Melbourne School of Population and Global Health - Theses
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ItemLifetime asthma and the development of fixed airflow obstruction( 2023-05)Asthma is a major public health problem worldwide and its prevalence has risen considerably over recent decades. Asthma prevalence in Australia is among the highest in the world and thus has been recognised as an Australian National Health Priority Area since 1999. There is now established evidence that asthma has adverse effects on lung health over the life course and strategies aimed at improving long-term outcomes are urgently needed. The natural history of asthma is influenced by complex interactions between genetic and environmental factors. Despite extensive research in this area over recent decades, many uncertainties remain. An important limiting factor has been the lack of suitable prospective studies with follow-up from childhood (when asthma is most prevalent) into middle-age (when respiratory complications manifest clinically). To address these knowledge gaps, my doctoral work utilises data from the Tasmanian Longitudinal Health Study (TAHS), the world’s largest and longest-running population-based study of respiratory disease. The primary aim within my thesis is to characterise the natural history of asthma and its cumulative effects on lung health over the life course, focusing on a complication known as fixed airflow obstruction. I also aim to evaluate strategies which might improve these outcomes in asthma, and to validate novel methods of detecting these complications earlier in the disease process. The findings of this work will have important clinical and public health implications, with the overall objective of improving asthma outcomes in Australia and worldwide. In chapter 4, I present a study on the diagnostic utility of bronchodilator responsiveness (BDR) as a test for adult asthma, both with and without fixed airflow obstruction (FAO). I provide specific data on the sensitivity and specificity of commonly-used BDR cut-offs, and additional normative data on BDR ranges in a general population cohort. In chapter 5, I present my findings that asthma follows five longitudinal pathways (phenotypes) from childhood to middle-age, each associated with different risks of developing FAO. Importantly, I found that even apparently remitted asthma was associated with FAO in middle-age, despite an absence of symptoms. In chapter 6, I present my findings of several biomarkers which hold prognostic value in adults in spontaneous asthma remission. I showed that abnormal serum cytokine profiles (Th2-high and Th2-low) were associated with accelerated lung function decline in these individuals. In chapter 7, I present the findings of a systematic review and meta-analysis showing that long-term use of inhaled corticosteroids (ICS) are associated with modest, age-dependent improvements in lung function children and adults with asthma. In chapter 8, I present my findings that lung function thresholds can accurately identify individuals at high-risk of developing FAO in the future. I describe a particular threshold of pre-BD FEV1/FVC < 10th percentile as accurately identifying 88% of individuals who developed COPD over an 8-year follow-up period, while excluding 87% of individuals who did not. Collectively these findings provide new insight into the complex relationship between asthma and lung function over the life-course, with a particular focus on the development of FAO. My work highlights lifetime asthma as a potentially-modifiable risk factor for FAO, and describes the high-risk subgroups in whom early detection and prevention strategies might be beneficial.
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ItemThe development, implementation and evaluation of first few X household transmission studies in Australia( 2023-04)New or re-emerging infectious diseases pose a serious threat to public health. First Few X (FFX) studies provide a platform for the rapid collection of detailed epidemiological data and specimens from cases and their close contacts to understand the potential impact of such diseases. When activated in the early epidemic stages, the data collected from FFX studies can be used to produce estimates of key transmissibility and severity parameters to inform public health and social measures. The Australian Government Department of Health recognise the value of FFX studies, however, detailed protocols in the Australian context were not finalised at the start of my doctoral research in 2019. This thesis documents my experience contributing to the development of a global FFX protocol for pandemic influenza in 2019, as part of my internship at the World Health Organization. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the advent of the global coronavirus disease (COVID-19) pandemic during the first year of my studies rapidly pivoted my PhD focus from piloting a FFX study during the 2020-2021 influenza seasons to implementation in a global health emergency. As such, I detail my role coordinating the design and implementation of the Australian FFX Project for COVID-19 – a national study of confirmed cases of COVID-19 and household contacts conducted between April-October 2020. Using a contact-level mixed-effects logistic regression model, I estimated the household secondary attack rate to be 12% (95%CI 7–17%), which aligned with the estimate produced by my collaborators (15%, 95%CrI 8–25%) using a mathematical model. As this was the first project of its kind in Australia, there were many challenges encountered with respect to logistics, ethics, governance, and data management. I subsequently led a qualitative evaluation of stakeholders involved in the project to consolidate on lessons learnt to inform future FFX platform development in Australia. Four main recommendations were developed from the series of modified Delphi surveys and interviews with key stakeholders, including: forming strong partnerships between health departments and researchers; developing FFX protocols that can be easily adapted for different pathogen contexts; investing in data infrastructure, and; having broad ethical approvals in place before a study begins. The learnings presented in this thesis have significant implications for pandemic planning in Australia, by reinforcing the need for pre-determined and pandemic-ready FFX protocols. The development of a fit-for-purpose FFX protocol in Australia, in advance of the next infectious disease emergency, will enable better understanding of the epidemiology in the early and subsequent epidemic phases of a novel or re-emerging pathogen and help inform a proportionate public health response.
