Chronic Obstructive Pulmonary Disease (COPD) Comorbidities Network
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1 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.
2 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 Age (mean±sd) 59 ± 8 58± Male n (%) 152 (49%) 176 (56%) Current smoker* n (%) 142* (49%) 142 (45%) Spirometry FEV1% predicted (mean±sd) 54 ± ± 15 < Body Mass Index (BMI) BMI (mean± SD) 27.03± ± Comorbidities (Median, IQR, Range) Number of comorbidities by Gender Comorbidities (whole) 3, (2-6), , (0-3), 0-14 < Male 4, (2-7), , (1-3), 0-14 < Female 2, (1-4), , (0-3), 0-8 < *Data missing in 22 subjects.
3 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 Hypertension 36.3 Hyperlipidemia 42.8 Hyperlipidemia DJD 27.8 Coronary Artery Disease* 22.9 Coronary Artery Disease Substance abuse 22.7 Diabetes Mellitus 22.0 DJD Depression 21.8 DJD 21.8 Diabetes Mellitus Coronary Artery Disease 19.7 BPH* 19.1 Peripheral Artery Disease GORD 19.2 Depression* 18.4 Congestive Heart Failure Anxiety 15.0 Substance abuse* 15.3 Chronic Renal Failure Diabetes Mellitus 13.7 GORD 14.0 Atrial Fibrillation Bipolar/Schizophrenia 13.7 Peripheral Artery Disease* 13.8 GORD Hepatitis 11.5 Chronic Renal Failure* 13.5 CVA Chronic Renal Failure 10.3 Anxiety 11.6 GORD Obstructive Sleep Apnea 10.3 Erectile dysfunction* 11.6 Pulmonary Hypertension BPH 8.6 Congestive Heart Failure* 10.8 Prostate CA Gastro-Duodenal ulcers 8.1 Obstructive Sleep Apnoea 10.2 Osteoporosis CVA 7.7 Gastro-Duodenal ulcers 9.5 Obstructive Sleep Apnoea Peripheral Artery Disease 7.3 Bipolar/Schizophrenia* 9.3 Lung CA Erectile dysfunction 6.4 Lung CA* 8.9 Pulmonary fibrosis Congestive Heart Failure 6.0 Atrial Fibrillation* 8.0 Gout Osteoporosis 6.0 Pulmonary Hypertension* 7.8 Bladder CA 3.9
4 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 Hypertension 11.4 Hypertension* 29.8 Hypertension Anxiety 7.4 Diabetes Mellitus 16.7 DJD DJD 6.0 DJD 16.7 Diabetes Mellitus Asthma 6.0 GORD 13.1 GORD CTD 6.0 Obstructive Sleep Apnea 11.9 Osteoporosis Depression 5.4 Osteoporosis 10.7 Obstructive Sleep Apnoea GORD 5.4 Anxiety 8.3 Prostate CA Diabetes Mellitus 5.4 Coronary Artery Disease* 7.1 Lung CA Obstructive Sleep Apnea 4.7 BPH* 6.0 Atrial Fibrillation Coronary Artery Disease 2.7 Cataract 6.0 Gout Gastro-Duodenal ulcers 2.7 Nephrolithiasis 4.8 CAD Nephrolithiasis 2.7 Ventricular Arrhythmias 4.8 PAD BPH 2.0 HIV* 4.8 Gastro-Duodenal ulcers Thyroid CA 2.0 Depression* 3.6 Bladder CA Peripheral Artery Disease 1.3 Gastro-Duodenal ulcers 3.6 CTD Hypothyroidism 1.3 Hypothyroidism 3.6 Pulmonary embolism Deep Vein Thrombosis 1.3 Chronic Renal Failure* 2.4 Asthma Ventricular arrhythmias 1.3 Pulmonary fibrosis 2.4 Congestive Heart Failure 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.
5 Male predominant Female predominant Table E3. Comorbidity prevalence and comparison between COPD females and males. Comorbidity Females (n=219) Males (n=1750) P Osteoporosis < Hypothyroidism Venous insufficiency Asthma Breast cancer 6.9 HTN < CAD < DM GERD Peripheral arterial disease CHF Substance abuse < Atrial Fibrillation/Flutter Gastric/Duodenal Ulcer CVA OSA < Cataract Pulmonary HTN Lung Cancer AAA Ventricular arrhythmia
6 Pulmonary fibrosis Hepatitis DM w/ Neuropathy Bladder and tract urinary cancer Pancreatitis Hypogonadism 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.
7 Figure E1. Disease prevalence by age distribution. Diseases with a statistically significant difference in proportion are indicated with an * Age Goup! 55 years 30.0 Prevalence (%) COPD (n=231) 15.0 Non-COPD Control (n=159) Age Goup between 56 and 64 years Prevalence (%) COPD (n=528) 30.0 Non-COPD Control (n=159) Age Goup " 65 years Prevalence (%) COPD (n=1191) Non-COPD Controls (n=100)
8 Prevalence (%) Prevalence (%) Figure E2. Disease prevalence by gender. Diseases with a statistically significant difference in proportion are indicated with an * Males COPD n=1794 Non-COPD Control n= Females COPD n=216 Non-COPD Control n=
9 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), (NOVEMBER 1991)
10 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.
11 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 p
12 Pearson s correlation Rho (! ) Panel B.! " ##$%&' " ( )*+, -#+. / ' " ( ). 0)123&%/ $)&( *)45" ) 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), (357 correlations) and (265 correlations). Correlations are positive or negative with values ranging from 0.06 to 0.42 and to
13 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)
14 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 Degree Degree Degree Pearson s ChiSquared p< H0= The data is from the Poisson distribution Small p-values reject H0 Kolmogorov s D P= H0= The data is from the Exponential distribution Small p-values reject H0 Shapiro-Wilk W test p< H0= The data is from the Normal distribution Small p-values reject H0
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