Clinical and radiographic predictors of GOLD-Unclassified smokers in COPDGene

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1 Clinical and radiographic predictors of GOLD-Unclassified smokers in COPDGene Emily S. Wan, John E. Hokanson, James R. Murphy, Elizabeth A. Regan, Barry J. Make, David A. Lynch, James D. Crapo, Edwin K. Silverman, and the COPDGene Investigators. Online Data Supplement

2 Supplement to Methods Section Variable definitions (continued) Pack-years was calculated as the product of the average number of cigarettes smoked per day divided by 20 and multiplied by the number of years smoked. Body mass index was calculated as weight (in kg) divided by height (in meters) squared. Chronic bronchitis was considered present if the subject responded affirmatively to the questions "Do you usually cough like this on most days, for 3 consecutive months or more during the year?" and "Do you usually bring up phlegm on most days for 3 consecutive months or more during the year?" and responded 2 to the questions "How many years have you had this cough?" and "How many years have you had this trouble with phlegm?". Physician diagnosed asthma (ever) was considered present if the patient responded affirmatively to the questions "Have you ever had asthma?" and "Was it diagnosed by a doctor or other health professional?" Current asthma was considered present if, in addition to the two preceeding questions, the subject also responded affirmatively to the question "Do you still have it?" Long acting beta agonist use was considered positive if the subject reported using either a long acting beta agonist or a combination long acting beta agonist and inhaled steroid combination medication. Inhaled corticosteroid use was considered positive if the patient reported a history of inhaled steroid use or combination medication use. Long acting muscarinic antagonist use was considered present if the subject reported tiotropium use. Airway wall measurement technique Using the Pulmonary Workstation Plus package (VIDA Diagnostics, Inc. Coralville, IA), the airway tree was generated using an automated region-growing technique and detailed airway analysis was performed along six selected airway paths (RB1, RB4, RB10, LB1, LB4, and LB10) emcompassing segmental bronchi and two generations of subsegmental bronchi. Emphysema, gas trapping, and wall area measurements were not available in some subjects due to technical limitations.

3 Lower-limit of normal (LLN) defined groups The univariate and multivariate analyses were repeated using the lower limits of normal (LLN)(1) to define COPD, smoking control, and Unclassified groups. Subjects with an FEV1 less than the predicted lower limit of normal and an FEV1/FVC ratio lower limit of normal were considered to have lowerlimit of normal unclassified spirometry (LLN unclassified). Lower limit of normal COPD subjects (LLN-COPD) were defined as subjects with both FEV1/FVC ratio and FEV1 below the LLN. Smoking controls (designated as LLN-controls) had both FEV1/FVC ratio and FEV1 greater than the LLN.

4 References E1. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general u.s. Population. Am J Respir Crit Care Med 1999;159:

5 Supplement to Results Section Supplementary Table E1 Ranges of values for key variables in of LLN -Unclassified subjects Variable Range BMI FEV 1 % predicted % emphysema

6 Supplementary Table E2 - Univariate comparisons between Lower-Limit of Normal Unclassified, Control, and COPD subjects LLN-Unclassified LLN-Controls LLN-COPD N Age 58.8 (8.7) 59.0 (9.4) 63.8 (8.4) * Male (%) Non-white race (%) * Pack-years 47.3 (27) 38.2 (21.4) * 53.5 (26.8)* Current smoking (%) * Heart rate 76.5 (13.3) 74.2 (12.6)* 78.3 (13.1) Body mass index 32.7 (7.2) 28.7 (5.9)* 27.8 (6.1)* 6 minute walk distance(feet) (405.8) (407.1)* 1115 (429.5)* Resting O 2 saturation 96.0 (2.5) 97.0 (1.8) * 94.3 (3.7)* FEV 1 (% predicted) 67.2 (7.5) 96.1 (12.8)* 46.3 (17.1)* FVC (% predicted) 69.8 (8.4) 95.9 (12.7) * 75.0 (17.5)* % emphysema 2.3 (2.7) 3.0 (3.4) * 16.5 (13.5)* % gas trapping 13.9 (9.8) 12.7 (10.1) 44.3 (20.1)* Pi10 ± 3.8 (0.1) 3.7 (0.1) * 3.8 (0.1) Subsegmental wall area % 64.9 (2.3) 63.1 (2.3)* 65.9 (2.4)* Total Lung Capacity (% predicted) 80.6 (13.3) 92.8 (15.3)* (16.8 )* Functional Residual Capacity (% predicted) 87.8 (18.6) 90.5 (20.0) (32.9)* Long acting beta agonist (% of users) * 55.1* Long acting muscarinic antagonist (% of users) * 47.5* Inhaled corticosteroids (% of users) * 57.3* Oral steroids (% of users) * 6.7* St. George's Respiratory Questionnaire 29.3 (22.7) 15.4 (17.1) * 42.0 (20.7)* MMRC 1.5 (1.5) 0.7 (1.1) * 2.3 (1.4) * Chronic cough (%) * 39.1 Chronic sputum (%) * 37.1* Chronic bronchitis (%) * 28.2* Asthma -- Ever (%) * Asthma -- Current (%) * 18* Positive bronchodilator response (%) * History of Congestive Heart Failure (%) * 5.4 Diabetes (%) * 11.9* Hypertension (%) * 47 Stroke (%) TIA (%) Obstructive sleep apnea (%) * 16.5* Data are presented as percent or mean (standard deviation). MMRC = modified Medical Research Council dyspnea score. LLN = Lower Limit of Normal. Bronchodilator response was considered positive if the subject had 0.2L increase in FEV1 or FVC and 12% change in FEV1 or FVC above baseline (pre-bronchodilator) measurements. * denotes p-value <0.05 when compared to GOLD-U subjects For emphysema and TLC, n = 196 (GOLD-U), 1158 (Controls), 939 (COPD) For gas trapping and FRC, n = 176 (GOLD-U), 1055 (Controls), 892 (COPD) ± For Pi10, n= 191 (GOLD-U), 1135 (Controls), 888 (COPD) For subsegmental wall area, n=191 (GOLD-U), 1134 (Controls), 887 (COPD)