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ItemPreventing violence-related death and morbidity among people who have had contact with the criminal justice system( 2022)Although rates of violence globally have been decreasing in recent decades, the risk of experiencing violence remains disproportionally concentrated among people who experience marginalisation and disadvantage. Many of the health and social inequities that predispose people to experiencing violence are highly prevalent among those who have had contact with the criminal justice system. However, there is little evidence on the risk of violence victimisation in this population. This constrains our ability to design effective violence prevention strategies that can meet and respond to the needs of those who have had contact with the criminal justice system. My thesis aimed to fill this gap in the literature by generating novel evidence on the epidemiology of violence-related death and morbidity among young people and adults who have had contact with the criminal justice system. I conducted a narrative review of the literature, five discrete original research studies, and I produced a protocol for a systematic review and meta-analysis, and a letter to the Editor. I also extended the Public Health Approach to Violence by applying it, for the first time, to those who have had contact with the criminal justice system. My thesis findings indicate that young people and adults who have had contact with the criminal justice system have a risk of violence-related death and morbidity that is far greater than that of the general population. Among people who have had contact with the criminal justice system, women, Indigenous people, and those with mental health and/or substance use issues are particularly at risk. Evidence-informed violence prevention strategies are urgently needed in this population. The findings of my thesis can be used to inform the development of such strategies. Taken together, the evidence suggests that in order to be effective, a violence prevention approach for this population should address the health and social inequities that are both drivers of violence and disproportionately impact people who have had contact with the criminal justice system. Effective responses must also take into consideration the sex- and culturally-specific needs of those who have had contact with the criminal justice system. Until such action is taken, people who have contact with the criminal justice system will continue to experience violence victimisation at a rate that far exceeds that in the general population.
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ItemEarly origins of childhood neurodevelopmental and emotional-behavioural disorders( 2022)Background: Neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), and emotional-behavioural disorders (EBD), such as internalising and externalising, are increasingly recognised as leading causes of morbidity in children. Identification of environmental influences and mechanisms that contribute to the increasing burden of these disorders remain a great challenge. Research objectives: I aimed to deeply investigate several early life (i.e., prenatal, perinatal, and postnatal) social and environmental factors and advance the understanding of downstream biological pathways –oxidative stress, inflammation, and telomere shortening– in early life, related to childhood ASD, ADHD and EBD. Method: Modern epidemiological approaches were applied to data from the Barwon Infant Study, a prospective birth cohort study of 1074 mother-infant pairs, to examine the prospective associations between early life factors, biological measures, and later neurodevelopmental and emotional-behavioural outcomes in young children. Results: In Chapter 4, I present my published findings that children with ASD symptoms at age two years are overrepresented in socioeconomically disadvantaged families and among mothers with poorer lifestyles and mental health challenges. A diverse range of early life modifiable risk factors, including maternal lifestyle factors during pregnancy and environmental air pollutants, may have an important role in the pathogenesis of ASD. In Chapter 5, I present my findings that greater maternal oxidative RNA damage during pregnancy is associated with increased childhood EBP, particularly emotional symptoms (depression and anxiety) at ages two and four years. Greater maternal oxidative RNA damage during pregnancy partly mediates the associations between several early life socioeconomic disadvantage indicators and prenatal lifestyle factors to increase EBP in young children. In Chapter 6, I present my published results that increased levels of the inflammatory biomarker, glycoprotein acetyls (GlycA), at birth were associated with greater EBD (internalising and externalising problems) at age two. The effects of several early life factors, such as socioeconomic disadvantage indicators, on internalising problems at age two were partly mediated by higher inflammation. In Chapter 7, I present my published findings of an inverse association between shorter telomere length at 12 months and subsequent ADHD symptoms in children at age two. Environmental air pollutants, such as infant secondhand smoke exposure at one month, were independently associated with shorter telomere length at 12 months and greater ADHD symptoms at age two. Conclusion: This thesis provides new knowledge from a deep investigation of the relationship between early life modifiable environmental risk factors and biological mechanisms of childhood ASD, ADHD, and EBD. My research may assist future preventative strategies and therapeutic efforts to target environmental insults and minimise oxidative stress and inflammation and accelerated telomere shortening in early life, particularly in high-risk groups, to reduce the incidence of these disorders and/or their impact on young children.
