Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 2011;364:

2 Data Supplement: This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Lung Volumes and Emphysema in Smokers with Interstitial Lung Abnormalities George R. Washko, M.D., M.M.Sc., 1 * Gary M. Hunninghake, M.D., M.P.H., 1, 2 * Isis E. Fernandez, M.D., 1 Mizuki Nishino, M.D., 3,4 Yuka Okajima, M.D., 3,4 Tsuneo Yamashiro, M.D., 3, 4 James C. Ross, M.S., 2,5 Raúl San José Estépar, Ph.D., 3,5 David A. Lynch M.D., 6 John M. Brehm M.D., M.P.H., 1, 2 Katherine P. Andriole Ph.D., 3 Alejandro A. Diaz, M.D., 1, 7 Ramin Khorasani, Ph.D., 3 Katherine D Aco M.S., 1,2 Frank C. Sciurba M.D., 8 Edwin K. Silverman M.D., Ph.D., 1, 2 Hiroto Hatabu M.D., Ph.D., 3, 4 and Ivan O. Rosas M.D. 1 and the COPDGene Investigators 1 Pulmonary and Critical Care Division, Brigham and Women s Hospital, Harvard Medical School, Boston MA; 2 Channing Laboratory, Brigham and Women s Hospital, Boston MA; 3 Department of Radiology, Brigham and Women s Hospital, Boston MA; 4 Center for Pulmonary Functional Imaging, Brigham and Women s Hospital, Boston MA; 5 Surgical Planning Laboratory, Department of Radiology, Brigham and Women s Hospital, Boston MA; 6 Department of Radiology, National Jewish Medical and Research Center, Denver CO; 7 Department of Pulmonary Diseases. Pontificia Universidad Católica de Chile, Santiago, Chile; 8 Division of Pulmonary and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

3 Study Population From November of 2007 to April of 2010, 2500 non-hispanic White (n=1,860, 74%), and African-American (n=640, 26%) smokers (with at least 10 pack years of smoking) between the ages of 45 and 80 were enrolled into COPDGene, an ongoing and previously described 1, 2 study designed to investigate the genetic and epidemiologic associations of COPD and other smoking related lung diseases. Participants with a history of any active lung disease other than asthma, emphysema, or COPD were excluded from COPDGene. Prior to the release of the April 2010 version of the COPDGene dataset we identified 8 participants, with high resolution chest computed tomographic (HRCT) evidence of extensive honeycomb changes and no history of interstitial lung disease, originally recruited to the COPDGene study. Although these 8 participants ultimately did not meet criteria for inclusion in the April 2010 COPDGene dataset (participants with history of lung disease other than asthma, emphysema, or COPD were excluded from COPDGene), they met our study inclusion criteria and are therefore included in this analysis. Further inclusion and exclusion criteria are available online ( The COPDGene study was approved by the institutional review boards of all participating centers. Pulmonary Function Testing Spirometry was performed at each of the COPDGene clinical centers with an NDD EasyOne TM Spirometer (Zurich, Switzerland) in accordance with American Thoracic Society/European Respiratory Society recommendations. 3 After baseline spirometry, two puffs (180 mcg) of Albuterol were administered, and spirometry was repeated twenty minutes later.

4 HRCT Scanning Protocol HRCTs were performed at full inflation and at relaxed exhalation using a 16 or 64 detector Siemens, GE, or Phillips CT scanner. Quantitative HRCT Analysis Quantitative measures of total lung volume and emphysema were performed using Airway Inspector ( for each inspiratory and expiratory HRCT scan as described previously. 4, 5 Briefly, the tracheobronchial tree is automatically extracted using a region growing approach starting from a seed point automatically placed in the tracheal lumen. Following segmentation of the central airways, the lungs were automatically identified and segmented from the chest. 6 The left and right lung was also extracted. The volume of the lung minus the central airways for each HRCT scan was then calculated and reported at full inspiration (TLC) and at relaxed exhalation (LV re ). The percentage of emphysematous lung was defined as the volume of lung with a HRCT attenuation value of less than -950 Hounsfield units (HU) 4 (and -910 HU) 7 divided by the total lung volume at full inflation, multiplied by 100. Quantitative measures of lobar segmented emphysema were obtained using VIDA software (VIDA Diagnostics, Iowa City, IA). Visual HRCT Analysis All inspiratory HRCT images were reviewed on Picture Archiving Communication Systems (PACS) workstations (Centricity, GE Healthcare) using axial images with a window level of -700 HU and a window width of 1500 HU. The HRCTs were evaluated by three readers (including one pulmonologist and two chest radiologists) using a sequential reading method as previously described. 2 We divided the visual HRCT

