HOW DID CHILD BEGIN?

The CHILD project is the result of work over several years to build a national cohort. The process has benefitted from the efforts of many people but was primarily structured by converging questions from government and academic perspectives. The three major drivers for the study were:

McMaster University / University of Toronto Researchers
Are children with persistent asthma born with small airways, or does the early environment (pollutants, infections, allergens) damage the airway?

AllerGen Network of Centres of Excellence Researchers
What are the underlying causes of the major increase in allergic diseases, including asthma?

Health Canada / CIHR:
What impact does the built environment have on the health of the growing child?

The Beginning of CHILD:
The federal government, via the Canadian Institutes of Health and Research (CIHR) and AllerGen NCE Inc., officially announced the funding of a $12-million, 6-year research initiative known as the CHILD study on June 6, 2008. The following diagram illustrates the important CHILD Study milestones to September 2008.

PRIMARY HYPOTHESIS:

Exposure to indoor pollutants including chemical agents and microbiological agents, by interaction with host genetics, hormonal, metabolic, psychosocial, physiological, nutritional and immunological factors, increases the risk of allergy and asthma in infancy and early childhood.

Some Specific Environmental Exposure Hypotheses

1: Children exposed to low levels of endotoxin (e.g., lowest quintile) in the first year of life who have specific CD14 polymorphisms are more likely to develop allergic asthma by age 5 compared with children with the same polymorphisms and high levels of exposure to endotoxin.

2: Parental report of indoor air quality of dampness and poor air quality in houses by questionnaire is associated with an increased incidence of childhood viral infections and wheezing through changes in mucosal innate immune responses.

3: Children who develop asthma will develop reduced airway flows in infancy and preschool, after controlling for other factors which may affect lung function such as maternal smoking, viral infections and gender. Lung growth and volume may be affected by environmental exposures at key times in fetal and childhood development; there may be a dose effect with levels of exposures to fine particulates.

4: Males regardless of parental atopy, and females with parental atopy, who are breast-fed for >4 weeks with breast milk with high levels of estrogen are more likely to develop atopy by age 5 than breast-fed children consuming breast milk with low levels of estrogen.

5: Children who are exposed to higher levels of pre-natal and post-natal chronic family stress are more likely to demonstrate heightened immunological responsiveness to allergens and to develop atopy by 5.

GENE BY ENVIRONMENT INTERACTIONS - IS IT NATURE OR NURTURE ?

The CHILD Study will examine two major hypotheses.

1. That genetic and immunological determinants lead to childhood allergic responses and, that clinical outcomes, including asthma, may be further modified by lung growth, hormonal and metabolic influences and psychosocial environment.

2. That the household environment - together with other specific environmental exposures - can affect which genes are expressed (the new science of epigenetics) leading to allergic outcomes, as well as having a direct impact on children’s immunity.

 

WHAT IS THE PRIMARY GOAL OF THE STUDY?

The primary objective of this national longitudinal birth cohort study is to determine the roles of a range of environmental factors and their interactions with genetic and host factors in the development of allergy and asthma in children.

To meet this goal we will be obtain multiple objective measurements, focusing especially on the indoor environment (home inspection, dust collection), child responses (immune function, endocrine, pulmonary function, infections, allergies and clinical assessment), and genetic factors, together with extensive questionnaire data (demographics, family history, diet, activity, housing environment, psychosocial environment and stress) in a prospective longitudinal birth cohort of 5,000 children  recruited in pregnancy in a general population.

Storage of biological material will allow testing of multiple hypotheses, and promote the formulation and testing of novel hypotheses not yet conceived. The study will provide unique Canadian data essential to determining environmental effects on childhood allergy and asthma.

Primary Outcome

The primary outcome on which the study is powered is specialist-physician diagnosed asthma at age five years (anticipated to occur in approximately 10% of the population-based cohort).  Other more common, important allergy-related outcomes (i.e., atopy (IgE/skin prick responses), atopic eczema, food allergy, transient wheezing, hay fever) will be assessed as secondary outcomes during the study and at 5 years.

Objective evidence will be used in assessing the primary outcome, including:
Spirometry
Exhaled Nitric Oxide Measurement
Methacholine Challenge

Secondary Outcomes
Preschool wheeze
Eczema
Allergic Rhinitis
Food allergy
Atopy
Preschool lung function 
Lung inflammation markers
Urine - metabolomic markers
Immunologic outcomes
Innate and adaptive
T-cell stimulation and cytokine assays
Innate immune effector cell assays

Read a more detailed presentation on the CHILD Primary Outcomes

 

WHAT ARE THE KEY COMPONENTS OF THE STUDY?