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ItemEstimating the effect of lifestyle over the course of adulthood on all-cause and cause-specific mortality( 2022)Background Existing evidence linking lifestyle-related factors (body mass index [BMI], physical activity, sedentary behaviour, and alcohol consumption) to mortality is primarily based on observational studies with single-time-point exposure assessments. However, the effects of lifestyle changes or benefits of long-term adherence to public health recommendations during adult life cannot be estimated without using data from additional time points. Despite the fact that many cohort studies have assessed exposures and confounders repeatedly over time, a limited number of studies have used these data. This thesis aims to estimate the effects of time-varying lifestyle-related exposures during adulthood on mortality using longitudinal studies with repeated exposure assessments. Lifestyle-related factors to be examined include BMI, physical activity, sedentary behaviour, and alcohol consumption. Methods This PhD research included four studies. In Study 1, I performed a systematic review of mortality studies that repeatedly assessed adulthood physical activity and sedentary behaviour. I summarised the study findings and critically appraised the analytic approaches used to analyse data on time-varying exposures. Studies 2 to 4 used data from three Australian cohorts with multiple data collection waves to estimate the mortality effects of adulthood lifestyle-related exposures. The three cohorts were the Melbourne Collaborative Cohort Study (MCCS), the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), and the Australian Longitudinal Study on Women’s Health (ALSWH) 1946-1951 birth cohort. Deaths in the three cohorts were ascertained through probabilistic record linkage to the Australian National Death Index. In Study 2, I used a group-based trajectory model to identify clusters of individuals in the MCCS who followed similar body mass index trajectories over adulthood, and estimated mortality for the identified trajectories. In Studies 3 and 4, I used the parametric g-formula to analyse the data from the AusDiab study and the ALSWH 1946-1951 birth cohort, which estimated potential mortality outcomes under hypothetical sustained population interventions on physical activity, TV viewing, and alcohol consumption. Results The systematic review found that the most common way to treat repeatedly measured exposures was to categorise them into a summary variable. The most widely used statistical analysis method was Cox regression. The included studies were subject to moderate to serious risk of bias, mainly arising from inadequate adjustment of time-varying confounding, selection of participants affected by post-baseline vital status, questionnaire-based exposure assessment, and changes from measured exposure during long passive follow-up periods. Despite heterogeneity in methods, the findings suggest that maintaining a more physically active and less sedentary lifestyle over adulthood reduces all-cause and cardiovascular mortality moderately. Findings from the MCCS suggested that midlife obesity increased mortality even when BMI was normal in early adulthood, and prolonged exposure to borderline obesity could increase mortality, compared with maintaining a higher-normal BMI. In AusDiab, sustained interventions during adulthood to increase leisure-time physical activity could lower all-cause mortality, and there might be limited gain from intervening on television (TV) viewing time in a relatively healthy population. In the ALSWH 1946-51 birth cohort, compared with having no alcohol intervention, sustained interventions of moderate alcohol consumption (up to 30 grams of ethanol per day) may lower all-cause mortality but not cancer mortality, while a high intake intervention (more than 30 grams of ethanol per day) would increase both all-cause and cancer mortality over the long term for women in their midlife. Conclusion The systematic review summarised existing mortality studies using physical activity and sedentary behaviour measured at multiple time points. It also critically appraised the methods used and potential sources of bias in these studies. The group-based trajectory approach used in the MCCS contributed to the understanding of mortality outcomes experienced by individuals who followed different BMI developmental courses over adulthood. The two applications of parametric g-formula in the AusDiab and ALSWH 1946-1951 birth cohort demonstrated estimation of causal effects of hypothetical sustained population interventions, producing policy relevant evidence. Collectively, research in this thesis showed that, with data measured at multiple time points, one could estimate mortality effects of long-term exposures, which cannot be achieved using single-time-point measurements. The research also demonstrated the use of observational data to emulate a target trial that is infeasible or unethical in a real-world setting. When analysed with appropriate statistical methods, exposure and confounder data assessed at multiple time points can be used to estimate potential mortality outcomes under hypothetical long-term lifestyle interventions. Future research should leverage repeatedly collected data in existing cohort studies to address the methodological challenges inherent in typical epidemiological studies. This would help provide greater insight into mortality effects of initiating or maintaining a certain health behaviour, guide population interventions, and refine evidence for guidelines and recommendations.