5 analysis into two stages. In stage 1 of the visual HRCT analysis, HRCTs were scored as follows: no evidence of ILA, indeterminate, and ILA. In brief, for each block of 100 HRCT scans, reader 1 would review all of the 100 HRCT scans. Reader 2, who was blinded to the initial interpretation, would review all of the scans labeled as ILA, indeterminate, and 20% of the normal scans. Finally, reader 3, also blinded to the previous interpretations, provided majority opinion on those scans discordantly scored. Readers rotated positions after each block of 100 HRCT scans were evaluated. ILA were defined as changes affecting >5% of any lung zone including, nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, 2, 8, nonemphysematous cysts, honeycombing, or traction bronchiectasis. (see Figure 1). 9 Indeterminate scans were defined as focal or unilateral ground-glass attenuation, focal or unilateral reticulation, and patchy ground-glass abnormality (<5% of the lung). The fraction of the lung that met radiologic emphysema criteria was not considered part of the ILA designation. In stage 2 of the visual HRCT analysis, all participants with ILA had 8 separate radiographic features characterized by consensus opinion of three readers who were blinded to the subject s clinical characteristics. These 8 features include; the presence of non-dependent ground glass, or reticular abnormalities, traction bronchiectasis, honeycombing, non-emphysematous cysts, centrilobular nodules, the predominant location of abnormalities (including upper lobe predominant, lower lobe predominant, diffuse, or multifocal), and the distribution of these abnormalities (including predominantly centrilobular, subpleural, or mixed centrilobular and subpleural abnormalities).

6 We divided the participants with ILA, in stage 2 of the visual HRCT analysis, into four major radiographic subtypes including 1) predominant centrilobular and/or peribronchial ground glass opacities sparing the peripheral lung parenchyma (Centrilobular, see Figure 1A1-4), 2) reticular/nodular and/or ground glass opacities in a predominant subpleural distribution (Subpleural, see Figure 1B1-4), 3) mixed centrilobular and subpleural abnormalities (Mixed, see Figure 1C1-4) and, 4) extensive changes consistent with firm radiologic evidence of ILD based on ATS guidelines 10 (Radiologic ILD, see Figure 1D1-4). Models of lungs and airway trees were generated using software built upon the Insight Toolkit (ITK), an open source software library designed for medical image analysis, and the Visualization Toolkit (VTK), an open source toolkit for visualization. The spatial distribution of disease was indicated and rendered in 3D with software tools based upon both ITK and VTK. Statistical Analysis Bivariate analyses were conducted with Fisher s exact tests (for categorical variables), and two-tailed t tests or Wilcoxon rank-sum tests (for continuous variables) where appropriate. Linear and logistic regression models were used in multivariate analyses to study the relation between ILA and measures of restrictive and obstructive lung disease. TLC was evaluated as both continuous (in liters, and as a percent of predicted 11 ) and as binary variables (< 80% of predicted, 12, 13 and < 5 th percentile of normal 11 ). LV re was evaluated as a continuous variable (in liters). Emphysema % was evaluated as both a continuous variable (at [-]950 14, 15 and [-]910 16, 17 Hounsfield Units [HU]) and as a binary variable (>10% emphysema at [-]950 HU). We defined COPD according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II (or greater) criteria. 18 All of the final multivariate models included age, sex, race, body mass index (BMI), packyears of smoking, current smoking status, COPD (where appropriate) and additional

7 covariates as described. All of the final multivariate models of the subtypes of ILA compare individuals in that subtype to the 1,361 individuals without ILA and are adjusted for covariates including age, sex, race, body mass index (BMI), pack-years of smoking, current smoking status, COPD (where appropriate, see Table 3). All analyses were performed using Statistical Analysis Software version 9.1 (SAS Institute, Cary, NC). P values <.05 were considered statistically significant. Figures 2B, 2C, and E1 were generated in R version Results Respiratory Symptoms At baseline there were non-statistically significant increases in positive responses to respiratory symptoms questionnaires in participants with ILA compared to participants without ILA (see Table 1). In models additionally adjusting for age, sex, race, BMI, pack years of smoking, current smoking and COPD status, participants with ILA had a 1.4 fold increase in their odds to have reported usually having a cough (OR 1.42 [95% CI ], P = 0.04) and a trend toward an increase in their odds to have reported shortness of breath when hurrying on level ground or walking up a slight hill (OR 1.36 [95% CI ], P = 0.09). Total Lung Capacity and Restrictive Lung Deficit No major differences in our findings of association with TLC (or LV re ) were noted in analyses excluding the 12 participants with Radiologic ILD (see Figure 1D1-4)(TLC ([- ]0.408 liters, 95% CI [-]0.563-[-]0.253, P<0.001). Similar to our finding with TLC < 80% of predicted (see Table 2), ILA was associated with an increased odds for a restrictive lung deficit using an alternate definition