7 Supplementary Table E3 Differences by race in LLN-Unclassified subjects White African American N Age 61.5 (8.8) 53 (4.6)* Pack-years 50.9 (28.7) 39.2 (20.7) * BMI 32.2 (6.8) 33.6 (7.8) Current smoking (% of subjects) * FEV1 % predicted 68.2 (7.6) 65.0 (6.9)* FEV/FVC ratio 0.74 (0.06) 0.76 (0.05)* 6MWD (417) 1109 (330.0) * TLC (liters) 5.1 (1.2) 4.2 (1) * % emphysema 2.0 (3) 1.3 (1.3)* % gas trapping 14.5 (9.6) 12.4 (10.3) Subsegmental wall area % 64.5 (2.1) 65.7 (2.6)* Pi (0.10) 3.86 (0.14)* Resting O2 saturation 95.7 (2.6) 96.8 (2.2)* MMRC 1.3 (1.4) 1.8 (1.7) * SGRQ 27.5 (22.1) 33.3 (23.5) Data are presented as mean (SD) or percent. * denotes p-value <0.05 when compared to white subjects.

8 Supplementary Table E4 Prevalence of Restrictive Abnormalities in Lower-Limit of Normal Unclassified, Control, and COPD Subjects LLN-Unclassified LLN- Controls LLN-COPD Total Lung Capacity** (liters) 4.8 (1.2) 5.4 (1.3)* 6.1 (1.5)* Total Lung Capacity % predicted 80.6 (13.3) 92.8 (15.3)* (16.8 )* FVC < 80% predicted (% of subjects) * 61.2* TLC <80% predicted (% of subjects) * 8.0* TLC< LLN (% of subjects) * 6.3* Data are presented as mean (SD) or percent. LLN=lower limit of normal. * denotes p-value <0.05 when compared to GOLD-U subjects. ** based on chest CT measurements

9 Supplementary Table E5 - Multivariable models of Lower Limit of Normal -Unclassified status LLN-Unclassified versus LLN-Controls Clinical variables OR 95% CI Resting O2 saturation [ ] Body mass index [ ] Pack years [ ] 6 minute walk distance (per 100 feet) [ ] Final model includes history of obstructive sleep apnea as a non-significant confounder. Variables tested but not retained in the final model include: chronic bronchitis, physician diagnosed asthma (current), resting heart rate, history of diabetes, congestive heart failure, and hypertension. Clinical + radiographic variables OR 95% CI Diabetes mellitus [ ] Pack-years [ ] Resting O2 saturation [ ] Body mass index [ ] Subsegmental Wall Area % [ ] Additional variables tested but not retained in the final model include: physician diagnosed asthma (current), resting heart rate, six minute walk distance (feet), chronic bronchitis, history of hypertension, congestive heart failure, obstructive sleep apnea, total lung capacity (liters) and % emphysema. LLN-Unclassified vs. LLN-COPD Clinical variables OR 95% CI Age (per 10 years) [ ]* Body mass index [ ] Resting O2 saturation [ ] Bronchodilator response [ ] 6 minute walk distance (per 100 feet) [ ] Asthma (ever) [ ] Current smoking [ ] Diabetes mellitus [ ] Chronic bronchitis [ ] Final model includes pack-years as a non-significant confounder. Additional variables tested but not retained in the final model include: nonwhite race and history of obstructive sleep apnea. * Becomes non-significant following addition of confounder. Clinical + radiographic variables OR 95% CI Bronchodilator response [ ] Resting O2 saturation [ ] Body mass index [ ] % emphysema [ ] % gas trapping [ ] Total lung capacity (liters) [ ] Subsegmental Wall Area % [ ] Final model includes six minute walk distance (feet) as a non significant confounder. Additional variables tested but not retained in the final model include: age, non-white race, current smoking, pack years, chronic bronchitis, history of asthma (ever), diabetes, and obstructive sleep apnea. TLC based on chest CT measurements.