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ItemThe Epidemiology and Management of Rectal Chlamydia( 2021)Thesis Summary Introduction Chlamydia trachomatis (“chlamydia”) is the most commonly reported sexually transmitted infection (STI) in the world. Untreated, chlamydia is associated with serious reproductive sequelae in women including infertility. Rectal chlamydia is an important public health problem in Australia with rates rising dramatically among men who have sex with men (MSM), increasing evidence to suggest it is also an issue for women, and ongoing concern about rectal chlamydia treatment failure. This PhD program of research aims to investigate the epidemiology of rectal chlamydia with particular focus on treatment. It includes the first double-blind randomised control trial to identify the most efficacious treatment (azithromycin vs doxycycline), a cross-sectional study to further our understanding about the management of rectal chlamydia infection in men who have sex with men, and a systematic review and meta-analysis of the factors associated with rectal chlamydia positivity in women. Chapter outline The objectives of this thesis were: 1) To determine whether azithromycin or doxycycline is the most efficacious treatment for rectal chlamydia infection; 2) To examine the factors associated with the resumption of sexual activity following treatment for rectal chlamydia among MSM; and 3) To investigate the factors associated with rectal chlamydia in women with concurrent infection at other sites, and to compare these with those observed for rectal gonorrohoea. This thesis is comprised of three major components: 1) the protocol, statistical analysis plan, and results of a double-blind randomised controlled trial (RCT) comparing the efficacy of 1g azithromycin with 7-day 100mg doxycycline (twice a day) for the treatment of rectal chlamydia; 2) a cross-sectional study examining factors associated with resuming sexual activity following treatment for rectal chlamydia among MSM; and, 3) a systematic review and meta-analysis on the factors associated with rectal chlamydia positivity in women. Chapter 1 is a comprehensive literature review on what we know about the chlamydia and in particular, rectal chlamydia. The review discusses the factors for rectal chlamydia, its management, and the treatment concerns to provide context and rationale for this thesis. The literature review demonstrates that rectal Chlamydia trachomatis infection remains an important public health concern with increasing prevalence in both men and women and ongoing uncertainty in the efficacy differences for the treatments used. Several gaps remain in the epidemiology and control of rectal chlamydia including: 1) uncertainty about the most efficacious treatment for rectal chlamydia - azithromycin 1g single dose versus 7-day of doxycycline 100mg (twice a day); 2) the risk of onward transmission or reinfection following treatment among men who have sex with men, and the risk of selection pressure and resistance with continued use of azithromycin; 3) the factors associated with rectal chlamydia among women, in particular with concomitant infection at other sites. Chapters 2 to 4 presents the protocol, statistical analysis plan, and results of the RCT to compare the efficacy of 1g azithromycin to 100mg doxycycline twice daily for seven days for the treatment of rectal chlamydia – the first such trial in the world. The trial observed a microbiologic cure of 281/290 (96.9%; 95CI% 94.9, 98.9) for doxycycline and 227/297 (76.4%; 95%CI 73.8, 79.1) for azithromycin, with an adjusted risk difference of 19.9% (95%CI 14.6, 25.3; p<0.001) in favour of doxycycline. The trial found that the treatment efficacy of 1g azithromycin was even lower than predicted by previous meta-analysis (82.9%; 95%CI 76.0, 89.8%) and confirm that the efficacy this regimen to be far below the World Health Organization efficacy threshold of 95% for STI treatments. The trial provided unequivocal evidence that 1g azithromycin should be removed from international STI management guidelines. Chapter 5 is a cross-sectional study that utilised data from the RCT to investigate factors associated with resuming sexual activity following treatment for rectal chlamydia as a marker for risk of reinfection. This chapter also highlights the possibility of selective pressure of antimicrobial resistance for STIs such as Neisseria gonorrhoeae (NG) or Mycoplasma genitalium through the continued use of azithromycin for the treatment of rectal chlamydia. The study found that 9.5% of men resumed condomless receptive anal intercourse within a week of commencing treatment for rectal chlamydia and that this was independently associated with PrEP use (aRR=3.4; 95%CI 2.5, 4.8) or a man living with HIV (aRR=3.2; 95%CI 1.0, 9.9), relative to an HIV-negative man who did not use PrEP, and reporting 9 or more partners in the last three months (aRR=2.9; 95%CI 1.6, 5.0), relative to reporting 3 or fewer. In addition, 40% of men resumed condomless anal sex within 3 weeks. The study also found that 75% of men resumed any sexual activity within 3 weeks of commencing treatment for rectal chlamydia and that this was associated with reporting 4-8 (aRR=1.2; 95%CI 1.1, 1.5) or 9 or more sexual partners in the last three months (aRR=1.5; 95%CI 1.3, 1.7), relative to reporting 3 or fewer. This study illustrates the risk of induced antimicrobial resistance if azithromycin is continued to be used for rectal chlamydia in populations where reinfection is common and suggests that new health promotion messages may be required in some subgroups. Chapter 6 presents the findings of a systematic review and meta-analysis investigating the factors associated with anorectal chlamydia positivity in women. The review was novel in that it both: 1) quantified the relationship between anorectal chlamydia with concurrent chlamydia infection at the urogenital or oropharyngeal sites; and 2) compared to the same for anorectal gonorrhoea infection within the same study populations for a more comprehensive understanding. The review found that among the 25 studies eligible for inclusion, anorectal chlamydia positivity (summary estimate=8.0%; 95%CI 7.0, 9.1, I2=88.5%) was higher than anorectal gonorrhoea positivity (summary estimate=2.1%; 