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original article

http://www.kidney-international.org
& 2007 International Society of Nephrology

Association of pulse wave velocity with vascular and


valvular calcification in hemodialysis patients
P Raggi1, A Bellasi1,2, E Ferramosca3, T Islam4, P Muntner4 and GA Block5
1

Division of Cardiology and Department of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA; 2Department of
Nephrology, Ospedale San Paolo and University of Milan, Milan, Italy; 3Department of Nephrology, Ospedale Malpighi and University
of Bologna, Bologna, Italy; 4Department of Epidemiology, Tulane University, New Orleans, Louisiana, USA and 5Denver Nephrology
PC, Denver, Colorado, USA

The recent Kidney Disease: Improving Quality Outcomes


(KDIGO) recommendations called for an investigation of the
relationship between various radiological methods to assess
cardiovascular calcification and measures of arterial stiffness.
Accordingly, in 131 adult maintenance hemodialysis patients,
we investigated the association of aortic pulse wave velocity
(PWV) with calcification of cardiac valves on
echocardiography, coronary artery, and thoracic aorta
calcium on computed tomography and a calcification score
of the abdominal aorta obtained on a plain abdominal X-ray.
All tests were performed within a week. Mean PWV increased
as the severity of coronary artery, thoracic, and abdominal
aorta calcium scores increased (each Po0.05). No trend was
present for number of valves with calcification. After
multivariable adjustment, abdominal aorta X-ray calcium
scores remained associated with PWV (P 0.004), whereas
the association of PWV with thoracic aorta and coronary
artery calcium scores became marginal (P 0.308 and
P 0.083, respectively). No association was found between
number of calcified valves and PWV. This study demonstrates
a strong association between abdominal aorta calcification
on plain X-ray and PWV and a borderline association with
thoracic aorta and coronary artery calcification. Sudden death
and congestive heart failure, two frequent causes of death in
hemodialysis, are likely caused by increased arterial stiffness
that can be closely predicted by the presence of aortic
calcification on plain X-rays.
Kidney International (2007) 71, 802807. doi:10.1038/sj.ki.5002164;
published online 21 February 2007
KEYWORDS: vascular calcification; dialysis; pulse wave velocity; cardiovascular disease

Correspondence: P Raggi, Emory University School of Medicine, 1365 Clifton


Road NE, AT-504, Atlanta, Gorgia 30322, USA. E-mail: praggi@emory.edu
Received 21 November 2006; revised 22 December 2006; accepted
9 January 2007; published online 21 February 2007
802

Patients with all stage of chronic kidney disease (CKD), but


especially those with end-stage renal disease (CKD-5), suffer
a very high rate of cardiovascular events.1,2 As a consequence,
both the National Kidney Foundation and the American
Heart Association have stated that CKD-5 patients should be
considered at the highest risk for cardiovascular disease.3,4
Although many traditional risk factors play an important
role, several nontraditional factors, such as alteration of bone
and mineral metabolism and a heightened oxidative and
inflammatory state, appear to contribute substantially to the
increased risk.57
It has also been suggested that extensive cardiovascular
calcification develops as one of the consequences of bone and
mineral metabolism derangement.8 The severity of vascular
and valvular calcification has been assessed by plain radiography, ultrasonography, echocardiography and, most
recently, cardiac computed tomography (CT).9 Regardless
of modality, cardiovascular calcification has been associated
with an increased risk of death in CKD-5 patients.1013
Although cardiac CT is very accurate and the only true
quantitative method currently available to assess the extent of
cardiovascular calcification, this technique is costly and
involves exposing patients to radiation.
Other noninvasive techniques to assess cardiovascular risk
have therefore gained considerable popularity.14 One of the
most helpful is pulse wave velocity (PWV), which is used to
evaluate vascular stiffness. Vascular stiffness translates into
higher conduction velocity of an impulse along the vessel
length. Decreased elasticity is the result of many contributing
factors, such as atherosclerosis, vascular wall calcification,
and changes in collagen and elastin content in the vessel
wall.15 Of note, an increased PWV has been associated with
an excess morbidity and mortality risk in CKD-5 and in the
general population.16,17 Because cardiovascular research is
actively employing radiological techniques and PWV measurements in CKD-5, it is important to know how these tools
relate to each other. Indeed, the recent Kidney Disease:
Improving Global Outcome (KDIGO) recommendations
called for further investigation into the relationship between
radiological tools for assessment of cardiovascular calcification and methods to assess vascular stiffness.18 Therefore, we
Kidney International (2007) 71, 802807

