Anita Kozyrskyj, PhD Research Chair & Associate Professor

1. A Novel Study Design to Investigate the Early Life Origins of Asthma in ChildrenSAGE Research Design & Epidemiologic Studies Anita Kozyrskyj, PhD Research Chair & Associate Professor Dept of Pediatrics, Faculty of Medicine & Dentistry University of Alberta Genes and the Environment: The Genesis Of Asthma and Allergy Workshop Vancouver: March 1, 2009

2. SAGE: Study of Asthma, Genes and the Environment To define the role of genetic, immunologic and environmental factors as they impact past, present and persistent asthma in a large population-based cohort RESEARCH OBJECTIVES

3. Founding Investigators Allan Becker, Anita Kozyrskyj, Kent HayGlass (University of Manitoba) Moira Chan-Yeung, Andrew Sandford, Peter Pare, (University of British Columbia) RESEARCH TEAM

4. A novel study design to investigate the early life origins of asthma in children. Kozyrskyj AL, HayGlass KT, Sandford AJ, Paré PD, Chan-Yeung M, Becker AB. Allergy 2009 in press SAGE Study Description

5. Record of every encounter with the health care system made by Manitobans since 1980. Data required for the administration of Canada’s health care system where the government is the primary payer. -physician visit claims, hospitalizations -prescriptions dispensed in retail pharmacies (provincial drug plan, Pharmacare) Stored at the Manitoba Centre for Health Policy in anonymized form so that individuals are not identifiable (scrambled PHIN) PHIN is a common element across all datasets and is used for linkage across data files Manitoba’s Health Care Databases

6. Manitoba’s Health Care Databases and Linkage Capabilities Clinical or Survey data Hospital Medical Home Care Personal Care Home Population-Based Research Registry Pharmaceuticals Provider Cost Vital Statistics Canada Education Family Services

7. Design for SAGE Cohort and Case-Control Study Births in MB in 1995 16320 Relocations/Deaths by 2002 2340 Still Resident in MB in 2002 13980 All Other Children FN Children Incorrect Addresses 12556 1424 810 No Response/ Declined 8161 FN Survey 2003-2005 Returned Surveys 2002-2003 Short Survey 3586 83 • Birth, pets, mold, ETS • Child asthma/allergy • Parents/Sib asthma allergy Recruited for SAGE 640 Data from SAGE Clinic Population •Detailed survey of environmental exposure & family history • Home assessment to collect dust for endotoxins, cat & dog allergen • Clinical assessment to confirm asthma, get blood • Mouthwash sample from parents • Permission to link data to healthcare DB Nested Case-Control Study 723

8. Nested Case-Control Study Surveys mailed to 1995 birth cohort Surveys returned (n = 3598) Parent-declared asthma (n = 398) Remaining children stratified by family history, income & location (n = 3200) Invited for clinic exam (n = 398) Randomly selected based on strata and invited for clinic exam (n = 450) Participated in clinic exam (n = 288) Participated in clinic exam (n = 435) 199 52 89 383 Doctor diagnosed asthma (n = 251) Non-asthmatic controls (n = 472)

9. Population Cohort Study of Children Born in Manitoba in 1995 Longitudinal health care database records for 13,980 children in the 1995 birth cohort Population-Based Study of Children Aged 7-8 Health and home environment survey data survey for 3,586 children. Linkage to health care database records. Nested Case-Control Study of Children Aged 8-10 Detailed survey, clinical assessment, immunologic, genetic and home assessment (endotoxin) data for 723 children. Linkage to health care database records. Longitudinal Follow-up of Case-Control Children at Ages 10-14 Detailed survey, clinical assessment, immunologic, nutritional and stress markers for 723 children. Qualitative interviews in a sample. PLATFORMS: 4 Studies

10. complete longitudinal health care records that accurately measure early life exposures such as antibiotic utilization and immunization no loss to follow-up of children and little migration out of province a population-based study with high & low risk children captures children living in urban & rural environments First Nations children included in study survey information on home environmental exposures in a subset SAGE Strengths: Cohort Study

