Periodic Reporting for period 3 - ALEC (Aging Lungs in European Cohorts)
Berichtszeitraum: 2018-05-01 bis 2019-04-30
The ALEC project aimed to improve the understanding of factors that influence lung health as people get older. To do this we combined information collected in pre-existing large surveys (cohort studies), in which many thousands of people provided information on respiratory symptoms and had their lung function tested over many years.
Lung function is a good measure of lung health and strongly associated with several major chronic diseases and overall health status. As adults age there is a ‘natural’ loss of lung function (‘lung function decline’), but in some people this decline is excessive. The impact of lung function decline on respiratory health and functioning in later life will be greater in those who, as children, had poor lung function growth and, as a result, did not achieve their maximum potential lung function by their early twenties. Adults with low lung function are at increased risk of clinical symptoms, respiratory disability and COPD.
COPD is a major cause of disability and death in Europe, and is of particular relevance due to the ageing of the European population. COPD has long been viewed as a predominantly smoking-related disease but it occurs in non-smokers too, and other factors contribute to its development.
We aimed to provide an evidence base for identifying individuals and populations at risk of poor lung health that could underpin future preventive and therapeutic strategies and policies. Broadly we wanted to 1) identify determinants and risk factors related to lung growth, lung function decline and COPD, 2) generate new data on pre-conception and multigenerational determinants, 3) identify epigenetic changes associated with poor lung health and exposure to disease risk factors and 4) develop an online interactive tool that can be used to assess COPD risk
Lung function is a good measure of lung health and strongly associated with several major chronic diseases and overall health status. As adults age there is a ‘natural’ loss of lung function (‘lung function decline’), but in some people this decline is excessive. The impact of lung function decline on respiratory health and functioning in later life will be greater in those who, as children, had poor lung function growth and, as a result, did not achieve their maximum potential lung function by their early twenties. Adults with low lung function are at increased risk of clinical symptoms, respiratory disability and COPD.
COPD is a major cause of disability and death in Europe, and is of particular relevance due to the ageing of the European population. COPD has long been viewed as a predominantly smoking-related disease but it occurs in non-smokers too, and other factors contribute to its development.
We aimed to provide an evidence base for identifying individuals and populations at risk of poor lung health that could underpin future preventive and therapeutic strategies and policies. Broadly we wanted to 1) identify determinants and risk factors related to lung growth, lung function decline and COPD, 2) generate new data on pre-conception and multigenerational determinants, 3) identify epigenetic changes associated with poor lung health and exposure to disease risk factors and 4) develop an online interactive tool that can be used to assess COPD risk
We collected information on respiratory health and risk factors across multiple generations of the same family and showed that health and lifestyle (eg. smoking and being overweight) of parents (and perhaps even grandparents) may influence a child’s respiratory health. Mothers who smoke during pregnancy are more likely to have children with asthma and we provided further evidence that fathers who smoke (particularly during early adolescence) are more likely to have children with asthma (even if they stopped smoking many years before conception). We developed appropriate complex statistical methods to do these analyses.
We showed that children with asthma, persistent wheezing through childhood, low levels of physical activity, obesity and early puberty may not achieve their maximal potential lung growth. Three lung function trajectories during the first five decades of life (“early below average, accelerated decline”, “persistently low” and “below average”) are strongly associated with COPD. Early-life predictors of these trajectories include childhood asthma, bronchitis, pneumonia, hayfever, eczema, parental asthma, and maternal smoking. Children with frequent asthma plus allergies, especially if they smoke as adults, seem to be particularly at risk of COPD.
We showed that in adult life, obesity, low physical activity, poor diet (particularity diets low in anti-oxidant containing foods such as fresh fruit and vegetables), and occupational exposure to some agents contribute to lung function decline and COPD. Chronic asthma or increased airway responsiveness may lead to accelerated loss of lung function and a higher risk of COPD. Poor sleep and sleep apnoea are associated with respiratory symptoms but not related with accelerated lung function decline
Where possible, we used sophisticated analytical approaches (for example Mendelian Randomisation) to provide strong evidence that associations between some of these risk factors are causal and not an artefact of other associations within the data. These approaches showed that early puberty is detrimental to lung function growth and development of asthma. Oestrogens and androgens may influence lung function but there were some inconsistencies.
We published a systematic review of studies that examined peripheral blood DNA methylation and associations with lung function/COPD – no study included large populations followed over a long time. Using the ALEC cohort biobanks we used state of the art tests to confirm that low lung function is associated with a measurable change in DNA-methylation – most of these changes are clearly linked with smoking. We also showed that the effects of the SERPINA 1 gene on lung function are unlikely to be mediated through DNA methylation.
Although smoking in the European population is decreasing, an analysis of the ALEC cohorts provides strong evidence that decreases are not even across Europe. Adolescent females in particular seem to show little change in smoking behaviours. Our health impact analysis suggested considerable decreases in COPD prevalence in Europe if tobacco prices were increased.