8 recommended by the American Thoracic Society/European Respiratory Society 11 (TLC < 5 th percentile of normal, OR 2. 99, 95% CI , P < 0.001). Emphysema and COPD In a subset of participants (n=1512, 60%) data were available on the percentage of emphysema (at -950 HU) in each of the five major lobar divisions of the lung. Reductions in emphysema in participants with ILA were noted in all lobar divisions of the lung ([-]3% to [-4]%, p values <0.001). No major differences in our findings of association with emphysema were noted in analyses excluding the 12 participants with the Radiologic ILD subtype (see Figure 1D1-4) ([-950 HU], [-]3%, 95% CI [-]6%-[-]2%, P<0.001). Participants with ILA had a 69% decrease in there odds to have >10% emphysema (- 950 HU) on HRCT (OR 0.31, 95% CI ( ), P<0.001). Assessment for Independent Effects of Reduced TLC and Emphysema In an analysis including both total lung capacity and emphysema (-950 HU), both variables demonstrated independent inverse associations with ILA (p values < 4 x 10-4 for both, see Supplemental Table E5). Additionally significant predictors of ILA include age (for each 10 year increase a subject had a 2.21-fold increase in their odds to have ILA [95% CI ], P<0.001), sex (females had a 40% decrease in their odds to have ILA, OR 0.60 [95% CI ], P = 0.02), pack-years of smoking, and current smoking status (see Supplemental Table E5). Tobacco Smoke Exposure

9 Comparable to previous analyses, 7 the intensity of tobacco smoke exposure in COPDGene participants was associated with the odds of having ILA. In a model additionally adjusting for age, sex, race, BMI, COPD status, and percentage of emphysema (at -950 HU), there was an 8% increase in the odds for ILA for each 10 pack-years of smoking (odds ratio [OR] 1.08, 95% confidence interval [CI] , p value [P] = 0.02). In contrast to the bivariate analysis which showed no relationship to current smoking status, in the adjusted model, current smokers had a 67% increase in their odds of having ILA (OR 1.67, 95% CI , P = 0.008).

10 Table E1: Chest HRCT characteristics of Smokers from COPDGene Stratified by Interstitial Lung Abnormalities (ILA) and COPD status Variable* Number(%) or Median (Interquartile Range) where appropriate Participants without Indeterminate Participants with ILA n=861 (36%) ILA n=194 (8%) n=1361 (56%) P values Chest CT Parameters: Participants without COPD (< Gold Stage 2) Emphysema % (-950 HU) 2.0 ( ) 1.5 ( ) 1.6 ( ) 0.08, 0.89, 0.36 Emphysema % (-910 HU) 21 (10-34) 14 (6-27) 13 (6-26) <0.001, 0.17, <0.001 Total Lung Capacity (TLC: Liters) 5.38 ( ) 4.92 ( ) 4.80 ( ) <0.001, 0.84, <0.001 TLC % of predicted 100 (88-114) 94 (77-108) 94 (81-107) <0.001, 0.64, <0.001 TLC < 80% of predicted 111 (14%) 141 (30%) 29 (22%) <0.001, 0.12, 0.02 LV re 2.70 ( ) 2.64 ( ) 2.59 ( ) 0.44, 0.37, 0.15 Chest CT Parameters: Participants with COPD (> GOLD Stage 2) Emphysema % (-950 HU) 14.8 ( ) 9.6 ( ) 4.8 ( ) <0.001, <0.001, <0.001 Emphysema % (-910 HU) 47 (31-57) 36 (22-48) 21 (10-36) <0.001, <0.001, <0.001 Total Lung Capacity (TLC: Liters) 6.02 ( ) 5.68 ( ) 5.10 ( ) <0.001, 0.03, <0.001 TLC % of predicted 113 ( ) 106 (93-118) 95 (84-112) <0.001, <0.001, <0.001 TLC < 80% of predicted 23 (4%) 28 (7%) 11 (17%) 0.04, 0.02, <0.001 LV re 3.97 ( ) 3.66 ( ) 3.06 ( ) <0.001, 0.005, <0.001 * Data missing for emphysema % (-950 HU) and TLC (n=19), emphysema % (-910 HU) (n=51, 1%) and LV re (n=195, 8%). The three P values include comparisons between 1) participants classified as indeterminate to those without ILA, 2) participants with ILA to those classified as indeterminate, and 3) participants with ILA to those without ILA using Fisher s exact tests (for binary variables), and paired t-tests or Wilcoxon ranksum tests (for continuous variables where appropriate). HU: Hounsfield units. Quantitative metrics of emphysema, TLC and Lung Volume at relaxed exhalation (LV re ) were performed using Airway Inspector ( for each inspiratory (emphysema and TLC) and expiratory (LV re ) HRCT. Percent of predicted total lung capacity based on ATS/ERS guidelines. 11

