Research themes

The determination of asthma and wheezing phenotypes, through the performance of lung function tests and of allergy skin tests. Lung function tests at age 8 years will include spirometry and methacholine challenge testing.

Data collection and management, analysis and integration.

Assessment of cardiometabolic traits at age 8 years, including blood pressure, weight, height, waist circumference, body fat, step test for fitness, activity, screen time amount and type, outdoor play, diet, sleep patterns and duration.

Assessment of environmental exposures related to the home, cleaning methods, heating and cooling, school, child and family activity, time spent in transit, mode of transport, use of swimming pools, and a multiplicity of chemical and environmental exposures. Outdoor air pollution is estimated by modeling.

Analysis of genetic material from parents and children, including epigenetics, and the broad field of ‘omics.

Blood components will be processed to provide RNA, DNA, whole blood, serum, plasma and peripheral blood mononucleocytes. Immunology investigations will focus on a comprehensive analysis of genetic, epigenetic, gene expression, innate and adaptive immunity and toll-like receptor profiles of children to understand the biological basis of allergic disease.

The detailed examination of respiratory infections in relation to outcomes of asthma and allergy

Analyses of the gut and respiratory microbiome.

A broad range of assessments to follow the trajectories of mental illness, including anxiety and depression prodromes during development.

The collection of nutritional information in mothers and children through questionnaires.

The assessment of the organized and unorganized physical activity of children in relation to disease outcomes.

The assessment of sleep duration and disruption together with determination of media consumption.

Analysis & Interpretation of Environmental Exposures Across the Cohort: Development of multiple methods to assess exposures related to the physical environment has been the role of the Environmental Working Group within CHILD. These data will enable CHILD exposure estimates to identify several risk factors, from some already well-recognized (dust mites and cockroaches, traffic-related air pollution) to those that represent newer hypotheses (semi-volatile organic compounds such as phthalates). Questionnaires will be validated, refined, published and synthesized to quantify the exposures and to derive new multi-exposure indices, such as potential oxidant stress burden. In addition to being used to study associations with early outcomes (wheeze, infant pulmonary function test, exhaled nitric oxide [eNO]) and primary endpoints (asthma diagnosis), the exposure data will be shared with partners such as Health and Environment Canada and the CMHC, providing new evidence to inform the establishment of standards and/or guidelines.

Analysis & Correlation of Environmental Exposures with wheezing phenotypes in the first five years of life: The exposures developed for the cohort will be related to clinical phenotypes from questionnaire data. For example, the relationship between the composite score of the oxidant stress burden and infant eNO measurement at birth, three, 12 and 18 months as a marker of airway inflammation will be investigated. The trajectories of wheezing phenotypes are of critical importance in determining those leading to more persistent asthma which is the major concern for early intervention and prevention.

Infant Pulmonary Function Phenotypes and Relation to Viral Infections: Growth- and respiratory infection-related changes in pulmonary function will be analyzed. It is hypothesized that earlier age of severe infection or multiple early viral infections will predispose children to have decreased growth in airflow measurements. Initial work among three month olds has shown that flow rates are lower than expected for normal controls; using lung clearance index (LCI), a parameter derived from MBW, this team is the first to definitively demonstrate an age-related increase, and the first study to longitudinally follow such a large group of healthy controls. The CHILD Study will provide longitudinal data to determine whether preschool and infant asthmatics have increased LCI compared to healthy controls, and thus identify early asthmatics.

Classification of innate immune phenotypes in relation to environmental exposure and the development of allergy/asthma: The innate immune system provides the first interface with the microbial world and is essential to initiation of an inflammatory allergic reaction. Toll-like receptors (TLRs) are central for innate recognition of critical pathogen-associated molecular patterns (PAMP). The response of TLRs to PAMPs differs from host to host. Early evidence suggests small differences in TLR sequence (polymorphism) may result in alterations of expression and/or function of the allergic immune response. As the immune system is the earliest final common pathway towards clinically relevant allergy and asthma, a thorough immunological assessment forms the centerpiece of any investigation aimed at correlating differences in environmental exposure with asthma and allergy.

