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3,500 children could change Canada’s approach to fighting chronic diseases

If just 24 children can help scientists discover that Caesarean sections and formula feeding may deprive babies of the protective gut bacteria needed for lifelong health, just imagine what will be discovered by collecting a wide range of health information from some 3,500 children. Scientists believe it will influence everything from health policy and building codes to parenting decisions for decades to come.

Those 3,500 children, along with their mothers and about 2,600 fathers from Vancouver, Edmonton, Toronto and several communities in Manitoba, are on the front-lines of the Canadian Healthy Infant Longitudinal Development (CHILD) Study, a national birth cohort study funded in part by the Allergy, Genes and Environment Network (AllerGen).

"There is no study like this in the world, involving so many children and their families and looking at so many environment-gene interactions, from nutrition and stress to air pollutants and chemicals in the home from conception through early life and onwards into childhood," says Judah Denburg, scientific director of AllerGen.

Launched in 2008 with $12 million from AllerGen and the Canadian Institutes of Health Research (CIHR), CHILD is examining how a child’s environment during pregnancy and in the first few years of life can interact with genetics to increase or decrease the risk of developing allergies, asthma, type 2 diabetes and other chronic diseases.

"I think this study will fundamentally change the way we understand a number of childhood diseases," says Stuart Turvey, who heads the Vancouver CHILD Study site and is studying the impact of "life stress" on healthy development. "We have 10 per cent of kids that are wheezing and an even larger percentage that have atopic dermatitis or eczema. If we know more about the causes, then we can figure out the best intervention to protect kids."

Researchers have already amassed a wealth of data, and continue to do so, including detailed dietary and socio-economic information, outdoor and indoor air quality, household dust, and biological samples such as breast milk, blood, urine, feces and nasal secretions. By 2018, the study will have collected more than 500,000 questionnaires and over 600,000 biological samples that will be available to researchers for decades.

Environment Canada is partnering on the study to better understand the impact of traffic pollution, while Health Canada is testing urine samples to measure levels of phthalates, a chemical found in soft plastic. For Canada Mortgage and Housing Corporation, the results could influence future building standards and designs.

Malcolm Sears, Director and Principal Investigator for CHILD, describes the study as "the centrepiece of the whole AllerGen network."

"Through AllerGen, we were able to bring together the initial core of about 40 investigators from some 30 different disciplines, including environmental science, epidemiology, genetics, psychosocial, paediatrics, neonatology, immunology, physiology and infectious disease. You need a multidisciplinary approach to understand the underlying causes of developing allergy and asthma," says Sears, who led the asthma and allergy component of a longitudinal birth cohort study (Dunedin) that started 40 years ago in New Zealand.

Natural delivery vs C-sections

Though considered still early days for a longitudinal study (the oldest children in the study are now five, the youngest about one), the CHILD Study made international headlines in 2013 when researchers at the University of Alberta found that babies born by C-section – as opposed to vaginal delivery – were deficient in a specific type of bacteria, called Bacteroidetes. Using fecal samples collected from four-month-old babies in Manitoba, the study also found that being formula-fed resulted in a different bacterial makeup than being breastfed.

"The potential long-term consequences of decisions regarding mode of delivery and infant diet are not to be underestimated," the authors wrote in the Canadian Medical Association Journal. "Infants born by caesarean delivery are at increased risk of asthma, obesity and type 1 diabetes, whereas breastfeeding is variably protective against these and other disorders."

Principal investigator and epidemiologist Anita Kozyrskyj has since confirmed those initial findings using samples from another 200 infants at the Manitoba site. She also found that infants born by emergency C-section were the most deficient in Bacteroidetes abundance at three months, compared to those delivered vaginally or by elective C-section.

But at one year of age among infants breastfed for longer than six months, these differences in gut microbiota were no longer evident in the elective C-section group. Researchers are now analyzing data from 500 infants from Edmonton and Vancouver to see if any of these children are wheezing or developing allergies.

Kozyrskyj says this research wouldn’t have been possible had it not been for a 2006 AllerGen NCE meeting where she met James Scott, an expert in microbiology and DNA sequencing at the University of Toronto. That discussion resulted in a successful bid two years later to CIHR for a $2.5-million team grant under the Canadian Microbiome Initiative. (The microbiome is the collection of trillions of microbes – a cocktail of bacteria, viruses and other microscopic creatures – that live on and in the human body.)

"I’m an epidemiologist. I didn’t have the microbiology background required to profile samples using this high throughput gene sequences, but James did," she says. "We then used samples from the Winnipeg CHILD site to pull together the pilot data we needed for the microbiome application. We were a bit of the underdog coming into this competition, but we were successful based on the strength of our team and access to CHILD data and samples."

Another microbiome team supported by CIHR and led by Brett Finlay at the University of British Columbia is using CHILD data and samples to examine the so-called "hygiene hypothesis," which suggests that our desire to be ultra-clean may be making children vulnerable to auto-immune diseases such as asthma and eczema.

Denburg says several other projects are launching that will rely on CHILD data, including one examining how nutrition in early life can affect the risks of chronic diseases such as obesity and type 2 diabetes.

"This study started with a focus on allergies and asthma," says Denburg. "But if it continues, and I strongly believe it should continue, it can be a platform for studying many of the chronic, non-communicable, inflammatory diseases that the World Health Organization says are the scourge of this world – obesity, type 2 diabetes, asthma, cancer and cardiovascular disease."

Many birth cohort studies continue to follow children well into adulthood. Sears says for CHILD that will require sustained funding beyond 2019, when the AllerGen NCE sunsets. "If we can keep this study intact and well-funded through both base funding and individual grant funding, this will become an ongoing platform for ideas, discoveries, treatment, diagnoses, public policy, guidelines and prevention. It could be one of Canada’s greatest legacies."

"As the late Canadian epidemiologist, Clyde Hertzman, said with respect to the 'biological embedding' of many determinants of health and illness: ‘Early in life, the environment talks to the genes, and the genes listen,’" adds Denburg. "CHILD is uniquely poised to capture and understand the complexity of factors and life trajectories which will form the basis for individual and population health prescription and disease prevention in this and generations to follow."