Negative impacts of unreported COPD exacerbations on health-related quality of
life at one year
Wanning Xu, Jean-Paul Collet, Stanley Shapiro, Yingxiang Lin, Ting Yang, Chen
Wang, Jean Bourbeau
Online Data Supplement A: Confounding evaluation using Directed Acyclic
Graphs (DAGs)
A priori subject-matter and causal knowledge for the association under study was
used to guide the confounder evaluation(1, 2). First, potential determinants of the
health-related quality of life (HRQL) in patients with COPD were identified from a
comprehensive literature review. Studies were searched from MEDLINE, EMBASE
and The Cochrane Library from 1980 to 2007, using the key words “Chronic
Obstructive Pulmonary Disease/COPD”, “quality of life/health status/well-being” and
“risk factor/determinant/cause”.
Then, the causal relationships of each risk factor
with the outcome (HRQL), the exposure (COPD exacerbation) and other determinants
were presented in causal diagrams (i.e., Directed Acyclic Graphs, DAGs)(1, 2). The
strengths of the causal assumptions were determined according to the critical review
of the findings from previous studies, clinical plausibility and respirologist (co-author)
opinion. The assumptions were considered as strong if supporting evidence was
consistent in the literature. For instance, frequent exacerbations in the previous year
are associated with frequent exacerbations in the current year(3-9). The assumptions
were considered as moderate if previous results were inconsistent or limited but
clinically plausible. Most of our assumptions fall into this category. For instance,
some studies and opinion papers(5,
6, 8, 10-17)
have suggested that the frequency of
COPD exacerbation increased with more lung function impairment (FEV1), but this
1
association was not found in other studies(18-21). Another example is the association
between the dyspnea level at baseline and the risk of COPD exacerbation. Many
multivariate analyses found that this association was not statistically significant,
except for a recent study(22). However, dyspnea is the major symptom of COPD and
can be used to categorize disease severity. It is therefore clinically plausible to assume
that the risk of exacerbations and hospitalizations increases with the severity of
dyspnea. The weak assumptions were those based upon the clinical reasoning only or
suggested in studies with critical methodological limitations. For instance, despite the
lack of reliable evidence, it is possible that the lower level of exercise capacity
(represented by 6-mintue walking distance) is associated with the increased risk of
COPD exacerbations, which may be mediated by the lower level of regular physical
activity. Our causal assumptions are summarized in Table E1. For this specific study,
we developed the causal diagram (Figure A1) based on the assumptions in all strength
levels in order to capture all potential confounders(1, 2). The relevant confounders
identified from our causal diagram for the association between COPD exacerbations
and the change of HRQL are: age, sex, socio-economic factors (marital status,
education level, current employment, living alone), current smoking, lung function
(FEV1%), dyspnea, daily productive cough, daily wheezing, 6-mintue walking
distance (6MWD), social support, COPD-specific self-efficacy (CSES), anxiety and
depression, significant co-morbidities, participation into pulmonary rehabilitation (PR)
programs, and the use of long-acting bronchodilator (LABD), inhaled corticosteroid
(ICS) and long-term oxygen therapy (LTOT) at baseline. Among these identified
confounders, pulmonary rehabilitation and living alone has very low variability (i.e,
less than 3% subjects in a certain category for dichotomous variables) and thus were
excluded from the multivariate models.
Disease history (i.e., COPD diagnosis for at
2
least 5 years) were neither included in the causal diagram nor the multivariate models
due to their potential co-linearity with other covariates.
This approach has been considered as a more appropriate strategy compared to
conventional methods based on stepwise regression, “change-in-estimation” approach,
or conventional epidemiological definition of confounding.
It allows consideration
of inter-relationships between multiple covariates; avoids unnecessary or harmful
adjustment that may result from conventional strategies; explicitly reveals the causal
assumptions between variables which were implied but obscured in most studies
based on data-driven approaches; and it is also mathematically rigorous while being a
qualitative and simple way to approach causal inference from observational data(1, 2).