95%CI 1.6, 2.8, I2=92.7%). It found that urogenital chlamydia was strongly associated with rectal chlamydia (summary prevalence ratio [PR]=32.2; 95%CI 25.6, 40.7, I2=70.3%), but urogenital gonorrhoea was even more strongly associated with anorectal gonorrhoea (PR=89.3; 95%CI 53.1, 150.3, I2=80.1%). Similarly, the association between oropharyngeal and anorectal positivity was also stronger for gonorrhoea than chlamydia (PR=34.8; 95%CI 10.2, 118.2, I2=89.9% vs PR=8.8; 95%CI 6.8, 11.5, I2=58.1%). Finally, anal intercourse was associated with anorectal gonorrhoea (PR=4.3, 95%CI 2.2, 8.6, I2=0.0%) but not anorectal chlamydia (PR=1.0; 95%CI 0.7, 1.4; I2=0.0%). Conclusions This thesis found that azithromycin 1g was inferior to 7-day doxycycline in the treatment of anorectal chlamydia in men who have sex with men, providing unequivocal evidence that doxycycline must replace azithromycin as first line treatment for rectal chlamydia. It is essential that while azithromycin is still in use, there must be stronger health promotion messages following treatment encouraging condom use to minimize exposure to sub-inhibitory levels of the drug. Continued use of azithromycin 1g may contribute to selection pressure for antimicrobial resistance in other STIs that are highly prevalent in those diagnosed with rectal chlamydia. Finally, this thesis found that re-testing following treatment with azithromycin in women diagnosed with urogenital chlamydia is very important because of its strong association with concurrent rectal chlamydia and its potential to autoinoculate a subsequent urogenital infection if not effectively cured.
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ItemA study of the effect of adverse psychosocial work stressors on health and mortality( 2021)The working environment is central in the lives of individuals in employment, influencing health outcomes including psychological and physical well-being. Psychosocial work stressors are common exposures in the workplace and are important and modifiable determinants of health and health behaviours. There is broad agreement in the literature that exposure to adverse psychosocial work stressors, such as high job demands, low job control, low job security and high effort-reward imbalance are associated with poor health outcomes. All of these exposures are, in turn, associated with unhealthy behaviours such as smoking, alcohol consumption, poor diet and inactivity, and to the development of hypertension, cardiovascular disease, diabetes, musculoskeletal disorders and depressive disorders. Psychosocial work stressors have been identified as significant emerging risks linked to global changes in the structure, organisation and management of work during previous decades, presenting pressing challenges to occupational health and safety and workplace health, in general. Most of the literature in this area assesses disease incidence or other morbidity outcomes, with a growing number of studies focusing on mortality. However, whether exposure to these psychosocial work stressors associated with adverse health outcomes translates into increased mortality remains unclear, and barriers to making causal interpretations about the relationship between psychosocial work stressors and health persist, mostly due to inherent biases in the methodology across studies. In this thesis, the effect of exposures to psychosocial work stressors in the working environment such as job control, job demands, job strain, long working hours, job insecurity and shift work on health and mortality were investigated. A comprehensive systematic review including meta-analyses of the epidemiological research was conducted. Panel data from the Household, Income and Labour Dynamics in Australia survey was used to capture natural experiments of psychosocial work stressors associated changes in health and well-being, and mortality to investigate whether and how the effect of psychosocial work stressors on mortality differ in relation to demographic and socioeconomic characteristics. The initial focus of the research included establishing and quantifying the risks associated with adverse psychosocial work stressors, which workers are commonly exposed to in the workplace, on mortality. The final study in the PhD focused on understanding the exposure-outcome dynamics. The dynamics of the connexions between psychosocial work stressor perceived job control and general health, a strong predictor of future morbidity and mortality, were investigated for evidence of a causal relationship. The first study showed that improving the quality of work might contribute to better health and well-being and decrease the effect of psychosocial work stressors on all-cause mortality and cardiovascular disease mortality. If this observed association is causal, then policy and practice interventions to improve job control could contribute to reductions in mortality. Study II adds to the growing body of evidence showing an effect of adverse psychosocial work stressors on mortality. Study III showed that long-term exposure to low job control and job security was associated with increased risk of all-cause mortality. In Study IV, the dynamics of job control and general health were explored for evidence of a causal relationship using three complementary longitudinal modelling approaches. This study, using improved causal inference methods than previous research, showed that increased job control was strongly associated with increasing general health. Although the estimates for the single measures suggest modest increases in the risk of death and poor health, this translates to large population impacts because the exposures are relatively common across the working population. Thus, reducing exposure to psychosocial work stressors associated with mortality and poor health could have considerable public health benefit. Awareness by stakeholders, government and organisations of the implications of the adverse effects of psychosocial work stressors on health and mortality in workplaces; and the availability appropriate, evidence-based work stress interventions to reduce the exposure to work stressors might contribute to better health and well-being, reduce sickness absence and presenteeism to the benefit of workers, workplaces and society.