original article

P Raggi et al.: Vascular calcification and PWV

RESULTS

Table 1 and 2 show the clinical characteristics for the entire


patient cohort and for patients with a PWVo12 m/s and
X12 m/s, separately. On average, patients with a
PWVX12 m/s were older and more likely to have a history
of diabetes mellitus (P 0.003 and P 0.004, respectively).
Also, systolic blood pressure and pulse pressure were
marginally higher among those with a PWV X12 m/s
(P 0.146 and P 0.172). No differences in medication use
were present for patients with a PWV o12 m/s and X2 m/s.
Finally, serum phosphorus was significantly lower and the
product Ca  P was marginally lower in patients with higher
PWV (P 0.046 and P 0.067, respectively).
Although twofold greater, the median coronary artery
calcium score of patients with a PWV X12 m/s was
nonsignificantly higher than that of participants with a
PWVo12 m/s (Figure 1; P 0.307). However, the thoracic
aorta calcium score was significantly higher in participants
with a PWV X12 m/s (Figure 1; P 0.002).
Mean PWV increased in a graded manner as the severity
of coronary artery calcium, thoracic aorta, and abdominal
aorta calcium scores increased (Figure 2; each Po0.05). No

trend was present for valve calcification. After multivariate


adjustment, abdominal aorta X-ray calcium scores remained
associated strongly with higher PWV (P 0.004; Table 3). In
contrast, only a marginal association was present between
thoracic aorta and coronary artery calcium scores and PWV
after multivariable adjustment (P 0.083 and P 0.308,
respectively). Finally, the number of valves with calcification
was not associated with PWV (P 0.523).
Figure 3 displays the prevalence rate ratio of a PWV
X12 m/s with each measure of calcification after multivariate
adjustment for age, race, diabetes mellitus, systolic blood
pressure, pulse pressure, and the use of calcium acetate.
Although not statistically significant, graded trends of
increased prevalence rate ratios were present at higher
abdominal aorta X-ray calcium scores (P 0.06), and
thoracic aorta and coronary artery CT calcium scores
(P 0.17 and P 0.23, respectively). No association
was present between PWV and number of valves with
calcification.
DISCUSSION

In this cross-sectional analysis of patients with CKD-5, we


investigated the association of several radiological measures
of cardiovascular calcification and arterial stiffness as
recommended by KDIGO recently.18 The recommendation
was based on mounting evidence that both measures of

Pulse wave velocity


Overall o12 m/s X12 m/s
(n=131) (n=98)
(n=33) P-value

Age (years)
Male (%)
Nonwhite (%)
Dialysis vintage (years)
Current smoker (%)

55.2
50.4
60.3
4.2
18.6

52.9
53.1
57.1
4.3
17.2

61.7
42.4
69.7
3.7
22.6

0.003
0.215
0.195
0.969
0.317

History of
Hypertension (%)
Diabetes mellitus (%)
ASCVD (%)
CHF (%)
Dyslipidemia (%)

96.2
48.1
37.4
21.4
48.9

95.9
38.8
32.7
21.4
48.0

97.0
75.8
51.5
21.2
51.5

0.881
0.004
0.446
0.702
0.821

Body mass index (kg/m2)


Systolic BP( mm Hg)
Diastolic BP (mm Hg)
Pulse pressure (mmHg)
Serum calcium (mg/dl)
Serum phosphorus (mg/dl)
Calcium  phosphorus (mg2/dl2)
Median iPTH (pg/dl)

26.0
146.3
78.5
67.8
9.00
5.12
45.9
404

25.8
144.4
78.6
65.8
8.98
5.28
47.1
410

26.6
151.9
78.0
73.9
9.06
4.66
42.2
384

0.682
0.146
0.561
0.172
0.593
0.046
0.067
0.782

ASCVD, cerebrovascular disease, peripheral vascular disease; angina pectoris; history


of previous MI; history of PTCA, coronary artery bypass.

Kidney International (2007) 71, 802807

PWV <12 m/s

1800

Table 1 | Demographic, health history, and vital status data


for the study cohort and by pulse wave velocity category

Variable

P -value = 0.002
1852.0

2000

Median calcium score

addressed this important question by performing simultaneously four tests in a cross-sectional cohort of hemodialysis
patients: PWV for vascular stiffness, echocardiography to
assess presence of valvular calcification, chest CT to measure
coronary artery and thoracic aorta calcification, and a lateral
lumbar X-ray to assess the presence of abdominal aorta
calcification.

