Melbourne School of Population and Global Health - Theses
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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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ItemBiomarkers of hormone activity and risk of prostate and breast cancers( 2012)Background: Hormonal factors have been implicated in the epidemiology of both prostate and breast cancer. While studies of circulating concentrations of sex hormones and cancer risk have been illuminating, they can only assess a limited aspect of hormone exposure. It has been suggested that biomarkers of hormone activity might provide a means to assess critical exposure to hormones. Androgenetic alopecia (AA, also known as male pattern baldness) and the ratio of the lengths of the 2nd and 4th digits (2D:4D) have been proposed as possible biomarkers of androgen action. AA is thought to reflect increased androgen action in tissue. 2D:4D, especially right 2D:4D and the difference between right and left 2D:4D (Δr-l), are thought to be inversely associated with prenatal exposure to testosterone. The primary aims of my doctoral research were to assess whether either of these markers are associated with risk of prostate (for both AA and 2D:4D) or breast (for 2D:4D only) cancers using data from the Melbourne Collaborative Cohort Study (MCCS). Methods: Both 2D:4D and AA were assessed at a face-to-face follow up of the MCCS conducted between 2003 and 2009. Cancer cases were identified as men and women with a first diagnosis of prostate or breast cancer post baseline attendance (between 1990 and 1994). Survival analysis techniques were used to estimate associations between the biomarkers and cancer risk. Classical and hierarchical linear regression models were used to estimate whether 2D:4D was associated with anthropometric measures or concentrations of circulating sex hormones respectively. Results: No strong association was observed between any 2D:4D measure and risk of prostate cancer. There was an indication that both right and left 2D:4D might be inversely associated with risk of early onset prostate cancer. Higher left 2D:4D was associated with slightly increased risk of breast cancer, and Δr-l was inversely associated with risk. No association was observed between right 2D:4D and risk. The inverse association between Δr-l and risk appeared to be somewhat stronger for poorly or undifferentiated tumours. There were no strong associations observed between 2D:4D measures and concentrations of circulating sex hormones. Nor was any anthropometric measure materially associated with 2D:4D. A strongly age dependent association between AA and prostate cancer risk was observed. Vertex AA at age 40 years was associated with increased risk of early onset prostate cancer, and younger age at diagnosis for prostate cancer cases. The cumulative risk of prostate cancer was greater up to approximately age 75 years for men with vertex AA at age 40 years compared with men with no AA at that age. At age 75 years the cumulative probability of prostate cancer was estimated to be 0.15, regardless of hair pattern at age 40 years. Conclusions: The results presented in this thesis suggest that prenatal testosterone exposure might play a role in the aetiology of prostate and particularly breast cancers. Additionally, the result that vertex AA at age 40 years is associated with increased risk of early onset prostate cancer lends support to the hypothesis that AA and prostate cancer might have analogous androgen-based aetiologies.