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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)
Comorbidities (whole) 3, (2-6), 0-15 2, (0-3), 0-14 <0.0001
Number of comorbidities by Gender
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.
Table E2. Top 20 comorbidities per group by age category.
Age ≤ 55
Age between 56 and 64
Age ≥ 65
Group Rank Disease Prevalence
(%) Disease
Prevalence
(%) Disease
Prevalence
(%)
CO
PD
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
Group Rank Disease Prevalence (%)
Disease Prevalence
(%) Disease
Prevalence
(%)
Non-
COPD
Controls
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.
Table E3. Comorbidity prevalence and comparison between COPD females and males.
Comorbidity Females (n=219) Males (n=1750) P
Fem
ale
pre
dom
inan
t 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
Mal
e pre
dom
inan
t
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 *.
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
Pre
vale
nce
(%
)
Age Goup ! 55 years
COPD (n=231)
Non-COPD Control (n=159)
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
50.0
Pre
vale
nce
(%
)
Age Goup between 56 and 64 years
COPD (n=528)
Non-COPD Control (n=159)
0
10
20
30
40
50
60
Pre
vale
nce
(%
)
Age Goup " 65 years
COPD (n=1191) Non-COPD Controls (n=100)
Figure E2. Disease prevalence by gender.
Diseases with a statistically significant difference in proportion are indicated with an *.
0
5
10
15
20
25
30
35
40
45
50
55
Pre
va
len
ce (
%)
Males
COPD n=1794
Non-COPD Control n=194
0
5
10
15
20
25
30
35
40
45
Pre
vale
nce
(%
)
Females
COPD n=216
Non-COPD Control n=146
Figure E3. Comorbidities network comparing COPD males and females.
The network layout is based on a force directed algorithm of attractions and repulsions called Fruchterman-Reingold algorithm1. 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)
COPD Females
o! 68 nodes
o! 206 edges
COPD Males
o! 87 nodes
o! 548 edges
Figure E4. Comorbidities network comparing matched COPD and controls by total number of subject, age, gender distribution and current smoking
status.
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.
Matched COPD Cohort
Nodes=69
Edges= 214
Non-COPD Controls
Nodes=56
Edges= 149
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
Panel B.
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.
-0.2
-0.1
0
0.1
0.2
0.3
0.4
Rh
o
0.01 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 0
p-value
! "##$%&' " ( )*+, -#+. / ' " ( ). 0)123&%/$)&( *)45" )
Pea
rson’s
co
rrel
atio
n (
!)
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)
Panel B. Fitted plot to test how distribution better fit the degree distribution in the cohort of COPD individuals.
P
ois
son
Qu
an
tile
4
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10
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16
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20
0 5 10 15 20 25 30 35
Degree
No
rmal
Pro
bab
ilit
y
0.015
0.05
0.09
0.16
0.3
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0.7
0.84
0.91
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0 5 10 15 20 25 30 35
Degree
Ex
po
nen
tial
Pro
bab
ilit
y
0.05
0.250.350.450.55
0.65
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0 5 10 15 20 25 30 35
Degree
Fitted Poisson Fitted Exponential Fitted Normal
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