PWV.12 m/s

1600
1400
1200
1000
800
600

P -value = 0.307

470.1

323.3

400
161.5

200
0

Coronary artery calcium


score

Thoracic aorta calcium


score

Figure 1 | Median coronary artery and thoracic aorta calcium


scores by level of PWV.

Table 2 | Concomitant medication use for the study cohort


and by pulse wave velocity category
Variable
Beta blockers (%)
ACE inhibitors (%)
Angiotensin receptor
blockers (%)
Statins (%)
Calcium acetate (%)
Calcium carbonate (%)
Sevelamer HCl (%)
Calcitriol (%)

Overall

o12 m/s

X12 m/s

P-value

46.2
39.2
10.0

46.4
39.2
9.3

45.5
39.4
12.1

0.692
0.846
0.570

36.2
21.5
30.8
58.5
14.6

34.0
24.7
28.9
57.7
15.5

42.4
12.1
36.4
60.6
12.1

0.729
0.170
0.375
0.668
0.756
803

P Raggi et al.: Vascular calcification and PWV

12.5

P -trend=0.044

11.5

11.1

10.7

10.5
9.5
9.5
8.5
<100

Pulse wave velocity


(m/sec)

Pulse wave velocity


(m/sec)

original article

.1000

100999

12.5

P -trend=0.001
10.4

10.5
9.5

8.9

8.5
<135

11.5
10.5
9.5

10.0
9.2

8.5
0

16

Pulse wave velocity


(m/sec)

Pulse wave velocity


(m/sec)

12.0

P-trend<0.001

1351924

.1925

Tertile of thoracic aorta calcium score

Coronary artery calcium score


12.5

11.5

11.5

12.5
P -trend=0.182

11.2

11.5
10.5

10.3

10.1

9.5
8.5
0

?7

Number of calcified valves

Abdominal aorta calcium score

Figure 2 | Mean PWV by level of vascular calcification.

Table 3 | Age and multivariate-adjusted difference in pulse wave velocity associated with higher vascular calcification
Level of coronary artery calcium score
o100
Mean age-adjusted PWV
Multivariate-adjusted PWV

100999

0.00 (ref)
0.00 (ref)

0.40 (1.02, 1.83)


0.58 (0.78, 1.94)

X1000

P-value

0.77 (0.96, 2.51)


0.80 (0.84, 2.45)

0.368
0.308

Tertiles of thoracic aorta calcium score


o135
Mean age-adjusted PWV
Multivariate-adjusted PWV

1351924

0.00 (ref)
0.00 (ref)

0.61 (0.98, 2.19)


0.40 (1.13, 1.92)

X1925
1.00 (0.84, 2.84)
1.65 (0.20, 3.51)

0.282
0.083

Tertiles of abdominal aorta calcium score


0
Mean age-adjusted PWV
Multivariate-adjusted PWV

16

0.00 (ref)
0.00 (ref)

0.26 (1.21, 1.74)


0.34 (1.08, 1.76)

X7
1.75 (0.15,3.35)
2.34 (0.77, 3.90)

0.038
0.004

Number of valves with calcification


Mean age-adjusted PWV
Multivariate-adjusted PWV

0.00 (ref)
0.00 (ref)

0.78 (2.23, 0.67)


0.52 (2.00, 0.96)

0.50 (1.01, 2.02)


0.52 (0.93, 1.97)

0.639
0.523

PWV, pulse wave velocity; ref, reference category.


Multivariate models include adjustment for age, race, diabetes mellitus, systolic blood pressure, pulse pressure, use of calcium acetate, serum phosphorous, and, the product
calcium  phosphorus.

vasculopathy are good markers for risk of subsequent adverse


events and their correlation is of interest. Our study was
conducted in a very homogeneous population of hemodialysis patients, whereas earlier analyses using CT technologies
included smaller and mixed populations of patients with
different degree of chronic kidney disease, renal transplant,
hemo- and peritoneal dialysis patients.19,20 Importantly, in
previous published reports, tests were conducted from 10
days to 9 months apart, whereas patients in the current study
had their tests performed within 1-week period. Finally, the
difference in the strength of the association of PWV with
coronary artery calcium scores reported by us and Haydar
et al.20 may be because of the choice of statistical tests
utilized. In fact, Haydar et al.20 correlated mean coronary
artery calcium scores with PWV. In the presence of a highly
804

