CHILDREN OF THE 90S 20/12/06. By Becky McCall The Avon Longitudinal Study of Parents and Children.

If pregnant women eat lots of fish, are their offspring more intelligent? Does depression in fathers have an adverse effect on their children? And are children brought up in very hygienic homes more likely to develop asthma? These are just some of the questions addressed by the Avon Longitudinal Study of Parents and Children (ALSPAC) – often called 'Children of the 90s' – which for 15 years has been studying more than 14 000 children and their parents in the former county of Avon.

The development, health and behaviour of children can vary markedly; but how much of this variation is due to genes, and how much is influenced by the environment they grow up in? Teasing out the relationships and interactions between environmental factors and individual genotypes is extremely difficult, and requires vast amounts of data for researchers to study – which is exactly what ALSPAC has collected from the Avon families. Detailed records are kept of everyday characteristics such as diet, lifestyle, socioeconomic status, parent–child contact and so on, as well as tens of thousands of samples of urine, blood and DNA. So rich is the ALSPAC resource that the World Health Organization and the US National Institutes of Health are formally referring to the study as a model for researchers wishing to set up similar birth cohort studies worldwide.

Since its inception in 1991, more than 260 papers relating to ALSPAC have been published (see box, below). For example, the study has found, to answer the opening questions above, that mothers who consume less fish during pregnancy have children with significantly lower IQs and impaired ability to focus; that depression in fathers is associated with adverse emotional and behavioural outcomes in children aged 3.5 years, and an increased risk of conduct problems in boys; and children brought up in very hygienic homes are indeed more likely to develop asthma.

ALSPAC papers in peer-reviewed journals

The last year has seen ALSPAC going through a transitional period. In December 2005, the study received new funding: a grant of almost £15 million jointly from the Wellcome Trust, the Medical Research Council and the University of Bristol. And in January 2006, Professor George Davey Smith took over as the new Scientific Director of ALSPAC, heading up a management team made up of Lynn Molloy, Dr Andy Ness, Dr John Henderson and Dr Sue Ring.

Professor Davey Smith welcomes taking over the reins at a pivotal time in the study: the children are reaching 15 years old. "So much is changing for them," he says. "Behavioural factors that influence health are beginning to feature in their lives – factors such as smoking, drinking, interest in sexual activity, diet, risk-taking – and they'll soon be going to college."

Genes meet environment

For a study such as ALSPAC, detailed information – and lots of it – is crucial. And, argues Professor Jean Golding, Scientific Director until 2005, the data need to come from different generations in a family and to go from pregnancy right through life. "I'd worked for large cohort studies before and I always found that they lacked the fine detail," she says. "You need more than information on the household: previous studies didn't collect and examine biological samples, and they never recorded information during pregnancy, which is absolutely vital."

More than 150 researchers, doctors, and health workers work on the project, collecting samples and information from children and their parents in clinics held every two years. The data are generated by hands-on examination of the children, questionnaires completed by parents and children, education, social and health records, assays of biological samples, and specific measurements of the environment in the home.

The database of measurements, and the all-important biological samples of urine, blood and DNA stored in Bristol, provides a comprehensive source of data and samples that researchers can access for their studies. The topics being examined cover many different aspects of childhood health and development, such as the onset of puberty, the development of obesity, educational achievements and mental health (see box, below).

"The differences in people's responses – their constitution if you like – are due to a combination of their biological inheritance and their developmental experience," says Professor Marcus Pembrey, ALSPAC's Director of Genetics. "ALSPAC has therefore created a DNA bank for the analysis of gene variants." One new study, for example, will be looking at a gene involved in the barrier function of the skin and implicated in the development of allergies and asthma. Eczema has long been associated with these two conditions, but earlier studies have failed to find a gene variant that showed an effect on the immune system. In 2006, however, a group at the University of Dundee found that a common variant of a gene involved in the barrier function of skin (encoding the protein filaggrin) was a pivotal risk factor for eczema. The Dundee team is now working with ALSPAC to move the investigation on to the next stage. "We want to try and answer the next question: what environmental factors, interacting with the poor skin barrier caused by this gene variant, can trigger the eczema?" says Professor Pembrey.