Psychosocial factors and stress in relation to immune function, pulmonary and allergy/asthma outcomes: The team will examine how the child’s psychosocial environment, both pre- and postnatal, relates to the emergence of intermediate phenotypes that foster asthma. On the psychosocial end, the focus will be on the family’s economic situation, the quality of the parent-child relationship, and the level of stress present in the home. These risk factors will be related to the newborn’s gut microbiota, innate immune response, and cord-blood epigenetic profiles. As the child grows, these risk factors will also be related to trajectories of immune response and pulmonary function, with the idea that high levels of stress will confer risk for a phenotype characterized by excessive cytokine responses to allergens and decreased growth in pulmonary flow measurements. Clinically, these changes will be related to sensitization and the development of wheeze. With the wealth of genomics data in CHILD, the team should also be able to unravel the epigenetic and transcriptional pathways that enable psychosocial factors to “get under the skin.” These pathways will suggest novel therapeutic targets.

Genetics and Epigenetics in Relation to Allergy / Asthma – Risk and Disease Expression: The asthma susceptibility gene variants identified in the European Allergy and Asthma Consortium: a Multidisciplinary Study to Identify the Genetics and Environmental Causes of Asthma in the European Community (GABRIEL) cohort accounted for 38-49% of the population-attributable risk, but to date have not been tested in a prospective cohort from the general population. CHILD will enable this critical analysis, avoiding the loss of power due to correction for multiple comparisons that is incurred, e.g., in a genome-wide association study, and applying results to many other clinical outcomes of interest (e.g., food allergy). Whole exome sequencing will be performed on children in the CHILD Study who have a family history of allergy (one or both parents with asthma or another allergic disease) in order to enrich for subjects likely to have rare variants.

The CHILD Study cord and peripheral blood samples will be an invaluable resource for epigenetic studies including indepth epigenetic profiling that will be associated with the wealth of early life phenotypic data as well as with environmental factors such as maternal stress, low socioeconomic status and the composite scores for exposures and viral infections. There have been no large-scale studies in humans of the role of micro RNA (miRNA) in the regulation of gene expression and its relevance to disease pathogenesis. CHILD is uniquely positioned to advance this extremely important and novel area.

Nutritional Factors in Allergy and Asthma: Using a validated Food Frequency Questionnaire to examine maternal diet during pregnancy and regular questionnaire data about the infants’ diets and their transition to table foods, analyses will focus on the role of prenatal food intake previously associated with the development of asthma and allergy. This includes Vitamin D, antioxidants (such as Vitamin E and zinc) and foods with purported anti-inflammatory properties such as omega-3 fatty acids. Novel analyses will examine the role of probiotics, nutraceuticals and alternative medicines (e.g., herbal teas) on atopy and on immune function development. In addition, the role of diet in altering the infant microbiome can be assessed.

CHILD will enable development of a quantitative risk assessment (analogous to dose-response) of these nutritional factors on health outcomes, a major goal of PHAC’s Chronic Disease Management and Prevention Strategy.

The Infant Microbiome – Microbial Diversity Plays a Significant Role in Atopic Diseases: Children treated with antibiotics are at greater risk for asthma; probiotics have shown beneficial prophylactic effects for asthma; and gnotobiotic (microbiota-free) animals cannot generate tolerance to antigens. Another example is emerging evidence of breast-milk transmission of the maternal microbiome, potentially impacting the child immune system, and perhaps explaining some of the confusing and conflicting data surrounding the benefit, or lack of benefit, of breastfeeding on the risk of developing allergy and asthma. New experimental approaches will be applied to examining meconium and stool, breast milk and nasal secretions in the CHILD Study. Maternal factors, including mode of delivery (vaginal versus caesarean section), antibiotic use, animal exposure, dietary factors (breast-feeding, introduction of table food) and other environmental influences, all impact the microbiome, both in the gut and airways. These microbiome studies will inform and guide the food and pharmaceutical industries with regard to healthy foods and novel, rational antimicrobial drugs and treatment regimens; public health professionals, regarding formulation of policies involving lifestyle choices for healthy maternal and infant diets and nutrition; and professional (pediatric and obstetric) management guidelines.