skewed distribution, as observed for calcium scores, our


approach of using median scores and prevalence rate ratios
was likely more appropriate.
The main results of our investigation are that there is a
strong association between PWV and measures of abdominal
aorta calcification, a weaker association with coronary artery
and thoracic aorta calcification, and no association with
valvular calcification. The good correlation between abdominal aorta calcification detected by simple X-ray techniques
and its functional impact, reflected in increased PWV,
deposes for the clinical significance of aortic calcification
on plain X-rays in CKD-5.
PWV has been shown to be a powerful noninvasive tool to
assess cardiovascular risk in patients affected by CKD-5.17
Arterial stiffening is dependent on several known risk factors
Kidney International (2007) 71, 802807

original article

5.0
4.0

1.45
1.58
(0.69, 3.03)
(0.82, 3.03)

3.0
2.0

P -trend=0.25

1.50
1.0

1.00 (ref.)

Prevalence rate ratio

Prevalence rate ratio

P Raggi et al.: Vascular calcification and PWV

2.10
(0.81, 5.21)

1.46
(0.57, 3.71)

5.0
4.0
3.0

P -trend=0.11

2.0
1.50
1.0
0.75

1.00 (ref.)

0.75
<100

100999

<135

?1000

1.03
(0.52, 2.04)

5.0
4.0

1.42
(0.67, 3.01)

3.0
2.0

1.65
(0.82, 3.33)

P -trend=0.13

1.50
1.00 (ref.)

1.0

2.0
Prevalence rate ratio

Prevalence rate ratio

1351924

?1925

Tertile of thoracic aorta calcium score

Coronary artery calcium score

0.89
(0.45, 1.76)

1.5
1.00 (ref.)

1.0
P -trend=0.72

0.75
0.50

0.75
0

16

?7

Abdominal aorta calcification score

0.25

Number of calcified valves

Figure 3 | Multivariate-adjusted prevalence rate ratio of PWV X12 m/s associated with increased vascular calcification. Prevalence rate
ratios are adjusted for age, race, diabetes mellitus, pulse pressure, systolic blood pressure, and use of calcium acetate.

such as aging (probably linked to atherosclerosis development and change in collagen content in the vessel wall15), and
deposition of advanced glycation end products in diabetes
mellitus. Earlier studies21,22 have indeed demonstrated that
use of breakers of advanced glycation end cross-links reduces
PWV. Additional mechanisms may be responsible for
increased PWV in CKD-5, namely the extensive amount of
calcification found in the vessel wall of these patients. Such
extensive calcification is because of both heavily calcified
atherosclerotic plaques23 and calcification of the muscular
media layer of the vessel wall.24 Calcification of the media
muscularis that occurs mainly in capacitative vessels25 is the
probable explanation for the very good correlation we
observed between aortic PWV and calcification of the aorta.
The association between aortic PWV and coronary artery
calcification, albeit weak, suggests that aortic PWV is a
marker for the development of atherosclerotic coronary
artery disease, as proposed in the general population.26
Congestive heart failure and sudden death are the most
frequent causes of cardiovascular death in hemodialysis,
followed by acute myocardial infarction, stroke, and
peripheral arterial disease (http://www.usrds.org/2006/ref/
H_morte_06.pdf). Increased aortic stiffness induces left
ventricular hypertrophy, which is accompanied by the
formation of islands of myocites among strands of fibrous
tissue, creating an optimal condition for induction of
reentrant arrhythmias.27,28 These two conditions, hypertrophy and fibrosis, may therefore predispose to the development of congestive heart failure and sudden death.
It has been shown that there exists a good correlation
between PWV and bone demineralization in CKD-5
Kidney International (2007) 71, 802807

patients,29 suggesting an interaction between bone and


vascular disease. Indeed, derangements in mineral metabolism and bone remodeling are almost ubiquitous and have
been linked to the development of cardiovascular calcification,8,24,30 and adverse events in CKD-5.1012 Appropriately,
treatments directed at reducing progression of vascular
calcification and inhibiting the effects of secondary hyperparathyroidism with phosphate binders12 and calcimimetics
are being investigated. The reason for a lack of association
between PWV and valvular calcification is likely multifaceted.
We did not use a quantitative tool to assess valvular
calcification but rather a binomial approach (present versus
absent). There were relatively few patients with this type of
pathology and, ultimately, the relationship between vascular
stiffness and valvular disease may be very distant. Although
valvular disease is currently thought to resemble atherosclerosis in subjects with normal renal function,31 the
calcification of valves in renal failure may involve different
processes.
There were a few limitations to our study. First, this was
an observational study and, as such, patients differed with
respect to a few characteristics. Second, the relatively small
sample size may have prevented some of the detected
associations from being statistically significant at the
Po0.05 level. Despite these limitations, this is the largest
and most homogeneous group of hemodialysis patients
studied to date with a variety of diagnostic tools trying to
address their relative association.
In summary, PWV is closely associated with radiological
measures of abdominal aorta calcification, even when
assessed with plain X-ray films, and less strongly associated
805

