how adult life factors interact with genetic and early life factors to influence lung function decline; and what are the determinants and consequences of different lifetime lung function trajectories. In this thesis, I aim to investigate risk factors for, and outcomes of, lung function deficits throughout the life course, using data from the Tasmanian Longitudinal Health Study (TAHS). My specific objectives are (1) to investigate the association between childhood lung function and asthma-COPD phenotypes in middle age, (2) to identify childhood respiratory risk factor profiles that influence lung function and COPD development in middle age and to examine the causal pathways involving potential mediators and effect modifiers, (3) to establish trajectories of lung function from childhood to the sixth decade and to investigate the association between identified lung function trajectories and both early life determinants and subsequent COPD risk, and (4) to investigate how interactions between major adverse exposures in adulthood, early life respiratory risk factors and potential genetic factors may influence lung function decline in middle age. In chapter 4, I present my findings that lower lung function at age seven years predicted higher risk of COPD and asthma-COPD overlap syndrome (ACOS) in middle age, independent of personal smoking. In particular, I found that being in the lowest quartile of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) at age seven years was associated with a 5.8 fold and 9.8 fold increase in the risk of COPD and ACOS, respectively. In chapter 5, I present my results identifying six distinct profiles of childhood respiratory risk factors. These risk profiles were associated with differing risks of reduced lung function and COPD in middle age. Among four risk profiles associated with increased risk of lung function deficits and COPD in middle age, the “frequent asthma, bronchitis, allergy” profile was found to be the most “at risk” group. The associations between this profile and COPD and reduced lung function were largely mediated through adult active asthma (62.5% for COPD), with some mediation through reduced childhood lung function (26.5% for COPD). I also found that the association between the “frequent asthma, bronchitis, allergy” profile and middle-aged lung function was aggravated by personal smoking. In chapter 6, I present my results identifying six distinct trajectories of FEV1 from the first to the sixth decade of life, using group-based trajectory modelling. I found that three “unfavourable” trajectories were associated with an increased risk of COPD and collectively contributed 75% of the COPD burden at the sixth decade. Two of the six trajectories were novel and contradict the long-held paradigm that lung function established in childhood tracks through life. I also found that childhood factors including childhood asthma, bronchitis, pneumonia, hayfever, eczema, parental asthma and maternal smoking during childhood predicted membership of the three unfavourable trajectories. In chapter 7, I report my findings that current smoking, current adult asthma, occupational exposures, and living close to major roads were associated with accelerated decline in post-bronchodilator FEV1 and FEV1/FVC, suggesting a predisposition to subsequent airflow obstruction; while body mass index (BMI) gain and incident obesity were associated with both FEV1 and FVC decline, suggesting a predisposition to restrictive lung deficits. Notably, I observed interactions between childhood factors and personal smoking and occupational exposure to vapors/gases/dusts/fumes (VGDF). In particular, accelerated lung function decline associated with current smoking and occupational VGDF was accentuated for those with low childhood lung function, a glutathione-S-transferase M1 (GSTM1) null genotype, or exposure to maternal smoking. Overall, my thesis findings have advanced the current knowledge of the influence of lifetime risk factors on lung function deficits across the life course and their consequences. My findings provide a basis for developing tools that clinicians could use to predict/assess long-term lung health for a child based on his/her exposure patterns. They also provide further impetus for close clinical monitoring of children with impaired lung function. From the public health perspective, my findings suggest that preventing impaired lung function from early life, avoiding unfavourable lifetime lung function trajectories, and promoting favourable lung function trajectories would reduce the burden of lung function impairment, particularly in relation to COPD. My findings also highlight the need for an integrated and comprehensive “life course” preventive strategy, taking into account genetic and lifetime environmental risk factors, and their interactions.