11 Table E2: Baseline characteristics of Smokers from COPDGene Stratified by GOLD stage and Radiologic Interstitial Lung Abnormalities (ILA) Variable* Number(%) or Median (Interquartile Range) where appropriate No ILA n=1361 (56%) ILA n=194 (8%) P value* Spirometric Parameters GOLD Stage Unclassified GOLD Stage GOLD 0 GOLD Stage GOLD 1 GOLD Stage GOLD 2 GOLD Stage GOLD 3 GOLD Stage GOLD 4 FEV 1 (% of predicted) 73 (68-77) 72 (64-76) 0.35 FVC (% of predicted) 74 (68-78) 74 (64-76) 0.70 FEV1/FVC % 76 (73-81) 75 (71-78) 0.08 FEV 1 (% of predicted) 97 (89-106) 94 (87-100) 0.01 FVC (% of predicted) 96 (88-105) 93 (86-99) 0.04 FEV1/FVC % 79 (75-83) 79 (74-82) 0.10 FEV 1 (% of predicted) 89 (85-97) 88 (83-94) 0.35 FVC (% of predicted) 105 (98-119) 106 (97-110) 0.09 FEV1/FVC % 66 (63-68) 66 (61-67) 0.52 FEV 1 (% of predicted) 64 (57-72) 67 (56-72) 0.75 FVC (% of predicted) 87 (78-95) 82 (75-93) 0.21 FEV1/FVC % 57 (51-64) 61 (54-66) 0.08 FEV 1 (% of predicted) 40 (34-44) 40 (34-44) 0.76 FVC (% of predicted) 71 (64-79) 77 (64-80) 0.77 FEV1/FVC % 42 (36-47) 39 (36-45) 0.43 FEV 1 (% of predicted) 23 (18-26) 18 (18-26) 0.83 FVC (% of predicted) 55 (46-64) 47 (43-61) 0.71 FEV1/FVC % 30 (26-36) 29 (27-32) 0.92 Chest CT parameters GOLD Stage Emphysema % (-950 HU) 1.0 ( ) 0.8 ( ) 0.34 Unclassified Total Lung Capacity (TLC) 4.65 ( ) 4.75 ( ) 0.16 GOLD Stage GOLD 0 GOLD Stage GOLD 1 GOLD Stage GOLD 2 GOLD Stage GOLD 3 GOLD Stage GOLD 4 Emphysema % (-950 HU) 1.9 ( ) 1.2 ( ) 0.12 Total Lung Capacity (TLC) 5.38 ( ) 4.75 ( ) <0.001 Emphysema % (-950 HU) 5.2 ( ) 4.7 ( ) Total Lung Capacity (TLC) 6.44 ( ) 5.88 ( ) 0.27 Emphysema % (-950 HU) 6.9 ( ) 2.2 ( ) Total Lung Capacity (TLC) 5.89 ( ) 4.78 ( ) <0.001 Emphysema % (-950 HU) 19.2 ( ) 2.3 ( ) 0.27 Total Lung Capacity (TLC) 6.01 ( ) 5.72 ( ) 0.91 Emphysema % (-950 HU) 33.5 ( ) 9.0 ( ) Total Lung Capacity (TLC) 6.82 ( ) 6.83 ( ) 0.95 * P values compares those with ILA to those without ILA using Fisher s exact tests (for binary variables), and paired t-tests or Wilcoxon rank-sum tests (for continuous variables where appropriate).

