Melbourne School of Population and Global Health - Theses
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ItemPhysical activity and asthma in youth: cause or consequence?( 2020)Asthma is the most common chronic disease in children, and often persists into and adulthood. Further, despite its known health benefits, it is estimated that more than 80% of the world’s adolescents are insufficiently physically active. Since both asthma and physical inactivity are significant problems in child and adolescent populations, it is essential to focus research on these populations. The relationship between asthma and physical activity is complex and controversial, and the temporality of these associations remains unclear. My doctoral work attempted to tease out these relationships. This work was divided into sections with distinct research questions, which together aimed to advance our current understanding of the relationship between asthma and physical activity in children and adolescents. Hence, this thesis contains two systematic reviews which were performed in order to understand the existing literature on the nature of the relationship between physical activity and asthma in children. These reviews are followed by three data analyses which employed a variety of statistical techniques to analyse data from questionnaires, accelerometry and clinical assessments collected by two well-established cohorts of Australian children: The Longitudinal Study of Australian Children (LSAC) and the HealthNuts study. The first of the two systematic reviews found no evidence that children and adolescents with and without asthma participated in different amounts of objectively measured physical activity. The second review, which aimed to investigate the effect of physical activity on subsequent asthma outcomes, found insufficient evidence to determine the effect of physical activity on subsequent asthma and lung function outcomes. Hence, in the first data analysis, I aimed to elucidate the direction of the association by investigating the possibility of bidirectionality. However, there was no evidence of longitudinal associations in either direction. Next, I compared the amount of time spent in moderate to vigorous physical activity (MVPA) between children and adolescents with and without asthma at 5 different ages and again found no evidence that youth with and without asthma engaged in differential amounts of time in physical activity. Finally, I investigated the effect of early wheeze and asthma on objectively measured physical activity in early childhood and again found no evidence that children who experience early life asthma and wheeze were less active at a later age. Thus, my thesis presents sustained and compelling evidence of a lack of association between asthma and physical activity in youth – in either direction. A number of implications can be drawn from these findings. First, physical activity campaigns targeted at children need not focus specifically on children with asthma. Second, the effect of physical activity on future asthma outcomes remains unclear. However, even without evidence that physical activity is beneficial for future asthma outcomes, physical activity should be encouraged from a young age for its many other health benefits.
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ItemAssociation between childhood asthma and allergies and adult chronic respiratory disorders in Sibship Data from Tasmanian Longitudinal Health Study( 2019)Background: Asthma in early and mid-life, and chronic obstructive pulmonary disease (COPD) in later life, are two very common respiratory disorders that contribute enormously to the burden of disease in developed countries such as Australia. Researchers have investigated the risk factors associated with the onset of these diseases and have conducted many studies exploring treatments that have the potential to provide effective control of disease symptoms. The analysis of family data with appropriate statistical techniques has the potential to ensure the magnitude of the effects of both genetic and environmental risk factors are estimated free from confounding by shared influences. My systematic review on asthma phenotypes on twins and sibship (CHAPTER 3) targeted only those studies that examined the atopic march diseases from infantile eczema to hay fever and asthma. My study was the first review to assess systematically these relationships using studies that generated family data. Most previous studies reported only estimates of prevalence, incidence, heritability, concordance rate and intraclass correlation between asthma and its phenotypes without synthesizing the evidence on associations between asthma phenotypes. Also, although there exist clear sequential and plausible biological mechanisms to explain such associations, previous evidence has been generated from studies featuring only young children. Such studies were not in a position to explore whether these allergic conditions continue to adult life was. My review confirmed the need for more sibship and or twin studies to investigate potential relationships between these phenotypes from childhood to adulthood. For childhood asthma and COPD association, there are, to my knowledge, no previously published analyses that feature sibship data of the type analysed in this thesis. Methods: In CHAPTER 4, I used data from the Tasmanian Longitudinal Health Study (TAHS) on which the research findings presented in this thesis are based. This study provides prospective data on respiratory and lung health and associated factors from the first to the fifth decade of life for sibling pairs with 29,615 participants. Comprehensively documented data collected within the TAHS cohort provide a unique opportunity to investigate the role of early-life factors such as childhood eczema, childhood hay fever in determining the risk of adult asthma, and the relationship between childhood asthma and Chronic Obstructive Pulmonary Disease (COPD). Both the traditional Conditional Logistic Regression (CLR) and B-W regression model (BWR) have been used to analyze the sibling pair data adjusting for possible confounders. These analyses generate estimates of the magnitude of the association between exposure and outcome within-pair free of confounding by factors shared within families. Results: In CHAPTER 6, I examined the associations between childhood eczema and asthma in adult life. My findings suggest that the effect of childhood eczema on asthma risk continues well past childhood. Although most children with eczema will not develop childhood asthma, childhood eczema in children who are asthma-free may progress to incident asthma in adult life. Also, childhood