However, as with any model there can be no guarantee that our causal diagram is
correct or that other models could not be put forward. Some of the causal assumptions
in our diagram may be of unknown validity and most are untestable(1, 2). However, this
approach allows us to make our causal assumptions explicit.
3
Table A1. Causal assumptions between the main exposure (COPD exacerbation),
the main outcomes (HRQL), and covariates.
Arrow # in
Figure A1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30
A31
A32
A33
A34
A35
A36
Causal assumptions (cause-effect)
Lung function – respiratory symptoms
Lung function – HRQL
Respiratory symptoms – exercise capacity (i.e., 6MWD)
Respiratory symptoms – depression/anxiety
Depression/anxiety – respiratory symptoms
Respiratory symptoms - HRQL
Exercise capacity (6MWD) – HRQL
Depression/anxiety – HRQL
Psychosocial factors (SES, social support, self-efficacy) –
HRQL
Psychosocial factors (SES, social support, self-efficacy) –
respiratory symptoms (i.e., dyspnea)
Psychosocial factors (SES, social support, self-efficacy) –
psychological status (i.e., depression/anxiety)
Age/sex – lung function
Age/sex – psychosocial factors (SES, social support,
self-efficacy)
Age/sex – depression/anxiety
Age/sex – HRQL
Past exacerbations – baseline lung function
Past exacerbations – baseline depression/anxiety
Smoking – lung function
Smoking – symptoms of chronic bronchitis
Significant co-morbidities – HRQL
Significant co-morbidities – Depression/anxiety
Hospital (representing health care levels and
environmental triggers) – HRQL
Treatment profile (ICS, LABD, LTOT, PR) – HRQL
lung function – COPD exacerbations
Respiratory symptoms (i.e., cough, sputum, dyspnea) –
exacerbations
Function capacity (6MWD) – exacerbations
Depression/anxiety – exacerbations
Psychosocial factors (SES, social support, self-efficacy) –
exacerbations
Age/sex – exacerbations
Age/sex – exercise capacity (6MWD)
Age – co-morbidities
Past exacerbations - future exacerbations
Co-morbidities - exacerbations
Treatment profile (ICS, LABD, LTOT, PR) exacerbations
Treatment profile (Vaccination/mucolytics) exacerbations
Hospital (i.e.,health care levels and environmental
triggers) - exacerbations
Strength of
assumptions
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Strong
Moderate
Moderate
Moderate
Strong
Moderate
Moderate
Moderate
Moderate
Weak to
moderate
Strong
Strong
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Weak
Moderate
Moderate
Moderate
Moderate
Moderate
Strong
Moderate
Moderate
Moderate
Strong
4
A1-36=Arrows 1-36 shown in Figure A1; SES=Socio-economic status; 6MWD=6-minute
walking distance; LTOT=Long-term oxygen therapy; PR=Pulmonary Rehabilitation;
LABD=Long-acting bronchodilator; ICS=Inhaled corticosteroid.
5
Figure A1. The Directed Acyclic Graph (DAG) for the association between COPD
exacerbations and the change of HRQL.
Past exacerbation
A17 (weak to moderate)
A16
Lung function
A24
Current
smoking
A18
A12
A15
Age, Sex
A29
A30
A14
A13
A1
SES; self-efficacy; social
support (representing coping
strategies, health perception,
access to health resource;
adherence of treatment plans)
A19
A28
A32
A10
A11
A31
A2
A5
A4
Respiratory
symptoms
A25
Depression/anxiety
A6
A3
Exercise capacity
(6MWD)
A26
A9
A27
A7
A8
COPD exacerbation
A35
A34
Change in HRQL
ICS, LABD, LTOT, PR
A23
Vaccination,
mucolytics
A33
A36
-
Significant comorbidities
A20
Hospital (representing health care
levels and environmental triggers)
A21
A22
The causal association under study is COPD exacerbationchange in HRQL (boxes in
dark grey). Other boxes represent measured covariates.