Using anonymised data from the ALEC cohorts we developed Bayesian methods to impute values where data is missing so that the information can be used most effectively. We developed a risk prediction tool for COPD - our earlier published systematic review showed there was no adequate or widely applicable instrument currently available that takes account of all relevant factors. We found that the best prediction model we could build was not highly discriminatory for lifetime risk of COPD but can be used by the public to assess how changing their lifestyles (particularly smoking) could alter their personal disease risk. We used ’Value of Information’ analysis to identify economically justifiable research priorities for the use of this risk tool as a motivation for smoking cessation. It , suggested resources should be prioritised towards effectiveness trials. The risk prediction tool was demonstrated to patients’ organisations and received positive feedback regarding its potential use in their work.
Our work has been published and/or presented at scientific meetings (particularly at the European Respiratory Society International Congress, the major European conference for respiratory physicians and lung researchers)
We showed that children with asthma, persistent wheezing through childhood, low levels of physical activity, obesity and early puberty may not achieve their maximal potential lung growth. Three lung function trajectories during the first five decades of life (“early below average, accelerated decline”, “persistently low” and “below average”) are strongly associated with COPD. Early-life predictors of these trajectories include childhood asthma, bronchitis, pneumonia, hayfever, eczema, parental asthma, and maternal smoking. Children with frequent asthma plus allergies, especially if they smoke as adults, seem to be particularly at risk of COPD.
We showed that in adult life, obesity, low physical activity, poor diet (particularity diets low in anti-oxidant containing foods such as fresh fruit and vegetables), and occupational exposure to some agents contribute to lung function decline and COPD. Chronic asthma or increased airway responsiveness may lead to accelerated loss of lung function and a higher risk of COPD. Poor sleep and sleep apnoea are associated with respiratory symptoms but not related with accelerated lung function decline
Where possible, we used sophisticated analytical approaches (for example Mendelian Randomisation) to provide strong evidence that associations between some of these risk factors are causal and not an artefact of other associations within the data. These approaches showed that early puberty is detrimental to lung function growth and development of asthma. Oestrogens and androgens may influence lung function but there were some inconsistencies.
We published a systematic review of studies that examined peripheral blood DNA methylation and associations with lung function/COPD – no study included large populations followed over a long time. Using the ALEC cohort biobanks we used state of the art tests to confirm that low lung function is associated with a measurable change in DNA-methylation – most of these changes are clearly linked with smoking. We also showed that the effects of the SERPINA 1 gene on lung function are unlikely to be mediated through DNA methylation.
Although smoking in the European population is decreasing, an analysis of the ALEC cohorts provides strong evidence that decreases are not even across Europe. Adolescent females in particular seem to show little change in smoking behaviours. Our health impact analysis suggested considerable decreases in COPD prevalence in Europe if tobacco prices were increased.
Using anonymised data from the ALEC cohorts we developed Bayesian methods to impute values where data is missing so that the information can be used most effectively. We developed a risk prediction tool for COPD - our earlier published systematic review showed there was no adequate or widely applicable instrument currently available that takes account of all relevant factors. We found that the best prediction model we could build was not highly discriminatory for lifetime risk of COPD but can be used by the public to assess how changing their lifestyles (particularly smoking) could alter their personal disease risk. We used ’Value of Information’ analysis to identify economically justifiable research priorities for the use of this risk tool as a motivation for smoking cessation. It , suggested resources should be prioritised towards effectiveness trials. The risk prediction tool was demonstrated to patients’ organisations and received positive feedback regarding its potential use in their work.
Our work has been published and/or presented at scientific meetings (particularly at the European Respiratory Society International Congress, the major European conference for respiratory physicians and lung researchers)
ALEC is one of the largest consortia of long running cohort studies within Europe that has comprehensively examined patterns and determinants of lung function throughout the lifecourse. We have collected novel data on health across multiple generations within the same family, generated novel information on DNA methylation patterns and lung health, and estimated risks of multiple exposures (including those amenable to intervention) that can affect lung function and increase COPD risk. We have gone beyond the state-of-the-art through development of modern statistical methods for multigenerational analysis, and for imputation of missing data across cohorts. This work has culminated in a publically available risk prediction tool for COPD that may be of value to individuals (and their health care practitioners) to assess how their risk of COPD may vary with smoking cessation.
ALEC provides compelling evidence that public health interventions to reduce smoking and obesity, increase physical activity and improve diet will have a positive effect on lung function of current and future generations. Our observation that up to 20% of COPD within populations may be attributable to work place exposures should prompt vigorous enforcement of measures to improve safety of European workers.
ALEC provides compelling evidence that public health interventions to reduce smoking and obesity, increase physical activity and improve diet will have a positive effect on lung function of current and future generations. Our observation that up to 20% of COPD within populations may be attributable to work place exposures should prompt vigorous enforcement of measures to improve safety of European workers.