National Health and Medical Research Council of Australia; European Union's Horizon 2020; The University of Melbourne; Clifford Craig Medical Research Trust of Tasmania; The Victorian, Queensland & Tasmanian Asthma Foundations; The Royal Hobart Hospital; Helen MacPherson Smith Trust; and GlaxoSmithKline.

Rationale: The burden of chronic obstructive pulmonary disease (COPD) is increasing, yet there are limited data on early life risk factors.Objectives: To investigate the role of childhood lung function in adult COPD phenotypes.Methods: Prebronchodilator spirometry was performed for a cohort of 7-year-old Tasmanian children (n = 8,583) in 1968 who were resurveyed at 45 years, and a selected subsample (n = 1,389) underwent prebronchodilator and post-bronchodilator spirometry. For this analysis, COPD was spirometrically defined as a post-bronchodilator FEV 1 /FVC less than the lower limit of normal. Asthma-COPD overlap syndrome (ACOS) was defined as the coexistence of both COPD and current asthma. Associations between childhood lung function and asthma/COPD/ACOS were examined using multinomial regression.Measurements and Main Results: At 45 years, 959 participants had neither current asthma nor COPD (unaffected), 269 had current asthma alone, 59 had COPD alone, and 68 had ACOS. The reweighted prevalence of asthma alone was 13.5%, COPD alone 4.1%, and ACOS 2.9%. The lowest quartile of FEV 1 at 7 years was associated with ACOS (odds ratio, 2.93; 95% confidence interval, 1.32-6.52), but not COPD or asthma alone. The lowest quartile of FEV 1 /FVC ratio at 7 years was associated with ACOS (odds ratio, 16.3; 95% confidence interval, 4.7-55.9) and COPD (odds ratio, 5.76; 95% confidence interval, 1.9-17.4), but not asthma alone.Conclusions: Being in the lowest quartile for lung function at age 7 may have long-term consequences for the development of COPD and ACOS by middle age. Screening of lung function in school age children may identify a high-risk group that could be targeted for intervention. Further research is needed to understand possible modifiers of these associations and develop interventions for children with impaired lung function.

Word count: 3499 AT A GLANCE COMMENTARY Scientific Knowledge on the SubjectChildhood factors may have long-term implications for adult lung function and development of Chronic Obstructive Pulmonary Disease (COPD). A systematic approach to investigating profiles of childhood respiratory risk factors as predictors of middle-age lung function and risk of COPD, and their pathways has not been previously undertaken. What This Study Adds to the FieldUsing an objective categorizing approach to establish patterns, we identified distinct childhood respiratory risk profiles in a large cohort. We found that specific risk profiles have different effects on middle-age lung function and COPD and that their effects have different pathways. Children with frequent asthma attacks and multiple allergies were found to be most at risk of developing COPD and lung function deficits in middle-age. This link was largely transmitted through active asthma in adulthood and to a lesser degree through reduced lung function in childhood. This highlights the importance of lifetime asthma control. The finding that subsequent personal smoking markedly increased the long-term risk for some risk profiles highlights an opportunity for targeted prevention. Our findings suggest that childhood risk factor profiles are useful to predict long-term lung health.This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org 1 Abstract Rationale:Childhood risk factors for long-term lung health often co-exist and their specific patterns may affect subsequent lung function differently. Objectives:To identify childhood risk factor profiles, their influence on lung function and chronic obstructive pulmonary disease (COPD) in middle-age and potential pathways. Methods:Profiles of 11 childhood respiratory risk factors, documented at age 7, were identified in 8352 participants from the Tasmanian Longitudinal Health Study using latent class analysis.We investigated: associations between risk profiles and post bronchodilator lung function, and COPD at age 53; mediation by childhood lung function and adult asthma; and interaction with personal smoking. Results:Six risk profiles were identified: 1 "unexposed or least exposed" (49%), 2 "parental smoking" (21.5%), 3 "allergy" (10%), 4 "frequent asthma, bronchitis" (8.7%), 5 "infrequent asthma, bronchitis" (8.3%) and 6 "frequent asthma, bronchitis, allergy" (2.6%). Profile 6 was most strongly associated with lower FEV1: (-261; 95%CI: -373,-148 mL); lower FEV1/FVC: (-3.4; -4.8,-1.9%) and increased COPD risk (OR: 4.9; 2.1,11.0) at age 53. The effect of profile 6 on COPD was largely mediated by adult active asthma (62.5%) and reduced childhood lung function (26.5%). Profiles 2 and 4 had smaller adverse effects than profile 6. Notably effects of profiles 2 and 6 were synergistically stronger for smokers. Conclusions:Profiles of childhood respiratory risk factors predict middle-age lung function levels and COPD risk. Specifically, children with frequent asthma ...

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