12 Gold Stages included Gold Unclassified (FEV 1 /FVC % > 0.70, FEV 1 < 80% of predicted), Gold 0 (FEV 1 /FVC % > 0.70, FEV 1 > 80% of predicted), Gold 1 (FEV 1 /FVC % < 0.70, FEV 1 > 80% of predicted), Gold 2 (FEV 1 /FVC % < 0.70, FEV 1 < 80% but > 50% of predicted), Gold 3 (FEV 1 /FVC % < 0.70, FEV 1 < 50% but > 30% of predicted), and Gold 4 (FEV 1 /FVC % < 0.70, FEV 1 < 30% of predicted). Post-bronchodilator pulmonary function measurements presented. Predicted values for FEV 1 and FVC are derived from Crapo et al. 20 Quantitative metrics of emphysema, TLC and Lung Volume at relaxed exhalation (LV re ) were performed using Airway Inspector ( for each inspiratory (emphysema and TLC) and expiratory (LV re ) HRCT. HU: Hounsfield units.

13 Table E3: Chest Computed Tomographic Characteristics of Radiologic Interstitial Lung Abnormalities (ILA) and Subtypes of ILA Pattern of ILA* ILA (overall) 194 (100%) Number(%) Ground Glass Reticular Markings Traction Bronchiectasis Honeycombing Centrilobular Nodules 188 (97%) 164 (85%) 59 (30%) 18 (9%) 54 (28%) 98 (51%) Centrilobular 36 (97%) 18 (49%) 1 (3%) 0 (0%) 37 (100%) 9 (24%) Subpleural 103 (96%) 105 (98%) 42 (39%) 13 (12%) 1 (1%) 59 (55%) Mixed 37 (97%) 29 (76%) 7 (18%) 0 (0%) 15 (39%) 23 (61%) Radiologic ILD 12 (100%) 12 (100%) 9 (75%) 5 (42%) 1 (8%) 7 (58%) Cysts Location Distribution ULP 59 (30%) CL 38 (20%) LLP 82 (42%) SP 116 (60%) Diffuse 9 (5%) Both 40 (21%) Multifocal 44 (23%) ULP 33 (89%) CL 37 (100%) LLP 1 (3%) SP Diffuse 2 (5%) Both Multifocal 1 (3%) ULP 12 (11%) CL LLP 74 (69%) SP 107 (100%) Diffuse 1 (1%) Both Multifocal 20 (19%) ULP 13 (34%) CL LLP 3 (8%) SP Diffuse 2 (5%) Both 38 (100%) Multifocal 20 (53%) ULP 1 (8%) CL 1 (8%) LLP 4 (33%) SP 9 (75%) Diffuse 4 (33%) Both 2 (17%) Multifocal 3 (25%) * Pattern of Radiologic Interstitial Lung Abnormalities (ILA); Centrilobular (predominant centrilobular and/or peribronchial ground glass opacities sparing the peripheral lung parenchyma), Subpleural (reticular/nodular and/or ground glass opacities in a predominant subpleural distribution), Mixed (mixed centrilobular and subpleural abnormalities), Radiologic ILD (radiologic evidence of interstitial lung disease characterized by extensive changes consistent with firm radiologic evidence of ILD based on ATS guidelines). 10

14 Location. ULP = upper lobe predominant, LLP = lower lobe predominant, Diffure = diffuse abnormalities, Multifocal = abnormalities present in both the upper and lower lobes. Distribution. CL = centrilobular, SP = subpleural, and Both = characteristics of both centrilobular and subpleural.