The essentials of the study include:

• Assess the home environment by questionnaire in pregnancy, and at 1, 3 and 5 years, and by direct inspection and sampling at 3 months
• Collect and store DNA at birth and 5 years
  
• Document viral/other infections in first year of life
  
• Examine immune / inflammatory responses to pathogens and allergens; markers of innate immune function
  
• Measure lung function in infancy, and at 1, 3 and 5 years
  
• Obtain family history of mother and father by questionnaires, skin tests, lung function, AHR, and obtain DNA.

The exposures of interest are illustrated below:

 

 

CHILD STUDY PROGRESS

The Canadian Healthy Infant Longitudinal Development (CHILD) Study consists of two recruitment phases; Vanguard and Main CHILD Study. The Vanguard phase recruited approximately 200 pregnant woment in Fall 2008. The Main CHILD Study began recruitment July 2009 and anticipates 4800 children joining the study. The lag period of six months between the Vanguard recruitment and the Main CHILD Study recruitment provided an opportunity for the investigators to review, evaluate and revise study methods and tools for implementation in the main CHILD Study.

The figure below illustrates the progress of both the Vanguard Phase and the Main CHILD Study.

 

EXECUTIVE SUMMARY (Modified from CIHR Grant Application June 2007)

The prevalence of allergy and asthma in children has increased dramatically over recent decades. Environmental exposures may be critical factors impacting allergy and asthma in children, either directly or mediated through epigenetic changes (methylation and de-methylation of regulatory sequences and/or chemical modification on the histones which influence gene expression). The effects of exposures to many indoor and outdoor pollutants, and of gene-environment interactions, remain unresolved. Patterns of allergy, airway inflammation and lung function abnormalities, which may predict future asthma, have not been well assessed in early infancy. CIHR in partnership with the NCE program AllerGen and Government sought proposals for examination of the role of the environment in childhood allergy and asthma.

CHILD is a multidisciplinary, longitudinal, population-based birth-cohort study (CHILD). This study of 5,000 children is powered to test multiple hypotheses within the theme that specific environmental exposures together with genetic and immunological determinants, lead to pathophysiological allergic responses, and that clinical outcomes including asthma may be further modified by lung growth, hormonal and metabolic influences and psychosocial environment. The cohort will provide a platform for many current and future studies of childhood allergy and asthma.

Following pilot studies, 5000 women will be recruited during pregnancy in 4 centres. Infants will be studied at birth, at a home visit at 3 months, and at clinic visits at ages 1, 3 and 5 years (with telephone questionnaires at 6 and 9 months, 1½, 2, 2½ and 4 years). Indoor and outdoor environmental exposures (questionnaires, home inspections, dust sampling) will be assessed, along with immunological studies, genetic and epigenetic testing of DNA from child and parents, and longitudinal measures of pulmonary function, airway inflammation, nutrition and infections, focusing particularly on the critical window of the first year of life. Environmental assessments will include sampling indoor allergens, endotoxin, beta (1,3)-D-glucans, phthalates, hopanes, and tobacco smoke.

Outdoor exposure assessment will involve models employing land use regression techniques and new methodologies supported by Geographic Information Systems. Environmental and biologic material will be assayed both in real time and stored for later analyses using family, cohort and nested case-control designs. The study is powered on the primary outcome of diagnosed asthma at 5 years, but intermediate outcomes of food allergy, allergic eczema, atopy and recurrent wheeze will be assessed throughout. For practical reasons, pulmonary function and airway inflammation in infancy will be assessed in only 750 children, but in all children at 3 and 5 years. Cellular and molecular readouts of acquired and innate immunity will be assessed in only 1000 infants. Psychosocial factors will be assessed in all children, with detailed evaluation of stress and its relation to immune function in 1,500 children. Family-based analyses will be used to validate previously identified asthma- or allergy-related genes, and support hypothesis generating studies. Inflammatory cell gene expression will be related to gene sequence variation, environmental exposures, epigenetic phenomena and outcome variables.

Storage of biological material will allow testing of multiple hypotheses, and promote the formulation and testing of novel hypotheses not yet conceived. The study will not only provide unique Canadian data essential to determining environmental effects on childhood allergy and asthma, but will also enable examination of important parental health research questions.