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ItemQuantifying the risk factors for age-related macular degeneration in the presence of survival bias( 2018)Background:Age-related macular degeneration (AMD) is the most common cause of severe irreversible visual impairment among adults living in developed nations. The number of people living with AMD is projected to increase considerably over the coming decades, thus there is a real need to identify modifiable risk factors to delay its onset and progression. Longitudinal studies have been conducted to track exposures and AMD status over many years. However, those at risk of AMD also face the competing risk of death and participant selection for analyses becomes conditional on survival. Under these conditions, traditional statistical methods may produce biased results. Aims: The principal aims of this thesis are: to investigate the plausibility of shared survival-AMD risk-factors by examining the association between AMD and mortality, to examine the performance of a marginal structural model (MSM) and a sensitivity analysis approach when estimating the causal effect of an exposure on an outcome in the presence of survival bias and loss to follow-up, and to extend the sensitivity approach for analysis of a time-varying exposure. In addition, this thesis aims to explore the effect of survival bias when investigating selected risk factors for AMD, namely dietary iron intake, smoking and Mediterranean diet. Methods: Illustrative examples have been drawn from the Melbourne Collaborative Cohort Study (MCCS), a large community-based study conducted between 1990 and 2007. During that time three study waves were completed with assessment of AMD status at the final wave. Analysis of the data from the MCCS and a meta-analysis are presented to assess the association between AMD and mortality. The performances of a MSM (with inverse probability weights for exposure, survival and having non-missing data) and a sensitivity analysis approach for survival bias were assessed via the generation and analysis of simulated data. The sensitivity analysis approach was then extended to allow for the analysis of a time-varying exposure. The performance of this extended approach was compared to that of a MSM in a second simulation study. These statistical methods were then applied to data from the MCCS to examine the association between the selected risk factors and late AMD. Results: Late AMD was found to be associated with increased all-cause and cardiovascular mortality after adjusting for known confounders. MSMs produced biased estimates in the presence of simulated unmeasured survival-outcome confounders. The sensitivity analyses captured the true magnitude of effect within their bounds; however, these bounds were wider than what would be considered clinically useful. The analysis of the effect of smoking on AMD was found to be highly susceptible to survival bias; unlike the exposures of dietary iron and Mediterranean diet, for which the association with mortality was not as strong. Conclusion: The evidence from this thesis supports the theory of shared survival-AMD risk factors which are likely to be unmeasured in large cohort studies such as the MCCS. Therefore, survival bias will be present when the risk factor under investigation is also associated with survival. Sensitivity analyses for survival bias should be considered when investigating AMD risk factors in studies which have been impacted by attrition due to death.
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ItemThe influence of the gestational age at malaria detection and treatment during pregnancy on adverse outcomes in an area of low endemicity( 2017)Background Each year, 125 million women are at risk of malaria in pregnancy (MiP). MiP is associated with several adverse pregnancy outcomes. The safety of artemisinins – the most effective antimalarials available – for the treatment of first-trimester falciparum MiP is a pressing question. Additionally, the influence of the gestational age (GA) when malaria is detected and treated on the effects of MiP is poorly elucidated, particularly in low endemicity areas. I sought to provide a temporal characterisation of the effects of falciparum and vivax MiP on adverse outcomes in a low endemicity area, starting with an assessment of the safety of first-trimester artemisinin treatment. This work will contribute to accurate quantification of the burden of MiP, and the evidence-base for safe treatment, and targeted, context-appropriate interventions for MiP. Methods I analysed observational data collected from antenatal clinics between 1986 and 2015. The clinics were located in refugee camps and migrant communities on the Thai-Myanmar border, where malaria endemicity is low, and were operated by the Shoklo Malaria Research Unit (SMRU). SMRU antenatal care included weekly-to-fortnightly malaria screening. Data on all MiP episodes and pregnancy outcomes were available for analysis. I assessed the association between firsttrimester malaria and miscarriage, and the safety of first-trimester artemisinin treatment. I then assessed associations between MiP and other adverse outcomes [stillbirth, small-for-gestationalage (SGA), and preterm birth] with regards to the GA at malaria detection and