Supplementary Appendix

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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Lange P, Celli B, Agustí A, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373: DOI: /NEJMoa

2 Supplementary Appendix Supplement to: Lange P, Celli B, Agusti A on behalf of the COPD Progression Group. Lung Function Trajectories Leading to Chronic Obstructive Pulmonary Disease CONTENTS Framingham Offspring Cohort: methods and flow chart page 2 Copenhagen City Heart Study: methods and flow chart page 4 Lovelace Smokers Cohort: methods and flow chart page 6 Statistical analyses page 7 Incident COPD page 8 FEV 1 decline in non-responders in the final examination of CCHS page 11 Distribution of FOC and CCHS participants into FEV 1 trajectories page 12 Analysis focusing on regression to the mean for FEV 1 decline page 13 References page 14 1

3 FRAMINGHAM OFFSPRING COHORT (FOC) METHODS The FOC includes 5124 adult children and spouses of the original Framingham Cohort in Massachusetts; USA. 1 Spirometry without a bronchodilator was performed at four visits in , , and in using a 6L Collins water-sealed bell spirometer with the subject standing and wearing nose clips. The largest forced vital capacity (FVC) and the largest forced expiratory volume in 1 second (FEV 1 ) were selected from at least 3 acceptable spirograms. Reference values for calculation of normal predicted were those based on the National Health and Nutrition Examination Survey (NHANES III). 2 We identified 187 subjects (42% females) aged years of age, current or former smokers with GOLD grade 2 COPD at the final examination who had a first spirometry performed before the age of 40 years. The flow chart describing the individuals selected for present analyses is shown in Fig. S1. The FEV 1 decline was calculated using the difference (ml) between the first available spirometry and the last obtained at years of age by the number of years between the measurements. 2

4 Figure S1. Flowchart describing recruitment of individuals in Framingham Offspring Cohort 3

5 COPENHAGEN CITY HEART STUDY (CCHS) METHODS The CCHS is a prospective population study of the general population of the city of Copenhagen, Denmark initiated in The study is approved by Danish Ethical Committee. It includes men and women examined at four investigations in , , and in At each examination participants filled out a questionnaire and had physical measurements taken. The flow-chart describing the selection of individuals for the present analysis is shown in Figure S2. In the first survey in , an electronic spirometer N 403 Monaghan, United States was used, whereas we used a Vitalograph TM spirometer, Maids Moreton, Buckinghamshire, UK, in the 4 th survey in , as the Monaghan spirometer was no longer in function. Spirometry was performed in the standing position without the use of a nose clip. Three sets of FEV 1 and FVC values were obtained and as a criterion for correct performance of the procedure at least two measurements differing by less than 5% had to be produced together with the correct visual appearance of the spirometry tracings. The highest obtained values for every single participant of both FEV 1 and of FVC were used in the analyses. Only pre-bronchodilator measurements were available. The calculation of normal reference values was based on the recently published equations relations for this population. 4 Annual change in FEV 1 was expressed in ml per year: FEV 1 at the initial examination minus FEV 1 at the final examination adjusted for the exact time between these two examinations. 4

6 Figure S2. Flowchart describing the participants in the first and the final examination of The Copenhagen City Heart Study and loss during the follow-up. 5

7 LOVELACE SMOKERS COHORT (LSC) METHODS LSC includes 2273 participants aged 40 to 75 years with a minimum of 10 pack-years of smoking. 5 The catchment area was Albuquerque, New Mexico, USA and its surrounding communities, comprising a diverse population of approximately 700,000 persons living at altitudes of approximately 1,500 meters above sea level. The study was approved by the Western Institutional Review Board (Olympia, WA). Participants were recruited from the community through newspaper or television advertisements and were paid a small stipend for their participation. The LSC disproportionately enrolled women ever-smokers since the disease prevalence is increasing among women, and women are under-represented in most COPD studies. Regular follow-up examination visits occurred at 18-month intervals for anthropometrics, spirometry, self-reported prescription drug use, detailed smoking and environmental exposure history, and induced sputum. For the present analyses, the participants who performed at least two with a minimum interval of 18 months between the baseline and final examinations were included. Among the 2273 participants enrolled in LSC between 2001 and 2011, 1553 eligible individuals met the inclusion criteria (Figure S3). The spirometers used were either Vmax Encore22 (Viasys, Respiratory Care, Yorba, Linda, CA) or Koko (Ferraris Respiratory, Louisville, CO) and the participants performed pre- and post-bronchodilator spirometry tests after the administration of 200 micrograms of inhaled albuterol. FEV 1 in percent of the predicted normal values were calculated using race and ethnicity specific NHANES III values. 2 In the analyses, where the LSC data were combined with the data from the FOC and CCHS, we used prebronchodilatatory FEV 1 values and calculated the FEV 1 decline using the two measurement with longest time interval apart. 6