eczema predicted asthma that persisted to middle age, but the association was weak. In CHAPTER 7, I examined the association between childhood hay fever and asthma incidence in adult life. From the sibling pair analysis, it is evident that childhood hay fever and childhood asthma are strongly associated, and that this association is apparently independent of childhood eczema, parental history of asthma and socioeconomic status. Childhood hay fever was associated with almost a two-fold increase in the risk of the onset of asthma in adult life, independent of those same covariates. The risk of Incident asthma risk in adult life is also apparently independent of active and passive smoking. In CHAPTER 8, I investigated the association between childhood asthma and COPD by mean age 45 years. From the sib-study, childhood asthma was found to be associated with an increased risk of COPD by middle age, but evidence against the null hypothesis of no association was weak and the effect of childhood asthma on COPD is substantially reduced when adjusted for current asthma, current smoking status, and childhood eczema and other childhood environmental factors, although the primary motivation for this was the study of effect modification. LLN classified more COPD cases as compared to GOLD for some sibling pairs with age range between 42 and 49. Both statistical models gave similar estimates of the magnitude of the association between childhood asthma and the risk of satisfying criteria for COPD in later life. Conclusions: Overall, my findings in the three results chapters add to the existing literature that has reported associations between atopic march features and childhood asthma towards COPD in sibling studies by providing a more precise and less biased estimation of the respective exposure-outcome association free of confounding. Previously published estimates of the magnitude of these associations may have been larger, but these estimates of risk are potentially confounded by many unmeasured early-life factors and are therefore overestimated. My finding through the analysis of data from a sibling study design has attempted to correct for these confounding effects and, at least theoretically, should produce a more precise estimate of these associations which still support the continued importance of asthma and COPD management plans.
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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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ItemGene-environment interactions and risk of asthma and sensitisation( 2018)Background: Asthma is a complex disease influenced by both environmental and genetic risk factors, and a complex interaction between the two. Exposure to microbes in early life is shown to be protective against several phenotypes of asthma and sensitisation, but this association is dependent on genetic polymorphisms of the Toll-like receptors and CD14. The aim of my doctoral work was to explore gene-environment interactions (GxE) on the risk of asthma. To do this, I examined the interactions between polymorphisms of the CD14, TLR2, TLR4, and TLR6 genes and proxies of microbial exposure such as exposure to sibling, cats and a farming or rural environment. Methods: First, I systematically reviewed the evidence for GxE studies, between endotoxin and polymorphisms in the CD14 gene and allergic disease. I then used data from the population-based Tasmanian Longitudinal Health Study (TAHS) and the Melbourne Atopy Cohort Study (MACS), an urban birth cohort enriched for allergic diseases to examine interactions between the CD14, TLR2, TLR4, and TLR6 gene polymorphisms and proxies of microbial exposures for the risk of asthma and sensitisation. Exposure to siblings, cats, farm and rural environment were used as proxies of microbial exposure. All four proxies were available in the TAHS, however for MACS only exposure to siblings was available. Multinomial and logistic regressions were used to investigate the associations while adjusting for confounders. Generalised estimating equations were used to estimate the overall risk from birth to 18 years for MACS and from ages 7 to 50 years for TAHS. Results: My systematic review of GxE studies, presented in Chapter 3 found that the association between endotoxin and sensitisation was modified by the CD14-rs2569190 polymorphisms in children. In the presence of high endotoxin levels, carriers of the rs2569190-CC genotype had a lower risk of sensitisation than those with the rs2569190-TT genotype. This finding, however, was restricted to studies with both exposure and asthma occurring in childhood, and no effect was seen for adult studies. In Chapter 5, I found evidence of GxE between cumulative exposure to siblings and the CD14-rs5744455 polymorphisms on risk of sensitisation. Using two cohort studies, the TAHS and the MACS, I found that increasing number of years of cumulative exposure to sibling were associated with a decreased risk of sensitisation between birth to young and middle-aged adulthood. This association was modified by the CD14- rs5744455 polymorphism, where individuals with the Calleles had a significantly reduced risk of sensitization than the T-allele when exposed to siblings. In Chapter 6, I found evidence of an interaction between the CD14-rs2915863 polymorphisms and cat exposure before age 4 years for risk of asthma. Exposure to cat increased the risk of asthma between the ages of 7 to 50 years in those with the CD14-rs2915863 CC-genotype but tended to iii reduce the risk in those with the CD14-rs2915863 TT/CT-genotype. Similar patterns of association were also observed with the CD14-rs2569190 polymorphisms. In Chapter 7, I found an evidence of an interaction between exposure to a farming environment, defined by father’s occupation, and the TLR6 gene polymorphisms for asthma was observed. Specifically, among those who were exposed to a farm, having the TLR6-rs1039559-Tallele or the TLR6-rs5743810-C-allele had a lower risk of early-onset asthma than those with TLR6- rs1039559-C-allele or the TLR6-rs5743810-T-allele, respectively. Conclusions: Overall, my doctoral work has contributed significantly to our understanding of GxE interaction, specifically the interaction between CD14/TLR genes polymorphisms and microbial exposure, for asthma. Preventive strategies should incorporate both genetic and environmental factors and the interaction between the two rather than focusing on one factor alone. Our greater understanding of GxE will provide opportunities to identify high risk groups through genetic screening or prediction tools, and subsequent strategies to manage or modify disease development will benefit individuals and community.