From child to adult

The first couple of decades of life bring profound changes to the body, and extensive experimentation with lifestyle. No wonder, then, that the foundations of an individual's future adult health are often laid down in childhood.

Take obesity, one of the most pressing public health problems of the modern era in developed countries. Although it is known that obesity levels are spiralling upwards, it is not clear whether inactivity is more important than overeating. An ALSPAC study is therefore examining the relationship between calorie intake, energy expenditure and obesity, and is using an accelerometer device, a electronic motion sensor that measures someone's physical activity, small and light enough to be worn around a child's waist.

"Physical activity in children is sporadic, and children are less able than adults to recall or record their activity." says Dr Andy Ness, principal investigator on the ALSPAC Obesity Interest Group. "We are finding that heart rate monitors and accelerometers provide a far more accurate measure than questionnaires. In our study, activity – or lack of it – appears to be strongly associated with obesity."

The first signs of coronary heart disease can also show up earlier than might be expected. "It has been known for many years that the beginnings of atherosclerosis can be seen early on – autopsies of 17-year-olds killed during the Vietnam and Korean wars showed that they already had arterial lesions," says Professor Davey Smith. "So we know that the disease starts developing early in some people, and that teenagers' lifestyles feed into this, but until now, this has not been characterised particularly well."

By examining the functioning of the ALSPAC children's arteries, and cross-referencing these data with factors such as birth weight, cholesterol levels, exercise and environmental tobacco smoke, Professor Davey Smith hopes to be able to understand what might cause the early signs of coronary heart disease. Dissecting the results is not straightforward, however: working out whether factors actually increase or decrease the risk of disease is difficult, and can be influenced by the design of the study. For example, observational studies appeared to show that vitamin supplements or hormone replacement therapy could prevent coronary heart disease. Millions of people worldwide were taking vitamin supplements in the belief that they had this effect, yet large-scale long-term randomised controlled trials showed that the observational findings were spurious: there was no protection given by their use.

Such contradictions are likely to be due to people taking vitamin supplements in observational studies being at lower risk of coronary heart disease because of other aspects of their lifestyle and social circumstances. "The misleading information provided by the over-interpretation of the observational findings is an indictment of epidemiology," says Professor Davey Smith. "We should be actively striving to use better methods that yield reliable evidence."

The willing participant

Scientists aside, one of the core strengths of ALSPAC lies in the willing participation of the children and parents in the study. "The families involved in ALSPAC are amazing," says Lynn Molloy, Executive Director. "They've shown an impressive and regular interest in the research. This has undoubtedly driven the high level of involvement and participation over the last 15 years."

With the children now in their mid-teens, however, a different approach is required. The young participants who regularly attend clinics for tests and complete questionnaires want to take a more active role in decision-making and in ethical issues. So in an effort to formalise such input, a Teenage Advisory Panel consisting of 25 young participants has been established.

"We are very excited about the Panel – it's a novel way of engaging with the young people who take part in the study," says Ms Molloy. "Our plan is that the Panel assists us in making decisions about ALSPAC. For example, we have asked them to give us their ideas on what the clinic environment should look like, to comment on the questionnaires, and to help us develop the new website." Ms Molloy is currently negotiating the setting up of a sub-committee of young people to complement the ALSPAC Ethics and Law Advisory Committee and incorporate their views in difficult ethical decisions. There are hopes that, one day, some of the participants may even be involved in the research process itself, such as by writing grant applications and papers.

Despite being in its 15th year, ALSPAC is still in its early days: the study intends to follow the children up to the age of 70, looking at their health and habits as they age, as well as those of their children and effects seen across the generations. Professor Davey Smith and colleagues have just completed a follow-up of the Boyd-Orr Cohort, a 70-year follow-up of a study in which the original examinations on 5000 children were carried out in the late 1930s; the doctor who carried out the original examinations, Professor John Pemberton, now in his mid-90s, was a co-author on a recent paper. So the long-term future of ALSPAC looks bright.

Becky McCall is a science writer based in Cornwall.

Links

ALSPAC website