15 Table E4: Baseline characteristics of Smokers from COPDGene Stratified by Subtypes of Radiologic Interstitial Lung Abnormalities (ILA) Variable* Number(%) or Median (Interquartile Range) where appropriate Demographic Parameters Centrilobular 37 (19%) Subpleural 107 (55%) Mixed 38 (20%) Radiologic ILD 12 (6%) Age (years) 55 (50-60) 68 (61-73) 61 (53-68) 69 (63-74) Gender (female) 21 (57%) 50 (47%) 26 (68%) 4 (33%) Race (African-American) 12 (32%) 27 (25%) 16 (42%) 1 (8%) Body Mass Index 26 (23-29) 30 (25-35) 28 (25-32) 29 (25-39) Pack years of smoking 44 (34-65) 44 (30-63) 42 (25-50) 59 (35-92) Current Smoker 31 (84%) 35 (33%) 25 (66%) 6 (50%) COPD (> GOLD Stage 2) 7 (19%) 41 (38%) 12 (32%) 3 (27%) Respiratory Symptoms Do you usually have a cough? (yes) 18 (49%) 34 (32%) 21 (55%) 6 (50%) Are you troubled by shortness of breath when hurrying on level ground or 14 (38%) 72 (67%) 20 (54%) 9 (75%) walking up a slight hill? (yes) Spirometric Parameters GOLD Stage Unclassified Normal (32%) 17 (46%) 1 (3%) 16 (16%) 1 (3%) 0 (0%) 11 (10%) 35 (33%) 20 (19%) 28 (26%) 9 (8%) 4 (4%) 3 (8%) 18 (47%) 5 (13%) 9 (24%) 2 (5%) 1 (3%) 2 (18%) 6 (55%) 0 (0%) 3 (27%) 0 (0%) 0 (0%) FEV 1 (% of predicted) 79 (68-94) 80 (67-92) 85 (66-94) 82 (65-99) FVC (% of predicted) 88 (76-98) 88 (77-98) 89 (79-105) 78 (74-85) FEV1/FVC % 73 (71-76) 68 (58-76) 72 (64-81) 79 (64-83) Spirometric Restriction 17 (46%) 40 (37%) 16 (42%) 8 (72%) Chest CT parameters Emphysema % (-950 HU) ** 0.9 ( ) 3.3 ( ) 1.0 ( ) 2.8 ( ) Emphysema % (-910 HU) ** 8 (5-15) 20 (10-33) 10 (5-24) 14 (9-26) Total Lung Capacity (TLC)** 5.22 ( ) 5.11 ( ) 4.41 ( ) 5.24 ( ) TLC % of predicted ** 97 (82-111) 96 (82-110) 90 (81-103) 90 (76-108) TLC < 80% of predicted** 7 (19%) 22 (21%) 8 (21%) 3 (25%) LV re ** 2.88 ( ) 2.70 ( ) 2.46 ( ) 2.49 ( ) * Data missing for COPD status, pulmonary function testing and self report of rheumatoid arthritis (n=1), Emphysema % (-950 HU) and TLC (n=1), Emphysema % (-910 HU) (n=2) and FRC (n=19).

16 Gold Stages included Gold Unclassified (FEV 1 /FVC % > 0.70, FEV 1 < 80% of predicted), Gold 0 (FEV 1 /FVC % > 0.70, FEV 1 > 80% of predicted), Gold 1 (FEV 1 /FVC % < 0.70, FEV 1 > 80% of predicted), Gold 2 (FEV 1 /FVC % < 0.70, FEV 1 < 80% but > 50% of predicted), Gold 3 (FEV 1 /FVC % < 0.70, FEV 1 < 50% but > 30% of predicted), and Gold 4 (FEV 1 /FVC % < 0.70, FEV 1 < 30% of predicted). Post-bronchodilator pulmonary function measurements presented. Predicted values for FEV 1 and FVC are derived from Crapo et al. 20 Defined as an FVC < the lower limit of normal and an FEV 1 /FVC ratio > lower limit of normal. 21 HU: Hounsfield units. ** Quantitative metrics of emphysema, TLC and Lung Volume at relaxed exhalation (LV re ) were performed using Airway Inspector ( for each inspiratory (emphysema and TLC) and expiratory (LV re ) HRCT. Percent of predicted total lung capacity based on ATS/ERS guidelines. 11

17 Table E5: Multivariate Logistic Regression Analysis of Association of the Odds for Radiologic Interstitial Lung Abnormalities (ILA) Variables in model Multivariate Logistic Regression Model* Odds Ratio (95% Confidence Interval) P value Age (per each 10 year increase) Sex (reference males) Race (reference whites) BMI (per 1 unit change) Pack years of smoking (per each 10 year increase) Current Smoker (reference former smoker) COPD (> GOLD Stage 2) (reference < GOLD Stage 2) Total Lung Capacity (per each 1 liter increase) Percentage of Emphsema (-950 HU) (per each 10% increase) 2.21 ( ) 1 x ( ) ( ) ( ) ( ) ( ) ( ) ( ) 2 x ( ) 4 x 10-4 * Hosmer and Lemeshow Goodness-of-Fit p value = 0.60 (indicating the model adequately fits the data). HU: Hounsfield units.

