Identification of Asthma Phenotypes using Cluster Analysis in the Severe Asthma Research Program

Transcription

1 Moore online supp 1 Online Data Supplement Identification of Asthma Phenotypes using Cluster Analysis in the Severe Asthma Research Program Wendy C. Moore, MD, Deborah A. Meyers, PhD, Sally E. Wenzel, MD, W. Gerald Teague, MD, Huashi Li, MS, Xingnan Li, PhD, MS, Ralph D Agostino, Jr., PhD, Mario Castro, MD, Douglas Curran-Everett, PhD, Anne M. Fitzpatrick, PhD, Benjamin Gaston, MD, Nizar N. Jarjour, MD, Ronald Sorkness, PhD, William J. Calhoun, MD, Kian Fan Chung, MD, Suzy A.A. Comhair, PhD, Raed A. Dweik, MD, Elliot Israel, MD, Stephen P. Peters, MD, PhD, William W. Busse, MD, Serpil C. Erzurum, MD, Eugene R. Bleecker, MD for the National Heart Lung Blood Institute s Severe Asthma Research Program.

2 Moore online supp 2 FIGURE E1. FIGURE E1. Reduction of the original 628 variables in the SARP database. * Numbers correspond to variable numbers in Table E2. The 17 composite variables from the questionnaire data incorporate answers from 63 individual questions. The 34 final variables in the cluster analysis include 23 variables from the questionnaire data, 6 related to lung function and 5 markers of atopy. Following the cluster analysis, stepwise discriminant analysis identified 11 significant predictors of cluster assignment. Three of these variables (Baseline and Maximal FEV1 % predicted, age of disease onset) were used in the Tree analysis.

3 Moore online supp 3 TABLE E1. Generation of a Variable: Frequency/Severity of HCU in Past year. Rank Weight of Rank Questions * n Severe Asthma Chronic Oral Steroids FEV1% pred Maximum FEV% 0 0 None reported % 2% 81% 92% urgent visit/yr 70 40% 4% 78% 89% 2 4 ED past year 83 42% 5% 77% 88% OCS burst/yr % 32% 67% 80% 4 8 Hospitalization past year 81 88% 36% 65% 81% 5 10 ICU past year 59 93% 42% 66% 84% n=856 for this table (composites were developed prior to excluding children < 12 years of age from the analysis). * Questions used to generate the composite variable are from two separate forms. Subjects receive the highest rank based on their answers (i.e. each subject appears only once). Weight of ranks within a composite variable are on a scale of 0-10 (each subject gets the weight assigned to their rank). Five variables are now one variable Frequency/Severity of HCU in Past year and each subject has a score. The four columns on the right verify that the composite variable effectively discriminates severity of health care utilization based on disease severity, need for oral corticosteroids and lung function. Severe asthma as defined by the ATS workshop on severe asthma (11).

4 Moore online supp 4 TABLE E2. List of Variables used in Cluster Analysis Variable Number Type of Data Variable Name Key 1 Binary Gender Male/Female 2 Categorical Race Caucasian/AA/Other 3 Continuous BMI 4 Age at Enrollment Continuous 5 Age of Asthma Onset Ages 6 Asthma Duration Continuous Baseline Lung Function Continuous Maximum Max or Best Lung Function Continuous Atopy Medication Use Health Care Utilization Asthma Symptoms Patterns of Skin Test Responses Triggers FEV1 % predicted FVC % predicted FEV1/FVC FEV1 % predicted FVC % predicted Maximal % change in FEV1 Pre-bronchodilator > 6 hours withholding of bronchodilators Post-bronchodilator Best values after 6-8 puffs of albuterol Number of Positive Skin Tests Range 0-12 Corticosteroid Use Total Number of Controllers Type of Controllers Beta-agonist Frequency Score Frequency/Severity past year Intensity/ ICU ever in lifetime General Symptoms Score Symptoms with Activities Cats/Dogs Dust Mites/Cockroach Molds Pollens Severity of Allergy Symptoms Aspirin Sensitivity/ Nasal Polyps Sinusitis/Sinus Surgery Bronchitis/Pneumonia GERD and HTN Number of positive tests for each type of allergen 30 Co-morbidity: 31 Parental Asthma 32 Family History Siblings with Asthma 33 Tobacco Exposure: Passive/Remote 34 Women s Hormone Exposure

5 Moore online supp 5 FIGURE E2. FIGURE E2. Dendrogram. Using Wald s minimum-variance hierarchical clustering method and an agglomerative (bottom-up) approach, 726 subjects were clustered to a single final group. At each generation of clusters, samples were merged into larger clusters to minimize the within-cluster sum of squares or maximize between-cluster sum of squares. With successive clustering, 5-6 groups became obvious, although the 6 th group was quite small (n=31, a subgroup of Cluster 5) and we chose to stop at five clusters instead.