8 Figure S3. Flowchart describing recruitment of individuals in Lovelace Smokers Cohort. Statistical Analyses Summary statistics, including means, standard deviations (SD), medians, and interquartile ranges for continuous variables and proportions for categorical variables, were obtained. Pearson s chi-square tests or Fisher s exact tests and Student s T tests were used to compare frequencies and means, respectively, between categories. We used the statistical software package R (version 3.0.1) and Statistical Analysis Software package version 9.3 (SAS, Cary, NC). 7

9 Incident COPD Using data from all three cohorts, we performed a multivariable logistic regression analysis with incident COPD at final examination as the dependent variable. In this analysis, the level of FEV 1 at baseline examination (< or 80% of predicted value) and FEV 1 decline during the observation period ( or > 1 SD of normal FEV 1 decline estimated for nonsmokers in each cohort) were the two independent variables of main interest. Additional variables included in the model were sex, age and pack-years during follow-up. In these analyses, we excluded individuals with COPD at the baseline examination. Table S1 shows the results of a multivariable logistic regression analysis with presence of GOLD grade 2 COPD at final examination as outcome in participants aged 50 to 65 years in each cohort and in all cohorts combined. Both, a low FEV 1 at baseline and a rapid FEV 1 decline were significant predictors of incident COPD at final examination. In LSC and CCHS the odds ratio for rapid FEV 1 decline was numerically higher than for low FEV 1 at baseline whereas the opposite relation was observed in FOC. Yet, the confidence intervals for the odds ratios for low baseline FEV 1 and rapid FEV 1 decline were overlapping and in the combined analysis the odds ratios for the two variables were quite similar. It is important to notice that the magnitude of the odds ratios is highly dependent on the used thresholds for rapid FEV 1 decline (Z score 1 or >1) and low baseline level of FEV 1 (< or 80% of predicted value). Additional analysis shown in Table S2, where we included a similar cut off value for baseline FEV 1, but a different cut off of 2 SD (Z score 2 or >2) for the FEV 1 decline, yielded odds ratio of 5.6 (95% CI, 4.2 to 7.5) for low baseline lung function and odds ratio of 13.0 (95% CI, 8.6 to 19.7) for rapid FEV 1 decline. 8

10 Table S1. Logistic regression analysis with incident COPD* at final examination as the dependent variable and the level of FEV 1 at baseline examination and FEV 1 decline during the observation period as variables of main interest and gender, age at baseline and pack years during observation period as covariates. Lovelace Smokers Cohort Framingham Offspring Cohort Copenhagen City Heart Study 3 cohorts combined N=686 N=1369 N=1069 N=3124 Incident cases of COPD OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value Exposure variable Male sex 0.84 (0.33,2.05) (0.52,1.14) (0.40,1.15) (0.61,1.09) 0.17 Age at baseline per yr 0.96 (0.90,1.03) (0.95,1.05) (0.95,1.07) (0.95,0.98) <0.001 Pack yr per yr 1.02 (1.00,1.04) (1.03,1.04) < (1.02,1.04) < (1.02,1.03) <0.001 Low FEV 1 at baseline 3.21 (1.38,7.48) (7.05,17.26) < (5.51,23.25) < (6.14,11.78) <0.001 Rapid FEV 1 decline 5.49 (2.38,12.70) < (4.97,13.15) < (11.69,49.37) < (6.69,13.10) <0.001 * Incident COPD was defined as GOLD 2 COPD developed during the observation period in ever smokers aged 50 to 65 years at final examination. Low FEV 1 at baseline was defined as FEV 1 below 80% of predicted value at the initial examination. Rapid FEV 1 decline was defined as Z score >1 e.g. annual decline FEV 1 above 1 SD of normal FEV 1 decline estimated for nonsmokers in each cohort. A Z score equal to 1 corresponds to FEV 1 decline of 103 ml/yr in LSC, 36 ml/yr in FOC and 38 ml/yr in CCHS. 9