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ItemAssociations between biomarkers in exhaled breath condensate (EBC) and allergic disease phenotypes and lung function( 2016)Asthma is a common chronic disorder of the airways that involves a complex interaction of airflow obstruction, bronchial hyperresponsiveness and underlying airway inflammation. It is increasingly clear that asthma is a heterogeneous group of conditions (phenotypes) with common symptoms. The underlying mechanisms of different phenotypes are not clearly understood and the treatment responsiveness and causative factors are likely to vary between phenotypes. The increasing interest in airway inflammatory biomarkers assessment has led to the development and evolution of tools to measure these biomarkers which identify various asthma phenotypes. Exhaled breath condensate (EBC) is a totally non-invasive, easy to perform, feasible and inexpensive method for sampling lung and airways fluid, which reflects the airway epithelial lining fluid (ELF). EBC comprises a variety of airway inflammatory mediators, such as oxidative stress and pH, which provides non-invasive indicators of ongoing biochemical and inflammatory activity in the airways. Although EBC samples the entire respiratory tract from the mouth to the alveoli, the precise origin of each sampled molecule cannot be determined. A number of studies have assessed the relationship between EBC biomarkers and adult airway diseases, such as asthma. However, these studies have had limited sample sizes and, as a result, were unable to compare associations between numerous phenotypes of airway diseases. It remains possible that the associations with EBC biomarkers may change with age, but this has not been examined in a single study using the same methods. Furthermore, previous studies have been conducted in clinical populations rather than epidemiologic settings. Therefore, the overall aim of this PhD research was to assess the associations between oxidative stress biomarkers and pH in EBC and asthma phenotypes, rhinitis phenotypes, atopic sensitisation, lung function and objective markers of airway inflammation, including bronchial hyperresponsiveness (BHR) and the fraction of exhaled nitric oxide (FeNO), in both the early adulthood and middle-aged groups. Within this thesis, cross-sectional analyses nested within the two Australian longitudinal studies have been performed. These studies are: (1) The Melbourne Atopy Cohort Study (MACS), a study of individuals with a family history of allergic disease (defined as the early adulthood group in this thesis); and (2) The Tasmanian Longitudinal Health Study (TAHS), a population-based study (defined as the middle-aged group in this thesis). EBC samples were collected at the 18-year follow-up of MACS and the BHR LAB Study of the 5th-decade follow-up of TAHS. Using these data, this thesis contributes knowledge to the field, specifically addressing the following issues: Methodological issues from the laboratory analysis of EBC biomarkers Findings from this doctoral research showed that EBC biomarkers were influenced by the long period of storage, particularly for hydrogen peroxide (H2O2). The vast majority of analysed samples for H2O2 were shown to be below the lower limit of detection (LOD). In addition, both decreased levels of EBC total nitric oxide products (NOx) and increased EBC pH were associated with a long period of sample storage. Therefore, the duration of sample storage was adjusted for in all analyses presented in this thesis. Associations between EBC NOx and different phenotypes of asthma and rhinitis, sensitisation, lung function, BHR and FeNO This PhD research showed that atopic asthma and atopic rhinitis phenotypes were associated with higher levels of EBC NOx. Also, atopic sensitisation was related to increased levels of EBC NOx and this association was stronger in individuals with poly- aero-sensitisation. These findings were generally consistent across the two age groups. In the early adulthood group only, elevated levels of EBC NOx were associated with reduced pre- and post-BD FEV1/FVC. Additionally, EBC NOx was not related to BHR and FeNO. Therefore, EBC NOx may be considered a marker for allergic airway inflammation in different age groups. Associations between EBC pH and different phenotypes of asthma and rhinitis, sensitisation, lung function, BHR and FeNO Reduced EBC pH was associated with the presence of asthma and strongly associated with severity of asthma symptoms, as well as atopic asthma and atopic rhinitis in the early adulthood group. Also, similar associations were observed in those with atopic sensitisation, particularly in those who were sensitised to more than one tested allergen. However, none of the above associations were observed in the middle-aged group, suggesting that these effects may be age-dependent. Alternatively, it may be due to differences in methods used between the projects (e.g. degree of deaeration of the sample post collection). In addition, there were no associations between EBC pH, lung function, BHR, and FeNO in either project. These findings suggest that associations between airway acidification and asthma and sensitisation phenotypes may be influenced by the age of an individual. Conclusion Overall, my doctoral work observed some novel and interesting associations. Results from this thesis will aid the current understanding of an underlying inflammatory process, help to discriminate between different phenotypes of airway diseases and help guide future research. Although EBC is a promising method, it lacks appropriate standardisation and reference values and is therefore not currently suitable for use in clinical practice.