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ItemThe impact of household risk factors and their interactions with antioxidative stress genes on respiratory health( 2019)Background: Asthma affects people of all ages and is associated with a substantial impact on both the individual and the community, yet there are few effective strategies to prevent its development or persistence. This is because the aetiology of asthma and factors influencing its progression or remission are currently poorly understood. Asthma primarily affects lung function. Progressive lung function decline associated with asthma is well-recognised but has not been commonly investigated as an outcome in asthma studies. Knowledge on the critical factors influencing maximal development of lung function in childhood is scarce. The development of asthma and allergic diseases is very complex and believed to be influenced by multiple genetic and environmental factors that may influence asthma risk from pre-conception through to adult life. A range of strategies modifying environmental exposures have been trialled to potentially reduce the risk of asthma, with many studies finding no evidence of substantial benefit, or only limited benefit, from the interventions. Additionally, although some genes are associated with increased asthma risk, the associations are small and only explain a small percentage of the large asthma burden. There is evidence of some gene-environmental interactions, but these relationships are varied and complex and have not yet been fully investigated or understood. Elucidating the interactions between environmental risk factors and genetic factors and their associations with respiratory outcomes in both childhood and adulthood may help identify asthma prevention strategies. The main aim of my PhD work was to investigate one group of gene-environment interactions; the relationship between oxidative exposures and antioxidant genes on asthma and lung function. Specifically, I investigated the associations between various household environmental oxidant exposures and respiratory outcomes from childhood to middle age and examined whether those associations were modified by Glutathione s-Transferase (GST) genes, which are known buffers of oxidative stress. Methods: I used a range of methods to address my research aims, including a systematic literature review and data analyses of two longitudinal cohort studies: the Melbourne Atopy Cohort study (MACS), and the Tasmanian Longitudinal Health Study (TAHS). MACS began as a randomised controlled trial investigating the effects of infant formulas at weaning and, has subsequently become a prospective birth cohort. Initially, 620 pregnant women were recruited between 1990 and 1994. The MACS children have now been followed up to 18 years of age. The TAHS is a population-based study of respiratory disease spanning from childhood to adulthood. The study began in 1968, recruiting 8,583 Tasmanian school children born in 1961 (approx. 98.8% of the Tasmanian population for 1961 births). Extensive follow-ups of initial participants were conducted in 2002 and 2012, respectively, when participants were in their 40s and 50s. Both the MACS and the TAHS collected a substantial amount of exposure and outcome data at multiple ages over the lifespan through questionnaires and clinical testing, providing a great opportunity to address questions concerning gene-environment interactions and respiratory health outcomes. I investigated the following oxidative exposures: early life tobacco smoke, early life paracetamol, heating and cooking facilities, mould, long term and current active and passive tobacco smoke. Previous evidence suggests that these common home environmental exposures are associated with increased oxidative stress, and therefore, their impacts are likely to be modified by GST genes. So, in conjunction with these exposures, I investigated potential interactions with GST gene polymorphisms at two significant developmental stages: during lung function growth in childhood and adolescence, and during lung function decline in middle age. Research Gaps: Firstly, I systematically reviewed the current evidence on interactions between indoor air pollution and GST genes in association with allergies, asthma and lung function (Aim 1: Chapter 3). I then conducted a study to examine the interactions between early life tobacco smoke exposure and GST genes on asthma and lung function in childhood and adolescence using Melbourne Atopy Cohort Study (MACS) data (Aim 2: Chapter 5). Another study on the potential interactions between paracetamol use before 2 years of age and GST genes in association with asthma and lung function in later life was performed using MACS data (Aim 3: Chapter 6). In this study, I adjusted for early life exposure to respiratory infections, an important confounding factor which has not been adjusted for by many previous studies. Finally, I conducted a study using data from the TAHS to investigate similar associations in middle-age (Aim 4: Chapter 7). In this analysis, I identified seven longitudinal exposure profiles using Latent Class Analysis (LCA) methods with common household air exposures including heating and cooking types, mould exposure, passive and active smoking. I then determined the associations between these risk profiles and respiratory outcomes, and whether these profiles were modified by GST genes. Linear and logistic regression were used to investigate these associations. Results: Aim 1. My systematic review of the relationship between indoor air pollution, GST genes and asthma identified 22 eligible studies, with 15 finding some evidence of gene-environment interactions. Overall, carriers of GSTM1/T1 null and GSTP1 Val105 genotypes exposed to indoor air pollution, were more susceptible to developing asthma and reduced lung function. However, these findings were more consistent in studies of children compared to studies of adults (Chapter 3). Aim 2. I found evidence that early life tobacco smoke exposure was associated with an increased risk of asthma, reduced lung function growth between 12 and 18 years, and reduced lung function at 