1. A Novel Study Design to Investigate the Early Life Origins of Asthma in Children SAGE 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. RESEARCH OBJECTIVES 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

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

4. SAGE Study Description 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. 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

5. Manitoba’s Health Care Databases  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

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

7. Design for SAGE Cohort and Case-Control Study 16320 142412556 723 640 833586 13980 2340 8161 810 Birth, pets, mold, ETS Child asthma/allergy Parents/Sib asthma allergy 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 Births in MB in 1995 Relocations/Deaths by 2002 Still Resident in MB in 2002 FN ChildrenAll Other Children Incorrect Addresses No Response/ Declined FN Survey 2003-2005 Returned Surveys 2002-2003 Recruited for SAGE Nested Case-Control Study Short Survey Data from SAGE Clinic Population

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) Doctor diagnosed asthma (n = 251)Non-asthmatic controls (n = 472) 1995289383

9. PLATFORMS: 4 Studies 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.

10. SAGE Strengths: Cohort Study  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

11. SAGE: Accurate exposure measures 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

12. SAGE: Validated outcome measures 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).

13. SAGE: Validated database measure of asthma

14. SAGE: Longitudinal measures 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) 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 Percent Urban (n=2143) South Rural (n=1328) North Rural (n=114) p value Asthma (parent report)13.910.37.90.0029 Allergy (hayfever, food allergy, atopic dermatitis) 12.66.97.9<0.0001 Allergic asthma7.44.02.00.0003 Non-allergic asthma7.26.57.10.7836 Male gender49.750.745.60.5557 Family history atopy45.736.634.2<0.0001 Tobacco smoke at birth32.330.450.9<0.0001 Mold at birth27.930.440.80.0139 LRI at birth1.73.811.2<0.0001 Transient Cat7.05.614.90.0005 Persistent Dog16.717.927.20.0141

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. SAGE Strengths: Case-Control Study  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

20. SAGE Strengths: Case-Control Study  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

21. SAGE Strengths: Case-Control Study  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

22. Creating a birth cohort in Manitoba to study the origins of asthma SAGE 1995 Birth Cohort 2002 CIHR New Emerging Team Grant 2002 CIHR Training Program Allergy & Asthma 2002 AllerGen NCE Operating Grant 2005 CIHR Intradisciplinary CE Grant 2004 CIHR NI Award & Operating Grant 2002/3 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. PLATFORM I: Population Cohort Study 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