Chronic Obstructive Pulmonary Disease (COPD) Comorbidities Network Miguel J. Divo MD, Ciro Casanova MD, Jose M. Marin MD, Victor M. Pinto-Plata MD, Juan P. de-torres MD, Javier Zulueta MD, Carlos Cabrera MD, Jorge Zagaceta MD, Pablo Sanchez-Salcedo MD, Juan Berto MD, Ana B. Alcaide MD, Claudia Cote MD, and Bartolome R. Celli MD The BODE Collaborative Group Online supplement Table E1. Demographic and anthropometric characteristics comparing the Non-COPD controls with a randomly selected matched COPD subset. Table E2. Comorbidities ranking by age category and group. Table E3. Prevalence comparison between Females and Males in the COPD cohort. Figure E1. Disease prevalence comparing COPD vs Control by age category. Figure E2. Disease prevalence comparing COPD vs Control by gender. Figure E3. Comorbidities network comparing COPD males and females. Figure E4. Comorbidities network comparing COPD and controls matched by total number of subjects, age, gender distribution and current smoking status. Figure E5. Comparison of COPD comorbidities networks using 3 cut-offs for statistical significance on Pearson s correlation values between comorbidities. Figure E6. Degree s distribution and tests for network characterization.
Table E1. Demographic and anthropometric characteristics comparing the Non-COPD controls with a randomly selected matched COPD patients subset. Demographic COPD Controls p-value N 311 316 Age (mean±sd) 59 ± 8 58± 11 0.132 Male n (%) 152 (49%) 176 (56%) 0.093 Current smoker* n (%) 142* (49%) 142 (45%) 0.328 Spirometry FEV1% predicted (mean±sd) 54 ± 21 100 ± 15 <0.0001 Body Mass Index (BMI) BMI (mean± SD) 27.03± 5.9 27.8 ± 4.9 0.0630 Comorbidities (Median, IQR, Range) Number of comorbidities by Gender Comorbidities (whole) 3, (2-6), 0-15 2, (0-3), 0-14 <0.0001 Male 4, (2-7), 0-15 2, (1-3), 0-14 <0.0001 Female 2, (1-4), 0-14 1, (0-3), 0-8 <0.0001 *Data missing in 22 subjects.
COPD Table E2. Top 20 comorbidities per group by age category. Age 55 Age between 56 and 64 Age 65 Group Rank Disease Prevalence Prevalence Disease (%) (%) Disease Prevalence (%) 1 Hyperlipidemia 38.5 Hypertension* 47.0 Hypertension 57.7 2 Hypertension 36.3 Hyperlipidemia 42.8 Hyperlipidemia 43.1 3 DJD 27.8 Coronary Artery Disease* 22.9 Coronary Artery Disease 30.0 4 Substance abuse 22.7 Diabetes Mellitus 22.0 DJD 28.4 5 Depression 21.8 DJD 21.8 Diabetes Mellitus 21.6 6 Coronary Artery Disease 19.7 BPH* 19.1 Peripheral Artery Disease 17.1 7 GORD 19.2 Depression* 18.4 Congestive Heart Failure 16.9 8 Anxiety 15.0 Substance abuse* 15.3 Chronic Renal Failure 16.4 9 Diabetes Mellitus 13.7 GORD 14.0 Atrial Fibrillation 15.9 10 Bipolar/Schizophrenia 13.7 Peripheral Artery Disease* 13.8 GORD 15.2 11 Hepatitis 11.5 Chronic Renal Failure* 13.5 CVA 12.0 12 Chronic Renal Failure 10.3 Anxiety 11.6 GORD 11.5 13 Obstructive Sleep Apnea 10.3 Erectile dysfunction* 11.6 Pulmonary Hypertension 9.7 14 BPH 8.6 Congestive Heart Failure* 10.8 Prostate CA 9.2 15 Gastro-Duodenal ulcers 8.1 Obstructive Sleep Apnoea 10.2 Osteoporosis 8.6 16 CVA 7.7 Gastro-Duodenal ulcers 9.5 Obstructive Sleep Apnoea 8.5 17 Peripheral Artery Disease 7.3 Bipolar/Schizophrenia* 9.3 Lung CA 8.2 18 Erectile dysfunction 6.4 Lung CA* 8.9 Pulmonary fibrosis 5.6 19 Congestive Heart Failure 6.0 Atrial Fibrillation* 8.0 Gout 3.9 20 Osteoporosis 6.0 Pulmonary Hypertension* 7.8 Bladder CA 3.9