treatment. I did a systematic review and meta-analysis to quantify the MiP-stillbirth association, and the influence of endemicity. Finally, I assessed associations between the GA at screening initiation and adverse outcomes in women with and without MiP, and associations between the length of screening absence prior to malaria detection and adverse outcomes in women with MiP. Results Between 6 January 1986 and 31 December 2015, 68919 pregnant women presented to SMRU antenatal clinics. Of these women, 61836 met my minimum inclusion criteria (women living in the migrant communities or refugee camps, with a singleton pregnancy and an estimated GA), and 9350 (15%) women had MiP. First-trimester falciparum and vivax malaria increased miscarriage risk. However, I found no evidence that first-line artemisinin treatment of firsttrimester falciparum malaria, compared to quinine treatment, further increased the risk of miscarriage or of major congenital malformations. Falciparum malaria detected and treated in third trimester was associated with stillbirth, and both vivax and falciparum malaria detected and treated in any trimester was associated with fetal loss (miscarriage or stillbirth). Mediation analyses suggested that the MiP-stillbirth associations were mediated through maternal anaemia and SGA. In a systematic review and meta-analysis, the falciparum MiP-stillbirth association was two-fold greater in low-to-intermediate endemicity settings compared to high endemicity settings. Falciparum malaria detected and treated from 12 weeks’ gestation, and vivax malaria detected and treated from 20 weeks’ gestation, were associated with SGA and/or preterm birth, regardless of symptoms. Delayed initiation of antenatal malaria screening, and longer absences from malaria screening prior to initial malaria detection, were associated with poorer pregnancy outcomes. Conclusion In this area of low malaria endemicity, falciparum and vivax MiP were associated with adverse outcomes, regardless of if and when during pregnancy it is detected and treated. The deleterious effects of MiP were present despite early detection and prompt treatment within the context of an intensive antenatal malaria screening program. MiP interventions should be started as early as possible during pregnancy. Control and elimination efforts in the general population and preconception interventions for women of reproductive age are needed to eliminate MiP and its adverse consequences.
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ItemThe contribution of outdoor fungal spores to child and adolescent asthma hospitalisations: lung function and airway inflammation( 2017)Outdoor fungal spores are among the most common aerobiological particles in the air we breathe. Although a limited number of outdoor fungal species are recognised as exacerbating agents of a number of allergic and respiratory conditions, their contribution towards asthma exacerbation is unclear, particularly among children and adolescents. Moreover, we have limited understanding of the impacts that inhaled fungal spores have on lung function or airway inflammation, which may be pre-clinical signs of asthma exacerbation. Therefore the aim of my doctoral research is to examine whether there are associations between common outdoor fungal spores and child and adolescent asthma hospitalisations, and also to explore if short term exposure to ambient fungal spores is associated with lower lung function or airway inflammation. In Chapter 2, a comprehensive literature review highlights that there are significant knowledge gaps in the contribution of outdoor fungal spores to child and adolescent asthma hospitalisations, lung function and airway inflammation. In order to address some of these gaps, my specific research objectives of this doctoral research were to: (a) systematically synthesise the current evidence as to whether outdoor fungal spores were significant triggers of child and adolescent asthma exacerbations resulting in health service attendances; (b) investigate if there were associations between short term exposure to outdoor fungal spores and child and adolescent asthma hospitalisations; (c) explore if any of these associations were modified by air pollutants, grass pollen, age group, sex, presence of human rhinovirus infection, or fungal sensitisation status; (d) investigate if there were associations between outdoor fungal spores and lower lung function or airway inflammation, and (e) explore if any associations were modified by air pollutants or pollen, age group or fungal sensitisation status. In Chapter 3, my systematic review found that only a small number of studies have been conducted, predominantly in countries located in the northern hemisphere. Children with fungal sensitisation appeared to be at greater risk of asthma hospitalisations. Severity of asthma exacerbation may vary between fungal spore taxa. There were inconsistent findings, possibly due to the lack of accounting for other significant triggers of asthma exacerbations. In Chapter 5, my ecological case-crossover study of child and adolescent asthma hospitalisations in south-west Sydney found that there were associations with Coprinus, Periconia, Chaetomium, Ganoderma and Cerebella, with same day and lagged effects. There was evidence of effect