11. Exposure Measure: Antibiotic Rx Brand and generic name of antibiotic dispensed Date of receipt of prescription and duration of therapy (days supply recorded) Antibiotic use measure: 0, 1-2, 3-4 and 5 or more courses of antibiotics in the first year of life and classified as narrow (pencillin, cloxacillin, cephalexin, cefadroxil, erythromycin) and broader-spectrum SAGE: Accurate exposure measures

12. Outcome Measure: Asthma at Age 7 At least two physician visits for asthma (ICD9=493), one hospitalization for asthma (ICD9=493) or two prescriptions for any asthma drug (inhaled/oral b-agonists, inhaled corticosteroids or cromones or leukotriene receptor antagonists) in the year following the 7th birthday. Validated against allergist diagnosis of asthma (high PPV). SAGE: Validated outcome measures

13. SAGE: Validated database measure of asthma

14. Maternal distress categories postpartum time period only one and 1-5 years (short-term) persistent over 1-7 years of child’s life late onset (after postpartum period) SAGE: Longitudinal measures Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma. Kozyrskyj AL, Mai XM, McGrath P, HayGlass KT, Becker AB, MacNeil B. Am J Respir Crit Care Med 2008; 177:142-7.

15. SAGE: Urban vs rural populations

16. Urban vs rural distribution of asthma phenotypes and home environment exposures

17. SAGE: Urban vs rural populations Increased risk of childhood asthma from antibiotic use in early life. Kozyrskyj AL, Ernst P, Becker AB. Chest 2007: 131: 1-7.

18. SAGE: Low vs high risk children Increased risk of childhood asthma from antibiotic use in early life. Kozyrskyj AL, Ernst P, Becker AB. Chest 2007: 131: 1-7.

19. minimal study bias because cases and controls selected from the same population control children were over-sampled from rural, low income areas and First Nation communities to ensure representation from diverse environmental exposures data on atopic phenotypes (asthma, atopic dermatitis, allergic rhinitis) from parent report (ISAAC questions), pediatric allergist diagnosis, longitudinal health care records, bronchial responsiveness and skin prick tests SAGE Strengths: Case-Control Study

20. home environment exposures which can be linked to health care records: endotoxin, beta-glucan, cat and dog allergen in house dust samples; home inspection (mold, allergen avoidance); parent report of breast feeding, tobacco use, pet ownership and daycare use in early life of the child assessment of innate and adaptive immune responses to a variety of immune stimuli (RSV, metapneumovirus, TLR agonists) from a large number of children genotyping to study the genetic and gene-environment interactions in the origins of allergic disease SAGE Strengths: Case-Control Study

21. Longitudinal follow-up at age 10-11 years: child/parent survey of body image, dietary restraint fasting blood sample: leptin, adiponectin, fatty acids, glucose, lipids, cortisol, DHEA, estradiol BMI, waist-hip ratio, blood pressure, C13 glucose breath test maternal depression survey Longitudinal follow-up at 12-14 years: child dietary intake, physical activity log, vascular stiffness fasting blood sample & weight measures as above maternal/child depression, family life events & SES surveys pediatric allergist diagnosed asthma/hayfever/atopic dermatitis/food allergy, methacholine challenge, skin prick test SAGE Strengths: Case-Control Study

22. Creating a birth cohort in Manitoba tostudy the origins of asthma Early home environment: Becker (pediatric allergy), HayGlass (immunology), Kozyrskyj (population health), Pare & Sandford (genetics) Obesity and insulin resistance: Dean & Sellers (endocrinology), Marchessault & Taylor (nutrition), Benoit (sociology) Maternal/child stress: MacNeil (neuroimmunology), McGrath (psychology)

23. Acknowledgements Conducted using the Data Repository at the Manitoba Centre for Health Policy Supported by programmer analysts, Shamima Huq and Matthew Dahl, and the SAGE study team PLATFORM I: Population Cohort Study