6 Moore online supp 6 TABLE E3. Demographics and Clinical Characteristics of Subjects Classified by Severity * Mild Moderate Severe Number of Subjects P-value Age at Enrollment (yrs) 31 (12) 38 (12) 41 (15) < Gender (% female) 73% 61% 63% Race (% Cauc /AA/Other) 67/27/6 61/30/9 62/29/ Body Mass Index > 30 (BMI) 26% 39% 47% < Age of Asthma Onset (yrs) 13 (13) 15 (14) 16 (16) 0.65 Asthma Duration (yrs) 18 (12) 23 (14) 25 (14) < Baseline Lung Function FEV1 % predicted 94 (11) 66 (13) 62 (21) < FVC % predicted 100 (12) 81 (15) 77 (20) < FEV1/FVC 0.79 (0.07) 0.67 (0.10) 0.65 (0.13) < Maximal Lung Function FEV1 % predicted 103 (10) 82 (13) 77 (21) < FVC % predicted 104 (12) 92 (15) 90 (18) < % change in FEV1 10 (8) 19 (18) 21 (21) < PC20 Methacholine, mg/ml 1.51 (0.65) 0.85 (0.65) 0.79 (0.77) F E NO, ppb 28 (0.37) 30 (0.35) 27 (0.39) 0.60 Atopy Status Total IgE, IU/ml 110 (0.72) 120 (0.62) 120 (0.75) 0.83 % with 1 positive test 83% 86% 67% < Asthma Medications LTRA 21% 22% 53% < ICS 55% 62% 98% < LABA 44% 50% 89% < OCS 3% 3% 48% < Xolair 0% 0% 14% < Numeric data expressed as Mean (SD) or Geometric Mean (log 10 SD) * Severity defined by prebronchodilator FEV1 and inhaled corticosteroid (ICS) use; Mild asthma = FEV1 80% predicted on no or low doses of ICS; Moderate asthma = FEV1 < 80% predicted on low to moderate doses of ICS; Severe = Meets ATS workshop definition of severe asthma. Pre-bronchodilator values with > 6 hours withhold of bronchodilators. Post-bronchodilator values after 6-8 puffs of albuterol. Subjects with FEV1 < 55% predicted pre-testing were excluded from methacholine challenge.

7 Moore online supp 7 TABLE E4. Geographic Distribution of Subjects in Clusters by Clinical Center Cluster 1 Cluster 2 Cluster 3 Cluster 4 Cluster 5 Number of Subjects Brigham & Women s Hospital Cleveland Clinic Emory University Imperial College, UK University of Pittsburgh * University of Virginia Wake Forest University University of Wisconsin Washington University * Includes subjects studied at National Jewish Hospital 8/2001 to 6/2006.

8 Moore online supp 8 FIGURE E3A. FIGURE E3B. % P< P< % of Subjects % of Subjects Figure E3A and B. Frequency of reported asthma symptoms (Fig. 3A) and albuterol use (Fig. 3B) in past 3 months as assessed by composite variable scores. Symptoms and albuterol use increase in frequency from Cluster 1 to 5. The mildest clusters (1 and 2) report similar bronchodilator use and symptoms suggesting a more active lifestyle may lead to albuterol use (pre-exercise) in these younger groups. Most of the subjects in Clusters 4 and 5 report daily symptoms and albuterol use that is likely due to their severe airflow obstruction at baseline. The majority of Cluster 3 subjects also report daily symptoms despite their near normal lung function suggesting that obesity may play a role in their daily shortness of breath. light grey bars = less than monthly, dark gray bars = weekly, black bars = daily.

9 Moore online supp 9 TABLE E5. Clinical Characteristics of Subjects in Cluster 6 Cluster 5 Cluster 6 Number of Subjects Age at Enrollment (yrs) 52 (10) 42 (11) Gender (% female) 62% 65% Race (% Cauc /AA/Other) 69/18/13 65/26/10 Body Mass Index 31 (7) 32 (8) Age of Asthma Onset (yrs) 23 (16) 15 (13) Asthma Duration (yrs) 30 (16) 27 (12) Baseline Lung Function FEV1 % predicted 43 (12) 45 (17) FVC % predicted 59 (13) 62 (16) FEV1/FVC 0.57 (0.11) 0.58 (0.13) Maximal Lung Function FEV1 % predicted 55 (12) 65 (16) FVC % predicted 72 (13) 85 (13) Change in % predicted FEV1 34 (29) 54 (40) F E NO, ppb 46 (46) 44 (43) Total IgE, IU/ml 204 (269) 329 (625) Numeric data expressed as Mean (SD) Pre-bronchodilator values with > 6 hours withhold of bronchodilators. Post-bronchodilator values after 6-8 puffs of albuterol.