The single-headed arrows represent direct links from causes to effects (causal
assumptions) (also see Table A1 for the meaning of arrows 1-36).
The thickness of the arrows represents the strength of the causal assumptions (strong,
moderate or weak).
6
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8
Online data supplement B: Characteristics of unreported and reported
exacerbations according to GOLD stages.
Table B1. Characteristics of unreported and reported exacerbations in GOLD
Stage II patients (n=211)
Unreported
Reported
exacerbations
Exacerbations
Number of exacerbations
157
163
Rate of exacerbations (number/person-year)
0.74
0.90
(0.62-0.86)
(0.77-1.02)
1 (1-3)
3 (1-3)
Sputum amount
74 (47.1)
123 (75.5)*
Sputum color
28 (17.8)
109 (66.9)*
Dyspnea
96 (61.2)
137 (84.1)*
One symptom
123 (78.3)
44 (27.0)*
Two symptoms
27 (17.2)
32 (19.6)
Three symptoms
7 (4.5)
87 (53.4)*
Untreated exacerbations
119 (75.8)
24 (14.7)
Treated exacerbations
38 (24.2)
139 (85.3)
Total number of key symptoms, median (range)
Type of key symptoms, n (%)
Proportion of treated and untreated exacerbations, n (%)
p value<0.0001 and †p value<0.01 for comparisons of proportions between reported and
*
unreported exacerbations, which were estimated from Generalized Estimating Equations
using each symptom as the dependent variable and the reporting status as the independent
variable, taking into account the potential individual-level clustering effect.
9
Table B2. Characteristics of unreported and reported exacerbations in GOLD
Stage III patients (n=204)
Unreported
Reported
exacerbations
Exacerbations
Number of exacerbations
233
162
Rate of exacerbations (number/person-year)
1.28
0.85
(1.12-1.43)
(0.72-0.98)
1 (1-3)
2 (1-3)
Sputum amount
110 (47.2)
110 (67.9)†
Sputum color
31 (13.3)
104 (64.2)*
Dyspnea
135 (57.9)
143 (88.3)*
One symptom
200 (85.8)
47 (29.0)*
Two symptoms
23 (9.9)
35 (21.6)†
Three symptoms
10 (4.3)
80 (49.4)*
Untreated exacerbations
191 (82.0)
19 (11.7)
Treated exacerbations
42 (18.0)
143 (88.2)
Total number of key symptoms, median (range)
Type of key symptoms, n (%)
Proportion of treated and untreated exacerbations, n (%)
p value<0.0001 and †p value<0.01 for comparisons of proportions between reported and
*
unreported exacerbations, which were estimated from Generalized Estimating Equations
using each symptom as the dependent variable and the reporting status as the independent
variable, taking into account the potential individual-level clustering effect.
10
Table B3. Characteristics of unreported and reported exacerbations in GOLD
Stage IV patients (n=76)
Unreported
Reported
exacerbations
Exacerbations
Number of exacerbations
76
85
Rate of exacerbations (number/person-year)
1.06
1.46
(0.83-1.30)
(1.18-1.74)
1 (1-3)
3 (1-3)
Sputum amount
29 (38.2)
59 (69.4)*
Sputum color
13 (17.1)
55 (64.7)*
Dyspnea
48 (63.2)
73 (85.9)*
One symptom
65 (85.5)
27 (31.7)*
Two symptoms
8 (10.5)
14 (16.5)†
Three symptoms
3 (4.0)
44 (51.8)*
Untreated exacerbations
63 (82.9)
10 (11.8)
Treated exacerbations
13 (17.1)
75 (88.2)
Total number of key symptoms, median (range)
Type of key symptoms, n (%)
Proportion of treated and untreated exacerbations, n (%)
p value<0.0001 and †p value<0.01 for comparisons of proportions between reported and
*
unreported exacerbations, which were estimated from Generalized Estimating Equations
using each symptom as the dependent variable and the reporting status as the independent
variable, taking into account the potential individual-level clustering effect.
11