11 Table S2. Logistic regression analysis with incident COPD* at final examination as the dependent variable and the level of FEV 1 at baseline examination and FEV 1 decline during the observation period as variables of main interest and gender, age at baseline and pack years during observation period as covariates. Lovelace Smokers Cohort Framingham Offspring Cohort Copenhagen City Heart Study 3 cohorts combined N=686 N=1369 N=1069 N=3124 Incident cases of COPD OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value Exposure variable Male sex 0.84 (0.33,2.05) (0.52,1.14) (0.40,1.15) (0.61,1.09) 0.17 Age at baseline per yr 0.96 (0.90,1.03) (0.95,1.05) (0.95,1.07) (0.95,0.98) <0.001 Pack yr per yr 1.02 (1.00,1.04) (1.03,1.04) < (1.02,1.04) < (1.02,1.03) <0.001 Low FEV 1 at baseline 3.21 (1.38,7.48) (7.05,17.26) < (5.51,23.25) < (6.14,11.78) <0.001 Rapid FEV 1 decline 5.49 (2.38,12.70) < (4.97,13.15) < (11.69,49.37) < (6.69,13.10) <0.001 * Incident COPD was defined as GOLD 2 COPD developed during the observation period in ever smokers aged 50 to 65 years at final examination. Low FEV 1 at baseline was defined as FEV 1 below 80% of predicted value at the initial examination. Rapid FEV 1 decline was defined as Z score >1 e.g. annual decline FEV 1 above 1 SD of normal FEV 1 decline estimated for nonsmokers in each cohort. A Z score equal to 1 corresponds to FEV 1 decline of 103 ml/yr in LSC, 36 ml/yr in FOC and 38 ml/yr in CCHS. 10

12 FEV 1 decline in non-responders in the final examination of CCHS We investigated the influence of non-response to the estimated annual FEV 1 decline by comparing it between the following two groups: Responders (Individuals attending both 1 st and 4 th examination) and Non-responders (individuals attending 1 st but not 4 th examination). In both groups, we analyzed the declines observed from 1 st to 2 nd examination (5 years) and declines observed from 1 st to 3 rd examination (15 years). The FEV 1 declines were significantly more rapid in the non-responders compared to the responders (Table S3). Table S3. Mean FEV 1 decline in ml/year in non-responders and responders in the 4 th examination of Copenhagen City Heart Study. FEV 1 -decline between 1 st and 2 nd examination (5 years observation) Nonresponders in 4 th examination Responders in 4 th examination P-value Number with data FEV 1 decline, ml/yr, mean±sd ± ± FEV 1 -decline between 1 st and 3 nd examination (15 years observation) Number with data FEV 1 decline, ml/yr, mean±sd ± ±

13 Distribution of FOC and CCHS participants into FEV 1 trajectories Figure S4. Distribution of the 2864 participants of FOC and CCHS into the four trajectories T1 to T4 defined according to baseline level of FEV 1 (below or above 80% of predicted value) and presence or absence of GOLD grade >2 COPD at the final examination. The solid lines represent the schematic natural history of FEV 1 for the age range of this study, whereas the broken lines represent hypothetical trajectories. 12

14 Analysis focusing on regression to the mean for FEV 1 decline Table S4. Mean FEV 1 decline in ml/year in participants of CCHS who in addition to participating in the 1 st examination (conducted in ) and 4 th examination of CCHS (conducted in ), which constitute the two points in time used to define the four trajectories, also participated in the 2 nd examination in FEV 1 -decline between 1 st and 4 th examination (25 years observation) FEV 1 -decline between 2 nd and 4 th examination (20 years observation) Trajectory 1 Number with data FEV 1 decline, ml/yr, mean±sd ± ±23 Trajectory 2 Number with data FEV 1 decline, ml/yr, mean±sd 254 5± ±24 Trajectory 3 Number with data FEV 1 decline, ml/yr, mean±sd 70 62± ±38 Trajectory 4 Number with data FEV 1 decline, ml/yr, mean±sd 55 32± ±23 The four Trajectories are constructed based on normal or low FEV 1 at the 1 st examination and the presence or absence of GOLD 2 COPD at 4 th examination. 13

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