modification by sex, with girls demonstrating stronger associations with Cladosporium, Coprinus and Chaetomium than boys. Age also acted as an effect modifier with older adolescents, demonstrating stronger associations with Coprinus and Ustilago/smuts than those aged under 14 years. In Chapter 6, my case-crossover study of child and adolescent asthma hospitalisations in Melbourne found associations between ambient Alternaria, Coprinus, Drechslera and Leptosphaeria, with signs of same day and lagged effects. These associations were independent of having a human rhinovirus respiratory infection. There was some evidence that Cladosporium sensitisation acted as an effect modifier. In Chapter 7, my cross-sectional study of a high allergy risk cohort comprising of children, adolescents and adults found differing associations between outdoor fungal spores and lower lung function and presence of airway inflammation. Fungal sensitisation acted as an effect modifier with some fungi and parameters of lung function and markers of airway inflammations. Overall, this research has contributed to filling some of the gaps in our current understanding of the contribution of outdoor fungal spore exposures to child and adolescent asthma hospitalisations, lower levels of lung function and airway inflammation. This research demonstrates that the contribution of outdoor fungal spores may be under-estimated. Importantly, species that have not been previously found to be associated with asthma exacerbations, but are genetically related to well-known fungal triggers of asthma exacerbation, may warrant further investigation. Future research needs to improve the modelling of dispersion and distribution of outdoor fungal spores on spatial and temporal levels. The development of reliable and standardised fungal reagents for detection of allergic sensitisation is needed. The presence of fungal spores in the air is important for the ecosystem, and may not be controlled on a large scale, but understanding how to prevent their effects on respiratory health will benefit public health.
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ItemImpact of traffic related air pollution on asthma, allergic diseases and lung function( 2016)Traffic related air pollution (TRAP), the most common type of air pollution in urban areas, has been hypothesised to increase the risk of asthma and allergic diseases. However, epidemiological studies investigating the associations of TRAP exposure and these outcomes have found inconsistent results. These inconsistencies can be partially explained by genetic variations associated with regulating oxidative stress. Therefore, the aim of my doctoral work is to investigate the effects of TRAP exposure on asthma, allergic diseases and lung function while examining these effects are modified by Glutathione S-Transferase (GST) polymorphisms. Polymorphisms of GST genes which are associated with regulating oxidative stress pathways are of special interest because of the biological mechanisms which play an important role in modulating inflammatory responses triggered by reactive oxygen species. In Chapter 2, a critical review of the literature revealed that there are major knowledge gaps in the effects of TRAP exposure on asthma, allergic diseases and lung function, and their interactions with GST polymorphisms. Hence, the specific research aims of the present thesis were to: (i) systematically synthesise the evidence for the association between early life TRAP exposure and the risk of asthma, hay fever and allergic sensitisation during childhood and adolescence, (ii) investigate the relationship between TRAP exposure during first year of life and asthma and hay fever to late adolescence, (iii) investigate the relationship between current annual TRAP exposure and current asthma in middle aged adults and asthma, allergic sensitisation and lung function, (iv) investigate the association of the effect of TRAP exposure over five years in adults and outcomes of asthma and lung function, and to examine if GST gene polymorphisms modify the associations in aims ii, iii and iv. In Chapter 3, my systematic review and meta-analyses of birth cohort studies found that: long term exposure to particulate matter less than 2.5 µm in diameter (PM2.5) or black carbon from birth associated with asthma incidence in childhood, and early life exposure to PM2.5, black carbon or nitrogen dioxide (NO2) exposure were associated with a trend of increased risk of asthma incidence throughout childhood. In Chapter 4, my work in the Melbourne atopy cohort study (MACS), a birth cohort of children with family history of allergic diseases showed that, early life TRAP exposure defined as the cumulative length of major roads within 150 metres of each participant’s residence during the first year of life associated with increased risk of asthma and wheeze at the age of 12 years in carriers of Glutathione S-Transferase theta1 (GSTT1) null genotype. In Chapters 6 and 7, I used two proxies for TRAP: (i) mean annual NO2 exposure, estimated for current residential addresses using a validated land use regression model or (ii) living less than 200 metres from a major road. In Chapter 6, I found that current mean annual exposure to NO2 was associated with increased risk of aero-allergen