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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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ItemA longitudinal study of atopy, asthma and lung function from birth to 18 years in a high risk birth cohort( 2012)Background: The global burden of allergic disease, including asthma, eczema and allergic rhinoconjunctivitis is still increasing. Of these, asthma is the most important in terms of morbidity, mortality and financial cost. Asthma is a global problem, estimated to affect 300 million people worldwide. Childhood asthma is the most common chronic disease of children in many westernized countries including Australia. We currently have no effective strategies to prevent development or persistence of asthma. A range of strategies have been trialled, including avoiding environmental triggers (dust mites, animal dander), modification of mothers’ and infants’ diets and randomized controlled trials of anti-inflammatory medications in children at high risk. To date, the results have been disappointing with very modest, if any, impact found. The lack of preventive strategies appears to be related to a poor understanding of asthma aetiology. There are many areas of controversy regarding the early life risk factors for the development of childhood asthma. Asthma is believed to result from a complex interaction between genetic, environmental and biological factors. Of these, the only consistent major risk factors to emerge to date are a family history of atopy or asthma, an individual history of atopy, early childhood eczema, environmental tobacco smoke and viral infections in early childhood. Asthma is known to be a heterogeneous disease in childhood, so that poor classification of asthma groups, or phenotypes, may be part of the reason for the lack of results within and inconsistent findings between studies. There is a critical need for studies which can provide a solid basis for accurate classification of asthma phenotypes as well as investigating plausible risk factors for the development and persistence of asthma. To address questions concerning the classification of asthma phenotypes and the natural history of asthma and allergic disease, along with genetic and environmental factors which may influence aetiology and progression, it is important to use the evidence provided by longitudinal studies. In longitudinal studies, especially birth cohorts with frequent ascertainment of potential aetiological exposures and allergic disease outcomes, it is possible to determine the temporal relationship between exposures and outcomes. This thesis addressed some of the issues in asthma and allergic disease research using data from a longitudinal birth cohort study. The Melbourne Atopy Cohort Study comprises 620 children who were selected before birth for familial allergic disease. These children were very closely followed in the first 2 years of life with 18 telephone interviews. They had yearly follow-ups between ages 3 and 7 and again at ages 12 and 18. Additionally they had clinic testing including cord blood, skin prick testing, and respiratory function testing. The three main objectives which I researched within the MACS were: Objective 1: To document the natural history of wheeze in early childhood (from birth to 7 years) and to use this information to identify longitudinal wheeze phenotypes and to identify potential risk factors for these phenotypes Objective 2: To determine the impact of longitudinal wheeze phenotypes on subsequent respiratory function, respiratory symptoms and allergen sensitization Objective 3: To identify early life risk factors for childhood and adolescent asthma and allergic disease Conclusions: I addressed three broad research areas and 9 specific research questions and to contribute to the existing literature concerning allergic disease in childhood. Firstly through defining childhood wheeze phenotypes using latent class analysis, I defined 5 wheeze classes and confirmed the presence of the newly discovered intermediate onset wheeze phenotype. Additionally, I found distinct patterns of associations with specific early-life factors for each wheeze phenotype. Furthermore, I investigated the respiratory and allergic outcomes of these phenotypes up to 18 years of age. An important finding of this analysis was that children who wheeze transiently in early life do not have an increased risk of allergic disease or sensitization, or any deficit in respiratory function by age 18 when compared to never/infrequent wheezers. Conversely, persistent wheezing phenotypes in childhood (including early persistent, intermediate and late onset) were associated with reduced growth in FEV1 over adolescence and persistent lung function deficits. These findings highlight the importance of categorizing early childhood wheeze in asthma research and the detrimental effects of persistent wheeze on adolescent respiratory health. Furthermore, investigating two specific early life factors: sensitization and pet keeping, I have shown that sensitization to dust mite at ages 1 or 2 years is a good predictor for long-term wheeze and that the presence of a cat or dog at birth in high risk families is not a risk factor for allergic disease in the child, and in fact may reduce the risk of asthma or hay fever by 12 years.