Download - 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.• 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”
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)
Cluster Phenotypes
Cluster nDoctor-diagnosed
Hay Fever (%)Doctor-diagnosed
Asthma (%)
1 106 52.8 31.1
2 226 28.8 17.7
3 215 45.6 40.0
4 391 42.2 18.2
5 127 31.5 24.4
6 441 31.1 15.6
7 464 20.2 5.4
Cluster Phenotypes
Cluster n Cluster Variables Outcome Variables “Descriptors”
1 106 High eNO, high eosinophils, low BHR, high atopy
Smoke low, HF high, asthma
Allergic sneezing, wheezing twitchers
2 226 Females, obese, no AHR, low atopy Fat Freewheelers
3 215 Reduced lung function, all AHR, moderate atopy High asthma Chronic wheezers
4 391 Males, no AHR, very atopic HF Blotchy blokes
5 127 Males, poor lung function, no AHR Smoke high Puffing Old Blokes
6 441 Younger females, no AHR, low eNO, low eosinophils, low atopy
Smoke low, asthma low Sanctimonious shielas
7 464 Older, good lung function, no AHR, low atopy
Smoke low, HF low, asthma very low
Survivors
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)?
Cluster Phenotypes
Cluster n Age Sex (%F) FEVPPR FEVFVC eNO EOSIN BMI AHR ATOPY
1 106 49.2 41.5 97.7 76.9 60.0 5.8 25.7 19.8 81.1
2 226 53.9 78.3 92.8 80.9 16.1 3.2 34.5 0.0 30.5
3 215 53.3 56.7 88.2 74.0 23.6 3.9 26.9 100.0 71.2
4 391 51.6 16.9 97.3 77.8 20.7 4.1 27.3 0.0 95.4
5 127 69.4 24.4 68.4 58.3 20.4 3.8 26.4 0.1 49.6
6 441 38.7 80.8 100.9 81.7 14.6 2.7 24.0 0.0 45.1
7 464 68.2 43.3 104.0 77.0 18.3 3.0 26.2 0.0 5.2
Excessive Airway Narrowing in a General Population
n = 201
James et al. ARRD 1992;146:895-9
Airway Compartments
Lumen area
Smooth muscle
Inner wall area
Outer wall area
Basement membrane perimeter
Excessive Airway Narrowing
Airway smooth muscle in asthma: collaborative study
James et al AJRCCM (rejected), Thorax (rejected), ERJ (submitted)
Decline in lung function - the Busselton Health Study
Females
James et al AJRCCM 2005;171:109
Sears M et al. N Engl J Med 2003;349:1414-1422
FEV1/FVC Mean (SE) from 9-26 Yrs in Males and Females, by Pattern of Wheezing
A Longitudinal Study of Childhood Asthma Followed to Adulthood
Asthma (ever)
(p <0.001)*
(p <0.001)*
(p <0.001)*
(p <0.001)*
*1981 vs 2005/07
Q. “Have you ever had asthma?” Q. “Has a doctor ever told you that you had asthma?”
Current Asthma(AHR + recent wheeze)
Wheeze (ever)
(p <0.001)*
(p <0.029)*
(p <0.001)*
Q. “Has your chest sounded wheezy on most days or nights?”
Q. “Has your chest ever made a wheezing or whistling
sound ?”
*1981 vs 2005/07
Recent WheezeWheeze <12 months
Shortness of Breath
Cough/Phlegm
(p <0.02)*
(p <0.02)*
(p <0.02)*
(p <0.02)*
*1981 vs 2005
Smoking
Bronchitis
Q. “Have you ever had bronchitis? Q. “Has your doctor ever told that you had bronchitis?”