18 Figure E1:

19 FIGURE LEGENDS: Figure E1: Plot of FEV 1 (% of predicted) against the FEV 1 /FVC % in the participants with ILA (in red, n=194), in indeterminate participants (in gray, n=861), and in the participants without ILA (in black, n=1361) from COPDGene. The table is partitioned into GOLD categorizations. 18 Gold Stages included Gold Unclassified (FEV 1 /FVC % > 0.70, FEV 1 < 80% of predicted), Gold 0 (FEV 1 /FVC % > 0.70, FEV 1 > 80% of predicted), Gold 1 (FEV 1 /FVC % < 0.70, FEV 1 > 80% of predicted), Gold 2 (FEV 1 /FVC % < 0.70, FEV 1 < 80% but > 50% of predicted), Gold 3 (FEV 1 /FVC % < 0.70, FEV 1 < 50% but > 30% of predicted), and Gold 4 (FEV 1 /FVC % < 0.70, FEV 1 < 30% of predicted).

20 Acknowledgements We acknowledge the support of both Augustine M.K. Choi in the division of Pulmonary and Critical Care Medicine and Steven E. Seltzer in the department of Radiology for their generous support of this project. The project described was supported by Award Number U01HL and Award Number U01HL from the National Heart, Lung, And Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis and Sepracor The members of the COPDGene study group as of June 2010 Ann Arbor VA: Jeffrey Curtis, MD (PI), Ella Kazerooni, MD (RAD) Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS (PI), Philip Alapat, MD, Venkata Bandi, MD, Kalpalatha Guntupalli, MD, Elizabeth Guy, MD, Antara Mallampalli, MD, Charles Trinh, MD (RAD), Mustafa Atik, MD Brigham and Women s Hospital, Boston, MA: Dawn DeMeo, MD, MPH (Co-PI), Craig Hersh, MD, MPH (Co-PI), George Washko, MD, Francine Jacobson, MD, MPH (RAD) Columbia University, New York, NY: R. Graham Barr, MD, DrPH (PI), Byron Thomashow, MD, John Austin, MD (RAD) Duke University Medical Center, Durham, NC: Neil MacIntyre, Jr., MD (PI), Lacey Washington, MD (RAD), H Page McAdams, MD (RAD) Fallon Clinic, Worcester, MA: Richard Rosiello, MD (PI), Timothy Bresnahan, MD (RAD) Health Partners Research Foundation, Minneapolis, MN: Charlene McEvoy, MD, MPH (PI), Joseph Tashjian, MD (RAD) Johns Hopkins University, Baltimore, MD: Robert Wise, MD (PI), Nadia Hansel, MD, MPH, Robert Brown, MD (RAD), Gregory Diette, MD Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA: Richard Casaburi, MD (PI), Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD (RAD), Matt Budoff, MD Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD (PI), Charles Trinh, MD (RAD), Hirani Kamal, MD, Roham Darvishi, MD Minneapolis VA: Dennis Niewoehner, MD (PI), Tadashi Allen, MD (RAD), Quentin Anderson, MD (RAD), Kathryn Rice, MD Morehouse School of Medicine, Atlanta, GA: Marilyn Foreman, MD, MS (PI), Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD (RAD)

