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