Pathways to peak lung function: Genetic, environmental and lifestyle influences on maximally attained lung function in young adults.

Obstructive lung diseases are a common cause of disease and disability throughout life. The aim of this research project is to understand factors during childhood that influence the development of peak lung function in early adulthood. We will measure the lung function of around 5,000 young adults who have been intensively studied since before birth as part of a longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Lung function increases with physical growth through childhood, reaching a peak in early adulthood. Following this peak, there is a gradual loss of lung function throughout the rest of life. Therefore, failure to attain maximal lung function during childhood could lead to early onset of respiratory illnesses in adult life. This study will build on previous measurements of lung function in the ALSPAC cohort linked to a wealth of data on early lifestyle and environment to try to find out what factors are associated with slow acquisition of lung function during childhood and low peak lung function in early adulthood.

The ALSPAC study is a birth cohort that was established in Bristol in the early 1990s by recruiting pregnant women. Their children have been followed up since birth using a variety of questionnaires and hands-on physical assessments at regular intervals. Now that these children have reached early adult life, the study has been funded to run a further hands-on assessment at a time when many physical functions are reaching their peak (although the study is not only interested in physical health). We can take advantage of the established clinic infrastructure to build on a session of the measurement of lung function at much lower cost than it would take to set up a stand-alone measurement.

The specific factors that we think are important influences on lung function development in childhood are birth size and gestation (being born small or early), physical growth particularly during infancy, exposure to second hand tobacco smoke, high body mass (obesity) and low physical activity. We will investigate how these factors are associated with the rate of lung function growth and with peak lung function. Also, because ALSPAC has such a rich data resource, we will be able to check whether these relationships are confounded by other factors and also whether there is any evidence that they interact with genes that are known to be associated with low lung function values in later adulthood.

Although the principal analyses planned as part of this study cover only a proportion of the many factors that could potentially influence lung function growth, they have been chosen on the basis of biological plausibility and because they are factors for which ALSPAC has an especially rich source of data with assessments having been made repeatedly since early childhood. We will also make the results of this study available to other scientists interested in lung function. For some of our analyses, it will be necessary to pool data with other studies to have enough statistical power to detect some of the influences on lung function growth. This may be especially true of some of the genetic analyses that we plan to carry out. We already have established collaborations with a number of large consortia that will enable us to maximise the value of the data collected during this project.

As lung function established during childhood is so important for lung health throughout the rest of life, we hope that the results of this project will point to factors in early life that could be amenable to intervention to improve the chances of reaching maximal peak lung function. If successful, these could have important impacts on reducing respiratory diseases in later life.

The research has two main objectives:
1. To measure lung function in a population of 5,000 young adults that have been followed from birth in a longitudinal cohort study
2. To model lung function developmental trajectories from mid-childhood to physiological peak and to investigate their association with specific early life exposures (birth size and gestation, early growth, obesity, physical activity, tobacco smoke exposure and wheezing phenotype).

Participants in the ALSPAC study will be invited to a research clinic. Lung function will be measured using spirometry according to accepted standards for performance and quality control of these measurements (European Respiratory Society/American Thoracic Society). The measurements will be made by research clinic staff trained and supervised by the principal investigator. Subjects will be asked to perform at least three technically acceptable forced expirations (from a maximum of eight attempts) into a pneumotachograph and the resulting flow volume curves will be displayed on a computer screen for immediate inspection by the fieldworker. Spirometry will be repeated 15 minutes after inhaled bronchodilator (salbutamol 400 mcg).

Data will be anonymously linked to other information collected during the course of the ALSPAC study. Lung function data will be analysed by modelling developmental trajectories using linear and non-linear models. Outcomes will be continuous and categorical (obstructive, restrictive). Associations between these and exposures will be analysed using linear and logistic regression equations respectively. We will use structured lifecourse epidemiological approaches to look for critical periods and cumulative effects of exposures. Structural equation models will be used to examine mediators on pathways between early life exposures and lung function. We will deal with missingness in the data using multiple imputation and , within SEM, Full Information Maximum Likelihood methods.

Who will benefit?
Academic: The principal beneficiaries of this research will be academics who are working in the field of lung development during childhood. There will be opportunities for cross-disciplinary collaborations through the EC COST Action: Developmental Origins of Chronic Lung Disease and we are working on collaborations across the life course, for example, with the ECRHS study to investigate comparative influence of genetic and lifestyle factors on lung function. ALSPAC is a member of several large-scale consortia working on genetic underpinnings of lung function, COPD and asthma, which will benefit from the additional data generated by this research. Data will be shared more widely through the existing ALSPAC data management and dissemination policy.

Patients and Public: Increased recognition and understanding of the childhood origins of obstructive lung diseases will benefit patients, their representative organisation, practitioners and the general public understanding of health and disease.

Policy Makers: Identification of factors in childhood that can influence life course lung development and resulting adult lung function has policy implications for early recognition of high risk populations, healthcare advice and public health policy to control exposure to adverse factors where possible.

Industry: Increased emphasis on early life factors with demonstrable long term influences on lung function potentially opens pathways to modification of current treatment strategies and new therapeutic targets. Linkage to a large repository of biological data has the potential to discover biomarkers of disease phenotypes that could be amenable to personalised approaches to treatment.

How will they benefit?
Scientific advancement: This proposal will generate new knowledge through understanding some of the important early life influences on the development of lung function. It will also provide the scientific community with data that can be applied to other research questions concerning the genetic and environmental influences on lung function acquisition. This will stimulate further research to identify pathophysiological mechanisms underpinning these associations, contributing to UK scientific capital.

Increased understanding and awareness: Patients and Practitioners will benefit from recognition that early life factors are important contributors to the development of obstructive lung diseases in adults. Clinicians will have evidence-based knowledge on which to advise patients about risk factors and interventions, including lifestyle changes. Public understanding about early life risk factors for COPD may shift their attitudes to research in this area, benefiting charitable organisations by increasing available research funding.

Translational pathways: Two products of this research have potential benefits to translational research. Identification of lifestyles and behaviours associated with increased risk of obstructive lung diseases has both policy and exploitable commercial implications for early intervention to prevent or alter disease natural history. Secondly, industry is already working with ALSPAC on proof-of-principle projects to establish whether biomarkers, including genetic and epigenetic variants, can identify individuals susceptible to disease phenotypes