18 years, with girls appearing to be more susceptible than boys (master research program). I also found an interaction between early life tobacco smoke exposure and GST genotypes on lung function at both 12 and 18 years. Carriers of GST null mutations and GSTP1 Ile/Ile alleles were more susceptible to tobacco smoke in early life, and these associations were not found in carriers of other GST genotypes (Chapter 5). Aim 3. I found some evidence that early life paracetamol use may be associated with impaired lung function and increased risk of asthma in adolescence after adjustment for the frequency of early life respiratory tract infections. Interaction analysis suggested that these associations were only for carriers of GSTM1 null and GSTP1 Ile/Ile genotypes, I did not find evidence for carriers of other GST genotypes (Chapter 6). Aim 4. I found that the exposure profiles of “Wood heating”, “All gas”, “Wood heating/smoking” and “Wood heating/gas cooking” were associated with persistent asthma and greater lung function decline by age 53 years. Carriers of GSTP1 Ile/Ile genotypes had a greater risk of asthma at age 53 years with exposure to “All gas” and “Wood heating/smoking” compared to a reference group (reverse cycle air conditioning, electric cooking and no smoking). Carriers of GSTM1 null and GSTP1 Ile/Ile genotypes had a greater risk of accelerated lung function decline when exposed to “Wood & gas heating/gas cooking/smoking” and “Wood heating/gas cooking” compared this reference group. These associations were not observed in carriers of other genotypes (Chapter 7). Conclusions: My work identified several household risk factors associated with the progression of asthma, limited maximal lung function development in childhood, or accelerated lung function decline in adulthood. Additionally, this work provides evidence on interactions between household exposures and GST polymorphisms and has contributed significantly to our understanding of gene-environment interactions in relation to respiratory health. These findings highlight the importance of considering potential gene-environment interactions in studies that investigate exposures associated with lung oxidative stress. These findings have the potential to inform guidelines and preventive strategies, especially for people who are at increased risk.
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ItemHow do socio-economic characteristics influence the effect of disability acquisition on mental health? An analysis of effect modification and mediation( 2019)Background People with disabilities in Australia experience poorer mental health than people without disability. However, the mechanisms by which disability leads to poor mental health are inadequately understood. This PhD thesis aims to form a better understanding of how people’s socio-economic circumstances influence the effect of disability acquisition on mental health. Elucidating the causal mechanisms underpinning this relationship will inform the development of effective public health and social policies to improve the mental health of people with disabilities. Methods I used data from the Household, Income and Labour Dynamics in Australia Survey – a large nationally representative longitudinal dataset – to quantify the effect of disability on mental health and to examine the socio-economic mechanisms leading from disability acquisition to poor mental health. I identified adults who acquired a disability during their participation in the survey and used data both before and after they acquired the disability to estimate the causal effect of disability on mental health. Firstly, I conducted analyses of effect modification, examining a wide range of different socio-economic factors to determine whether they influenced the magnitude of the effect of disability acquisition on mental health, using inverse probability weighting and fixed effects models to better control for confounding. Secondly, I conducted causal mediation analyses to further examine the socio-economic mechanisms leading from disability to poor mental health, using sequential mediation analysis to examine a broad range of socio-economic characteristics and an interventional mediation approach to quantify indirect effects operating through two distinct socio-economic characteristics: employment and income. Finally, I examined the indirect effect mediated by employment in greater detail, further decomposing the natural indirect effect through employment to estimate the proportion attributable to interaction, mediation and their joint effects. Results There is a clinically significant and large effect of disability acquisition on mental health. The analyses of effect modification provided evidence that the magnitude of the effect differed according to people’s socio-economic characteristics, with greater effects observed for more disadvantaged groups. The mediation analyses provided additional evidence that socio-economic characteristics contribute to the effect of disability acquisition on mental health. A third of the effect was found to be mediated by material socio-economic factors such as employment, income, wealth, financial hardship and housing characteristics, and a further investigation of the indirect effect through employment and income highlighted employment (but not income) as an important contributing factor, explaining 11% of the effect alone. Finally, further decomposition of the indirect effect through employment suggested that the mediated effect was due to interaction between disability and employment, rather than pure mediation. Conclusion The findings of this thesis highlight the importance of the social determinants of health in generating mental health inequalities. Interventions should prioritise addressing the social determinants of health to improve the mental health of people with disabilities and reduce disability-related mental health inequalities. Furthermore, the evidence that employment is a key mediator of the effect of disability acquisition on mental health indicates that policy strategies are needed to target the causes of low employment rates for people with disabilities.