Age 55 Age between 56 and 64 Age 65 Prevalence Group Rank Disease Prevalence (%) Disease Disease (%) Non- COPD Controls Prevalence (%) 1 Hyperlipidemia 20.1 Hyperlipidemia 44.1 Hyperlipidemia 49.0 2 Hypertension 11.4 Hypertension* 29.8 Hypertension 48.0 3 Anxiety 7.4 Diabetes Mellitus 16.7 DJD 31.0 4 DJD 6.0 DJD 16.7 Diabetes Mellitus 24.0 5 Asthma 6.0 GORD 13.1 GORD 18.0 6 CTD 6.0 Obstructive Sleep Apnea 11.9 Osteoporosis 14.0 7 Depression 5.4 Osteoporosis 10.7 Obstructive Sleep Apnoea 11.0 8 GORD 5.4 Anxiety 8.3 Prostate CA 6.0 9 Diabetes Mellitus 5.4 Coronary Artery Disease* 7.1 Lung CA 6.0 10 Obstructive Sleep Apnea 4.7 BPH* 6.0 Atrial Fibrillation 5.0 11 Coronary Artery Disease 2.7 Cataract 6.0 Gout 5.0 12 Gastro-Duodenal ulcers 2.7 Nephrolithiasis 4.8 CAD 4.0 13 Nephrolithiasis 2.7 Ventricular Arrhythmias 4.8 PAD 4.0 14 BPH 2.0 HIV* 4.8 Gastro-Duodenal ulcers 4.0 15 Thyroid CA 2.0 Depression* 3.6 Bladder CA 4.0 16 Peripheral Artery Disease 1.3 Gastro-Duodenal ulcers 3.6 CTD 4.0 17 Hypothyroidism 1.3 Hypothyroidism 3.6 Pulmonary embolism 4.0 18 Deep Vein Thrombosis 1.3 Chronic Renal Failure* 2.4 Asthma 4.0 19 Ventricular arrhythmias 1.3 Pulmonary fibrosis 2.4 Congestive Heart Failure 3.0 20 Venous insuficiency 1.3 Prostate CA 2.4 Hepatitis 3.0 Abbreviations: AAA= Abdominal Aortic Aneurism, BPH= Benign Prostatic Hypertrophy, CAD = Coronary Artery Disease, CHF=Congestive Heart Failure, CRF=Chronic Renal Failure, CVA=Cerebro-Vascular Accident, DM= Diabetes Mellitus, DVT= Deep Venous Thrombosis, GORD= Gastro- Oesophageal Reflux Disease, HTN= Systemic Hypertension, OSA= Obstructive Sleep Apnoea, PAD: peripheral artery disease, Pulmonary HTN= Pulmonary Hypertension.
Male predominant Female predominant Table E3. Comorbidity prevalence and comparison between COPD females and males. Comorbidity Females (n=219) Males (n=1750) P Osteoporosis 20.1 6.3 <. 0001 Hypothyroidism 11.9 5.7 0.0011 Venous insufficiency 6.9 3.7 0.0417 Asthma 4.1 1.5 0.0141 Breast cancer 6.9 HTN 38.4 54.1 <. 0001 CAD 13.2 28.5 <. 0001 DM 15.5 21.6 0.0423 GERD 7.8 16.2 0.0007 Peripheral arterial disease 3.2 15.9 0.0069 CHF 6.8 14.9 0.0009 Substance abuse 3.7 12.7 <. 0001 Atrial Fibrillation/Flutter 5 12.4 0.0004 Gastric/Duodenal Ulcer 4.6 11.4 0.0011 CVA 6.4 10.7 0.0447 OSA 0.5 10.2 <. 0001 Cataract 3.2 9.3 0.0013 Pulmonary HTN 4.6 9.1 0.0212 Lung Cancer 3.7 8.7 0.0082 AAA 2.3 6.2 0.0139 Ventricular arrhythmia 2.3 5.7 0.0359
Pulmonary fibrosis 0.9 5.5 0.0358 Hepatitis 0.9 3.7 0.0279 DM w/ Neuropathy 0.5 3.7 0.008 Bladder and tract urinary cancer 0 3.2 0.002 Pancreatitis 0.5 2.2 0.0422 Hypogonadism 0 0.9 0.2432 BPH 29.2 Erectile dysfunction 9.9 Prostate cancer 8.1 Testicular cancer 0.2 Abbreviations: AAA= Abdominal Aortic Aneurism, BPH= Benign Prostatic Hypertrophy, CAD = Coronary Artery Disease, CHF=Congestive Heart Failure, CRF=Chronic Renal Failure, CVA=Cerebro-Vascular Accident, DM= Diabetes Mellitus, DVT= Deep Venous Thrombosis, GERD= Gastro- Oesophageal Reflux Disease, HTN= Systemic Hypertension, OSA= Obstructive Sleep Apnoea, PAD: peripheral artery disease, Pulmonary HTN= Pulmonary Hypertension, TB= tuberculosis.