sensitisation. In addition, current mean annual NO2 and living less than 200 metres from a major road were associated with increased risk of wheeze. In this group of middle age adults, living less than 200 metres from a major road was associated with lower levels of pre- and post-BD FEV1. Carriers of the GSTT1 null genotype had an increased risk of asthma and allergic outcomes when exposed to TRAP compared to GSTT1 non null genotype. In Chapter 7, I found that exposure to higher levels of NO2 over five years was associated with increased risk of asthma. Furthermore, over a five year period, living less than 200 metres from a major road was associated with asthma, wheeze and lower levels of FEV1, FVC and FEV1/FVC. Increased risk of asthma and wheeze associated with living less than 200 metres from a major road over five years was more marked in carriers of the GSTT1 null genotype. Overall, the present thesis has contributed significantly to the current knowledge of TRAP exposure, asthma, allergic diseases and lung function. Consistently, GSTT1 null genotype carriers exposed to TRAP showed an increased risk of these outcomes. The overarching goal being to establish an integrated strategy to improve air quality especially in urban areas, which will benefit the community and reduce the burden of asthma, allergic diseases and poor lung function. An integrated plan can be adopted in controlling TRAP in urban areas including; providing efficient public transport network, use of clean fuel in vehicles, reducing house densities near major roads and vehicles should be monitored regularly for emissions. In setting future air quality guidelines high-risk groups should take into account including genetically susceptible populations and standards should consider lower levels of air pollution which can cause potential adverse health outcomes in these vulnerable subgroups.
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ItemThe acceptability and feasibility of a chlamydia testing intervention in Australian general practice( 2014)Chlamydia trachomatis is the most common bacterial notifiable sexually transmissible infection in Australia with over 80 000 cases diagnosed in 2013. Rates are highest amongst young people aged 16 to 29 years, but the highly asymptomatic nature of chlamydia makes it difficult to ascertain the true burden of infection in the population. Untreated chlamydia can have severe health consequences such as pelvic inflammatory disease, thus it is essential to prevent transmission. This thesis aims to assess the acceptability and feasibility of a chlamydia testing intervention in the general practice setting using data from the Australian Chlamydia Control Effectiveness Pilot (ACCEPt). ACCEPt is a cluster randomised control trial in 54 areas in four Australian states – New South Wales, Queensland, Victoria and South Australia. This thesis has three objectives – 1) to estimate the prevalence of chlamydia in young people aged 16 to 29 attending general practice and assess acceptability of chlamydia testing in this age group; 2) to determine if there are any associations between a general practitioner’s (GP) demographic characteristics, their chlamydia knowledge and chlamydia testing rates in order to inform the feasibility of increased testing in the general practice setting; 3) to qualitatively assess whether a chlamydia testing intervention as conducted in ACCEPt in general practice was acceptable and feasible to GPs. Chapter 1 to Chapter 4 form the literature review for this thesis. Specifically, Chapter 4 is a narrative review of the literature of the barriers and facilitators to chlamydia testing and was published in the Australian Journal of Primary Health. It found that while barriers were well-identified, facilitators had not been the focus of much research. Gaps in the current literature and future areas of research were also described. The methods used in ACCEPt that are relevant to this thesis are outlined in Chapter 5. Chapter 6 describes the results of a baseline survey to estimate the prevalence of chlamydia in young people aged 16 to 29 attending general practice. The prevalence of chlamydia was 4.6% (95%CI: 3.9, 5.3) and was similar between men and women (5.2% versus 4.4%, p=0.25). Over 80% of participants had attended the practice for non-sexual health-related reasons. In conjunction with a high response rate of 70%, this indicates that young people were amenable to being offered a chlamydia test. The high chlamydia prevalence in both men and women highlighted the need for chlamydia control strategies to include both genders. Chapter 7 reports the results of an analysis conducted to determine the associations between a GP’s demographic characteristics, chlamydia knowledge and chlamydia testing rates using logistic regression. Two models were used to distinguish between the influence of GP demographic characteristics and GP knowledge on chlamydia testing. In the first model, which included GP characteristics, higher testing rates were associated with being a female GP (OR=2.5, 95%CI: 1.9, 3.3) and working in a metropolitan clinic (OR=3.2, 95%CI: 2.4, 4.3). In the second model which excluded GP characteristics, increased knowledge of the chlamydia testing guidelines was associated with higher chlamydia testing rates (3-5 correct answers – AOR=2.0, 95%CI: 1.0, 4.2; 6+ correct answers – AOR=2.29, 95%CI: 1.4, 6.2), suggesting that female and metropolitan GPs are more likely to test because they have greater knowledge of the testing guidelines. A qualitative analysis of the data collected from interviews with the GPs at baseline and midpoint to assess the acceptability and feasibility of the ACCEPt intervention is found in Chapter 8. This analysis was informed by the Normalisation Process Theory, a sociological framework, which describes the principles by which an intervention can be embedded into everyday clinical practice. It was found that the facilitators provided by the ACCEPt research team, particularly the feedback report combined with a visit from the research officer, were able to shift GP thinking from symptom-based testing to aged-based testing for chlamydia. The intervention was found to be acceptable to GPs but the feasibility of testing was limited due to the constraints of the structure of the general practice such as the inability to recall young patients. These results demonstrate that the ACCEPt intervention is acceptable to GPs and to young people. However, the feasibility is restricted as many GPs experienced several barriers to increasing testing in general practice. In addition, further research is needed to determine the acceptability and feasibility of chlamydia testing in general practice to the Australian government and supporting agencies if a national chlamydia screening program, as modelled in ACCEPt, were initiated. In conclusion, increasing chlamydia testing in general practice is acceptable to young people and GPs, and is feasible to GPs but requires a targeted, multidisciplinary intervention to normalise it into routine practice.
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ItemUnderstanding the determinants of pertussis spread to improve herd protection of vulnerable infants( 2014)In the first half of the 20th century, 2-5 yearly whooping cough epidemics caused a substantial burden of death and disease in Australia. The introduction of mass vaccination in the 1950s dramatically reduced disease incidence, but from the 1980s onwards resurgence of cases was observed, placing vulnerable infants at risk. Similarly to other countries with well-established vaccine programs, from 2008-2012 pertussis incidence reached the highest levels in Australia since the implementation of vaccination. I developed an age structured, deterministic, compartmental transmission model to investigate the underlying infection patterns consistent with Australia's observed pertussis epidemiology, using a variety of local data resources. Varying levels of susceptibility to infection were included to account for the possible dependence of susceptibility and infection characteristics on the time since prior infection or vaccination. Biologically plausible parameter ranges were explored using Latin Hypercube Sampling and the model simulated through the pre-vaccine and vaccine eras. Simulation results were filtered to match aspects of pertussis epidemiology about which we can be reasonably certain from long term surveillance data, including persistence of 2-5 year epidemic cycles, relative maintenance of infant protection and declining natural immunity across all age cohorts. Only simulations with natural immunity lasting decades simultaneously reproduced the adult immunity profiles observed in serosurveillance and the substantial impact of vaccination on incidence. Although the initial impact of vaccination was substantial, fluctuations in vaccination coverage through the pertussis vaccine scare of the 1970s were sufficient to allow breakthrough increases in circulation in the model. The long duration of natural immunity required to match observed epidemiology meant that cohorts infected during periods of low coverage were primed to experience a resurgence decades later. In order to replicate the observed sustained, substantial impact of vaccination on infants, the model had to be configured with the primary course delivered as three separate doses, with additional protection against infection acquired with each dose. This finding was consistent with the reduction in infant disease observed across the 2, 4 and 6 month schedule age points. Additionally, an emergent property of the model was that pertussis vaccines induce herd protection of infants. Using my model to project alternative historical vaccination schedules for simulations matching the key characteristics of pertussis in Australia, I found that of the changes made after 1990, the addition of the pre-school booster in 1995 had the largest impact on infection incidence in infants. While the replacement of the 18mth booster with an adolescent dose from 2003 had a limited impact on infants, the direct effect on the 18mth-4yr age group was substantial. More generally, the addition of extra doses to the vaccine schedule increased herd protection in the model, while altering the ages at which doses are given had substantial direct effects but a limited impact on infants. The challenge for policy makers is to design a vaccine program that allows circulation sufficient to maintain immunity in older age groups through boosting while simultaneously protecting infants from such circulation.