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ItemNatural history and consequences of food sensitisation: results from two birth cohort studies( 2016)The prevalence of allergic diseases is increasing worldwide, particularly in Australia and other “westernised” countries. More recently, evidence suggests a second wave of the “allergy epidemic”, with an increase in the prevalence of food allergies. Despite intense research in this area, there are numerous questions concerning the potential risk factors for the development of allergic diseases. It has been shown that sensitisation to aeroallergens is strongly associated with allergy progression. However the associations between food sensitisation and the development of allergic conditions remain unclear. Therefore, my doctoral work has investigated the natural history of food sensitisation from infancy up to adolescence in an allergy high-risk cohort. I have also investigated the associations between early life food sensitisation and subsequent probable food allergy, asthma, allergic rhinitis and lung function during later childhood and adolescence. Data from an Australian allergy high-risk cohort (Melbourne Atopy Cohort Study (MACS)), and a German population-based cohort (Influence of Life-style related factors on the development of the Immune System and Allergies in East and West Germany PLUS the influence of traffic emissions and genetics (LISAplus)), were used to address the aims of this thesis. MACS recruited 620 infants with a family history of allergic disease prior to birth. The infants were followed from birth up to 18 years and skin prick test (SPT) was conducted at 6, 12 and 24 months, 12 and 18 years. LISAplus recruited 3,097 neonates from four German cities: Munich, Leipzig, Wesel and Bad Honnef. The participants were followed from birth up to 15 years and serum specific IgE was measured at age 2, 6, 10 and 15 years. In both cohorts, multiple surveys, that assessed the occurrence of allergic disease, were distributed throughout the follow-up period. Using these data along with sensitisation data, this thesis has contributed knowledge to address the following issues: Natural History of food sensitisation from infancy up to 18 years A better understanding of the natural history of food sensitisation provides insight, from a public health perspective, to appreciate the likely subsequent burden of food allergy and other allergic diseases over the life course. Longitudinal data on the natural history of food sensitisation beyond early childhood are scarce. Using MACS data, the prevalence of food sensitisation was found to be highest in infancy and declined after the age of 12 months. In the first two years of life, egg white was the most common food sensitisation followed by peanut and cow’s milk while peanut was the most prevalent food allergen at 18 years. Boys with eczema had the highest prevalences of egg and milk sensitisation throughout the follow-ups. A small proportion of children developed late onset food sensitisation (after the age of 2 years) which was unlikely to be clinically relevant. Consequences of early life food sensitisation Longitudinal birth cohort studies with prospective collection of data are the most appropriate design to evaluate the temporal association between early life food sensitisation and development of probable food allergy, asthma, allergic rhinitis and lung function during later childhood and adolescence. An association between food sensitisation at 12 months and the presence of adolescent food sensitisation and probable food allergy was noted in MACS, with sensitisation to more than one food allergen being the strongest predictor. I also demonstrated that early life sensitisation to food without concurrent aeroallergen sensitisation was associated with increased risk of asthma and allergic rhinitis during later childhood (i.e. 10-12 years) in both the MACS and LISAplus studies. Stronger associations were observed for co-sensitisation to both food and aeroallergen. However, only co-sensitisation to both food and aeroallergens in early life was found to be associated with asthma and allergic rhinitis at 18 years in MACS. These findings support the concept of an “atopic march”, in which early life food sensitisation progresses to later asthma and allergic rhinitis. Moreover, I have demonstrated evidence that sensitisation to food allergens only at 6 or 12 months in MACS was associated with reduced FEV1 in adolescence. Most of the observed effect was a direct association, although early life asthma but not aeroallergen sensitisation mediated these associations in part. However, these associations need to be confirmed in population-based studies as sensitisation was not assessed in the first year of life in the LISAplus study. In conclusion, the results I present in this thesis increase our knowledge of the relationship between food sensitisation and allergic disease. Additionally, they suggest that further efforts to prevent the development of food sensitisation, and hence the progression from food sensitisation to food allergy, asthma, allergic rhinitis and lung function impairment should be explored.