Association between childhood asthma and allergies and adult chronic respiratory disorders in Sibship Data from Tasmanian Longitudinal Health Study

Abstract

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.