Figure E1. Disease prevalence by age distribution. Diseases with a statistically significant difference in proportion are indicated with an *. 40.0 35.0 Age Goup! 55 years 30.0 Prevalence (%) 25.0 20.0 COPD (n=231) 15.0 Non-COPD Control (n=159) 10.0 5.0 0.0 50.0 Age Goup between 56 and 64 years Prevalence (%) 45.0 40.0 35.0 COPD (n=528) 30.0 Non-COPD Control (n=159) 25.0 20.0 15.0 10.0 5.0 0.0 60 50 Age Goup " 65 years Prevalence (%) 40 30 20 10 0 COPD (n=1191) Non-COPD Controls (n=100)
Prevalence (%) Prevalence (%) Figure E2. Disease prevalence by gender. Diseases with a statistically significant difference in proportion are indicated with an *. 55 50 45 40 35 30 25 20 15 10 5 0 Males COPD n=1794 Non-COPD Control n=194 45 40 35 30 25 20 15 Females COPD n=216 Non-COPD Control n=146 10 5 0
Figure E3. Comorbidities network comparing COPD males and females. COPD Males o! 87 nodes o! 548 edges COPD Females o! 68 nodes o! 206 edges The network layout is based on a force directed algorithm of attractions and repulsions called Fruchterman-Reingold algorithm 1. Note that 1. The network is denser in the male cohort, 2. There are more current smoker, more individuals younger than 55 years, higher prevalence of psychiatric (depression and anxiety), osteoporosis and more perception of dyspnoea in the female cohort, while the male cohort has higher prevalence and influence of cardiovascular diseases. 1. Fruchterman T, Reingold E, Graph Drawing by Force-directed Placement. Graph Drawing by Force-directed Placement. SOFTWARE PRACTICE AND EXPERIENCE, VOL. 21(1 1), 1129-1164 (NOVEMBER 1991)
Figure E4. Comorbidities network comparing matched COPD and controls by total number of subject, age, gender distribution and current smoking status. Matched COPD Cohort Nodes=69 Edges= 214 Non-COPD Controls Nodes=56 Edges= 149 Note that 1. The network is denser in the Matched COPD cohort, the prevalence of common diseases in both groups is higher for COPD and there is a higher influence (by prevalence and connections) of psychiatric, behavioural and cardiovascular comorbidities.
Figure E5. Comparison of COPD comorbidities network using 3 cut-offs for statistical significance on Pearson s correlation values between comorbidities and clinical variables. Panel A. p 0.01 p 0.001 p 0.0001
Pearson s correlation Rho (! ) Panel B.! " ##$%&' " ( )*+, -#+. / ' " ( ). 0)123&%/ $)&( *)45" ) 0.4 0.3 0.2 0.1 0-0.1-0.2 0.01 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 0 p-value Combination of plot chart and histogram demonstrating the distribution of p-values at the following cut-off point (doted lines): 0.01 (520 correlations), 0.001 (357 correlations) and 0.0001 (265 correlations). Correlations are positive or negative with values ranging from 0.06 to 0.42 and -0.05 to -0.16.
Figure E6. Degree s distribution and tests for network characterization. Panel A. Histogram of the distribution of links per nodes (degree), superimposed with a fitted Poisson s (red), normal (blue) and exponential (green) distribution curves. Note that the distribution better approximate an exponential distribution (long rightward tail)
Poisson Quantile Exponential Probability Normal Probability Panel B. Fitted plot to test how distribution better fit the degree distribution in the cohort of COPD individuals. 20 Fitted Poisson Fitted Exponential Fitted Normal 18 16 14 12 10 8 6 4 0 5 10 15 20 25 30 35 Degree 0.97 0.95 0.93 0.91 0.85 0.75 0.65 0.55 0.45 0.35 0.25 0.05 0 5 10 15 20 25 30 35 Degree 0.95 0.91 0.84 0.7 0.5 0.3 0.16 0.09 0.05 0.015 0 5 10 15 20 25 30 35 Degree Pearson s ChiSquared p< 0.0001 H0= The data is from the Poisson distribution Small p-values reject H0 Kolmogorov s D P=0.0785 H0= The data is from the Exponential distribution Small p-values reject H0 Shapiro-Wilk W test p< 0.0001 H0= The data is from the Normal distribution Small p-values reject H0