A Novel Study Design to Investigate the Early Life Origins of Asthma in Children SAGE Research Design & Epidemiologic Studies
Anita Kozyrskyj, PhDResearch Chair & Associate Professor
Dept of Pediatrics, Faculty of Medicine & DentistryUniversity of Alberta
Genes and the Environment: The GenesisGenes and the Environment: The Genesis
Of Asthma and Allergy WorkshopOf Asthma and Allergy WorkshopVancouver: March 1, 2009Vancouver: March 1, 2009
RESEARCH OBJECTIVES
SAGE: Study of Asthma, Genes SAGE: Study of Asthma, Genes and the Environmentand the Environment
To define the role of genetic, immunologic To define the role of genetic, immunologic and environmental factors as they impact and environmental factors as they impact past, present and persistent asthma in a past, present and persistent asthma in a large population-based cohortlarge population-based cohort
RESEARCH TEAM
Founding InvestigatorsFounding Investigators
Allan Becker, Anita Kozyrskyj, Kent HayGlass Allan Becker, Anita Kozyrskyj, Kent HayGlass (University of Manitoba) (University of Manitoba)
Moira Chan-Yeung, Andrew Sandford, Moira Chan-Yeung, Andrew Sandford, Peter Pare, (University of British Columbia)Peter Pare, (University of British Columbia)
SAGE Study Description
A novel study design to investigate A novel study design to investigate the early life origins of asthma in the early life origins of asthma in children. children. Kozyrskyj AL, HayGlass KT, Kozyrskyj AL, HayGlass KT, Sandford AJ, Paré PD, Chan-Yeung M, Becker Sandford AJ, Paré PD, Chan-Yeung M, Becker AB. AB. Allergy 2009 in press
Manitoba’s Health Care Databases
Record of every encounter with the health care system made by Record of every encounter with the health care system made by Manitobans since 1980. Data required for the administration of Manitobans since 1980. Data required for the administration of Canada’s health care system where the government is the primary Canada’s health care system where the government is the primary payer.payer.
-physician visit claims, hospitalizations-physician visit claims, hospitalizations--prescriptions dispensed in retail pharmaciesprescriptions dispensed in retail pharmacies (provincial (provincial
drug drug plan, Pharmacare)plan, Pharmacare)
Stored at the Manitoba Centre for Health Policy in anonymized form Stored at the Manitoba Centre for Health Policy in anonymized form so that individuals are not identifiable (scrambled PHIN) so that individuals are not identifiable (scrambled PHIN)
PHIN is a common element across all datasets and is used for PHIN is a common element across all datasets and is used for linkage across data fileslinkage across data files
Population-Based Research Registry
Medical
Vital StatisticsCanada
Home Care Personal
Care Home
Hospital
ProviderPharmaceuticals
Cost
Education
FamilyServices
Clinical or Survey data
Manitoba’s Health Care Databasesand Linkage Capabilities
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 2003-2005Returned Surveys 2002-2003
Recruited for SAGE
Nested Case-Control Study
Short Survey
Data from SAGE Clinic Population
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)
199 52 89 383
PLATFORMS: 4 Studies
Population Cohort Study of Children Born in Manitoba in 1995Population Cohort Study of Children Born in Manitoba in 1995 Longitudinal health care database records for 13,980 children in the 1995 birth Longitudinal health care database records for 13,980 children in the 1995 birth
cohortcohort
Population-Based Study of Children Aged 7-8Population-Based Study of Children Aged 7-8 Health and home environment survey data survey for 3,586 children. Linkage Health and home environment survey data survey for 3,586 children. Linkage
to health care database records.to health care database records.
Nested Case-Control Study of Children Aged 8-10 Nested Case-Control Study of Children Aged 8-10 Detailed survey, clinical assessment, immunologic, genetic and home Detailed survey, clinical assessment, immunologic, genetic and home
assessment (endotoxin) data for 723 children. Linkage to health care database assessment (endotoxin) data for 723 children. Linkage to health care database records.records.
Longitudinal Follow-up of Case-Control Children at Ages 10-14 Longitudinal Follow-up of Case-Control Children at Ages 10-14 Detailed survey, clinical assessment, immunologic, nutritional and stress Detailed survey, clinical assessment, immunologic, nutritional and stress
markers for 723 children. Qualitative interviews in a sample.markers for 723 children. Qualitative interviews in a sample.
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
SAGE: Accurate exposure measures
Exposure Measure: Antibiotic RxExposure 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: Validated outcome measures
Outcome Measure: Asthma at Age 7Outcome 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 database measure of asthma
SAGE: Longitudinal measures
Maternal distress categoriesMaternal 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 Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma.childhood asthma. Kozyrskyj AL, Mai XM, McGrath P, HayGlass KT, Becker AB, MacNeil B. Kozyrskyj AL, Mai XM, McGrath P, HayGlass KT, Becker AB, MacNeil B.
Am J Respir Crit Care Med 2008; 177:142-7.Am J Respir Crit Care Med 2008; 177:142-7.
SAGE: Urban vs rural populations
South Rural 10%Urban 14%
North Rural 8%
Legend: Asthma Children by Geographic Region
South Rural 10%Urban 14%
North Rural 8%
Legend: Asthma Children by Geographic Region
Urban vs rural distribution of asthma phenotypes and home environment exposures
PercentUrban (n=2143)
South Rural (n=1328)
North Rural (n=114)
p value
Asthma (parent report) 13.9 10.3 7.9 0.0029
Allergy (hayfever, food allergy, atopic dermatitis)
12.6 6.9 7.9 <0.0001
Allergic asthma 7.4 4.0 2.0 0.0003
Non-allergic asthma 7.2 6.5 7.1 0.7836
Male gender 49.7 50.7 45.6 0.5557
Family history atopy 45.7 36.6 34.2 <0.0001
Tobacco smoke at birth 32.3 30.4 50.9 <0.0001
Mold at birth 27.9 30.4 40.8 0.0139
LRI at birth 1.7 3.8 11.2 <0.0001
Transient Cat 7.0 5.6 14.9 0.0005
Persistent Dog 16.7 17.9 27.2 0.0141
SAGE: Urban vs rural populations
Increased risk of childhood asthma from antibiotic use in early life. Increased risk of childhood asthma from antibiotic use in early life. Kozyrskyj AL, Ernst P, Becker AB. Chest 2007: 131: 1-7.
SAGE: Low vs high risk children
Increased risk of childhood asthma from antibiotic use in early life. Increased risk of childhood asthma from antibiotic use in early life. Kozyrskyj AL, Ernst P, Becker AB. Chest 2007: 131: 1-7.
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
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
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
Creating a birth cohort in Manitoba tostudy the origins of asthma
CIHR New Emerging
Team Grant2002
CIHR Training ProgramAllergy & Asthma
2002
AllerGen NCEOperating Grant
2005
CIHR Intradisciplinary
CE Grant2004
CIHR NIAward & Operating
Grant2002/3 SAGE 1995
Birth Cohort2002
Early home environment: Becker (pediatricallergy), 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)
PLATFORM I: Population Cohort Study
AcknowledgementsAcknowledgements
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
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