21 National Jewish Health, Denver, CO: Russell Bowler, MD, PhD (PI), Adam Friedlander, MD, David Lynch, MB (RAD), Joyce Schroeder, MD (RAD), John Newell, Jr., MD (RAD) Temple University, Philadelphia, PA: Gerard Criner, MD (PI), Victor Kim, MD, Nathaniel Marchetti, DO, Aditi Satti, MD, A. James Mamary, MD, Robert Steiner, MD (RAD), Chandra Dass, MD (RAD) University of Alabama, Birmingham, AL: William Bailey, MD (PI), Mark Dransfield, MD (Co-PI), Hrudaya Nath, MD (RAD) University of California, San Diego, CA: Joe Ramsdell, MD (PI), Paul Friedman, MD (RAD) University of Iowa, Iowa City, IA: Geoffrey McLennan, MD, PhD (PI), Edwin JR van Beek, MD, PhD (RAD), Brad Thompson, MD (RAD), Dwight Look, MD University of Michigan, Ann Arbor, MI: Fernando Martinez, MD (PI), MeiLan Han, MD, Ella Kazerooni, MD (RAD) University of Minnesota, Minneapolis, MN: Christine Wendt, MD (PI), Tadashi Allen, MD (RAD) University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD (PI), Joel Weissfeld, MD, MPH, Carl Fuhrman, MD (RAD), Jessica Bon, MD University of Texas Health Science Center at San Antonio, San Antonio, TX: Antonio Anzueto, MD (PI), Sandra Adams, MD, Carlos Orozco, MD, Mario Ruiz, MD (RAD) Administrative Core: James Crapo, MD (PI), Edwin Silverman, MD, PhD (PI), Barry Make, MD, Elizabeth Regan, MD, Sarah Moyle, MS, Douglas Stinson Genetic Analysis Core: Terri Beaty, PhD, Barbara Klanderman, PhD, Nan Laird, PhD, Christoph Lange, PhD, Michael Cho, MD, Stephanie Santorico, PhD, John Hokanson, MPH, PhD, Dawn DeMeo, MD, MPH, Nadia Hansel, MD, MPH, Craig Hersh, MD, MPH, Jacqueline Hetmanski, MS, Tanda Murray Imaging Core: David Lynch, MB, Joyce Schroeder, MD, John Newell, Jr., MD, John Reilly, MD, Harvey Coxson, PhD, Philip Judy, PhD, Eric Hoffman, PhD, George Washko, MD, Raul San Jose Estepar, PhD, James Ross, MSc, Rebecca Leek, Jordan Zach, Alex Kluiber, Jered Sieren, Heather Baumhauer, Verity McArthur, Dzimitry Kazlouski, Andrew Allen, Tanya Mann, Anastasia Rodionova PFT QA Core, LDS Hospital, Salt Lake City, UT: Robert Jensen, PhD Biological Repository, Johns Hopkins University, Baltimore, MD: Homayoon Farzadegan, PhD, Stacey Meyerer, Shivam Chandan, Samantha Bragan Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO: James Murphy, PhD, Douglas Everett, PhD, Carla Wilson, MS, Ruthie Knowles, Amber Powell, Joe Piccoli, Maura Robinson, Margaret Forbes, Martina Wamboldt

22 Epidemiology Core, University of Colorado School of Public Health, Denver, CO: John Hokanson, MPH, PhD, Marci Sontag, PhD, Jennifer Black-Shinn, MPH, Gregory Kinney, MPH

23 REFERENCES: 1. Regan EA, Hokanson JE, Murphy JR, et al. Genetic Epidemiology of COPD (COPDGene) Study Design. Copd 2010;7(1): Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung disease in smokers from the COPDGene Study. Acad Radiol 2010;17(1): Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med 1995;152(3): Gevenois PA, De Vuyst P, de Maertelaer V, et al. Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1996;154(1): Dransfield MT, Washko GR, Foreman MG, Estepar RS, Reilly J, Bailey WC. Gender differences in the severity of CT emphysema in COPD. Chest 2007;132(2): Hu S, Hoffman EA, Reinhardt JM. Automatic lung segmentation for accurate quantitation of volumetric X-ray CT images. IEEE Trans Med Imaging 2001;20(6): Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is associated with subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)- lung study. Am J Respir Crit Care Med 2009;180(5): Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA. Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest 2000;117(1): Gochuico BR, Avila NA, Chow CK, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med 2008;168(2):

24 10. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June Am J Respir Crit Care Med 2002;165(2): Stocks J, Quanjer PH. Reference values for residual volume, functional residual capacity and total lung capacity. ATS Workshop on Lung Volume Measurements. Official Statement of The European Respiratory Society. Eur Respir J 1995;8(3): Watters LC, King TE, Schwarz MI, Waldron JA, Stanford RE, Cherniack RM. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis 1986;133(1): Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. Am Rev Respir Dis 1991;144(5): Yuan R, Mayo JR, Hogg JC, et al. The effects of radiation dose and CT manufacturer on measurements of lung densitometry. Chest 2007;132(2): Kim WJ, Silverman EK, Hoffman E, et al. CT metrics of airway disease and emphysema in severe COPD. Chest 2009;136(2): Muller NL, Staples CA, Miller RR, Abboud RT. "Density mask". An objective method to quantitate emphysema using computed tomography. Chest 1988;94(4): Hersh CP, Washko GR, Jacobson FL, et al. Interobserver variability in the determination of upper lobe-predominant emphysema. Chest 2007;131(2): Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176(6): R Development Core Team (2009) R: A Language and Environment for Statistical Computing. Vienna, Austria.

25 20. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981;123(6): 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(1):