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Cluster Phenotypes - Background

Cluster Phenotypes - Background. Phenotypes such as “asthma” are difficult to define, variable over time and/or are subject to recall bias and are “ syndromic ”. Subtypes of asthma are known to exist - Eosinophilic , neutrophilic , paucigranulocytic , atopic, occupational.

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Cluster Phenotypes - Background

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  1. Cluster Phenotypes - Background • Phenotypes such as “asthma” are difficult to define, variable over time and/or are subject to recall bias and are “syndromic”. • Subtypes of asthma are known to exist - • Eosinophilic, neutrophilic, paucigranulocytic, atopic, occupational. • There are intermediate phenotypes – • IgE, atopy, AHR, FEV1, eNO • Phenotypes do not “capture” “asthma” • Ho: Clusters will capture phenotypes that more strongly associate with genetic variation than “asthma”

  2. Cluster Phenotypes • Cluster Analysis (SAS) • Busselton Health Survey 2005-7 • All adults with: • Age, Sex, FEV1, FVC, eNO, eosinophil count, BMI, airway hyper-responsiveness (AHR), atopy (skin tests) • n = 1,970 • 7 clusters (each with n > 100)

  3. Cluster Phenotypes

  4. Cluster Phenotypes

  5. Cluster Phenotypes - Questions • How many clusters? • ? Sub-clusters • What other variables to collect? • Include exposure? • Include questionnaire data? • Include treatment? • Do clusters suggest pathways? • Best gene association strategy • GWAS, candidate (from lit. or pathways)?

  6. Cluster Phenotypes

  7. Excessive Airway Narrowing in a General Population n = 201 James et al. ARRD 1992;146:895-9

  8. Smooth muscle Outer wall area Inner wall area Basement membrane perimeter Airway Compartments Lumen area

  9. Excessive Airway Narrowing

  10. Airway smooth muscle in asthma: collaborative study James et al AJRCCM (rejected), Thorax (rejected), ERJ (submitted)

  11. Decline in lung function - the Busselton Health Study Females James et al AJRCCM 2005;171:109

  12. A Longitudinal Study of Childhood Asthma Followed to Adulthood FEV1/FVC Mean (SE) from 9-26 Yrs in Males and Females, by Pattern of Wheezing Sears M et al. N Engl J Med 2003;349:1414-1422

  13. Asthma (ever) (p <0.001)* (p <0.001)* (p <0.001)* (p <0.001)* *1981 vs 2005/07 Q. “Has a doctor ever told you that you had asthma?” Q. “Have you ever had asthma?”

  14. Current Asthma(AHR + recent wheeze)

  15. (p <0.001)* Wheeze (ever) (p <0.001)* (p <0.029)* *1981 vs 2005/07 Q. “Has your chest sounded wheezy on most days or nights?” Q. “Has your chest ever made a wheezing or whistling sound?”

  16. Wheeze <12 months Recent Wheeze

  17. Shortness of Breath

  18. Cough/Phlegm (p <0.02)* (p <0.02)* (p <0.02)* (p <0.02)* *1981 vs 2005

  19. Smoking

  20. Bronchitis Q. “Have you ever had bronchitis? Q. “Has your doctor ever told that you had bronchitis?”

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