original article

with thoracic aorta and coronary artery calcification. These


data provide evidence of a good correspondence between
functional and structural assessment of vascular disease in
CKD-5. Hence, the presence of abdominal aorta calcification
on a lateral X-ray film of the lumbar spine may provide a
good indication of the presence of increase vascular stiffness
and the attendant increased cardiovascular risk.
MATERIALS AND METHODS
Patient selection
Consecutive, prevalent, adult hemodialysis patients were recruited at
one community center in Denver, Colarado, and one academic,
tertiary referral center in New Orleans, Louisiana. All patients gave
informed consent to participate in this study, which was approved
by the local internal review board. All ethical principles as listed in
the declaration of Helsinki32 on human subjects research were
closely followed.
Demographic and clinical data were collected from the patients
chart at enrollment and included age, sex, race, hemodialysis
vintage, history of diabetes mellitus, hypertension, dyslipidemia,
smoking habit, cardiovascular history including angina, myocardial
infarction, revascularization, vascular surgery, or heart failure, and
current medications. Systolic and diastolic pressure were obtained in
the supine position after 1520 min rest and measured from the arm
that did not contain an arterio-venous fistula or a shunt. Arterial
blood pressure was measured with a manual sphygmomanometer
and pulse pressure was assessed as the difference between peak
systolic and trough diastolic arterial pressure.
Of 152 enrolled participants, medical history information was
missing for two participants and hence excluded. We also excluded
five participants who did not undergo a PWV measurement, and six
who had a PWVo3 m/s, a level consistent with a measurement or
recording error. Of the remaining 139 patients, we excluded six
participants who did not undergo electron beam CT imaging of the
coronary arteries and thoracic aorta or lateral lumbar spine X-ray
imaging, and two participants who did not undergo an echocardiographic study. In total, 131 patients had complete data and
constitute the cohort represented in the current analysis.
Electron beam CT imaging
Electron beam CT was performed according to a standard protocol
as described previously.9,33 In brief, 4050 consecutive slices, 3 mm
thick, were obtained from the top of the aortic arch to the
diaphragm. Tomographic imaging was performed at end inspiration
and timed to 60% of the R (wave)-to-R interval on the surface
electrocardiogram. A calcium score for each calcific focus with a
radiographic attenuation X130 HU was calculated according to the
Agatston method.34 The total calcium score for the coronary arteries
and the thoracic aorta, separately, was calculated as the sum of all
individual foci in each vascular territory. The inter- and intrareader
reproducibility of this method is approximately 810%.35 The total
radiation dose administered with electron beam CT was about
1.0 mSv (total recommended dose is 5 mSv yearly for nonmedical
personnel). All scans were reviewed by two experienced investigators
(PR and AB) and a consensus was reached on interpretations of all
results.
Abdominal aorta imaging with plain radiography
The lower abdominal aorta was imaged on lateral lumbar X-rays as
described by Kauppila et al.36 A lateral plain radiograph of the
806

P Raggi et al.: Vascular calcification and PWV

abdomen was obtained and the aorta was identified as the tubular
structure coursing in front of the anterior surface of the spine. We
utilized a semiquantitative scoring system assigning 13 points to
areas of calcification identified along the anterior or posterior
surface of the aorta extending from the 1st to the 4th lumbar
vertebra.36 The points were assigned as follows: 1 for a small 2 for a
moderate and 3 for a large size calcification according to the length
of each calcified plaque with respect to the craniocaudal length of
the closest vertebra. With this method, the score could vary from a
minimum of 0 to a maximum of 24 points. All X-rays were read by
two investigators (EF and AB) and a consensus was reached on the
interpretation of all films.
Echocardiography
Bi-dimensional echocardiographic studies were performed utilizing
Sequoia 512 (Siemens, Erlangen, Germany) or Vivid 7 (General
Electric, Milwaukee, WI, USA) equipment. Digital loops were
acquired in the long- and short-axis parasternal views, and the
apical four and two-chamber views and stored on magnetic optical
disks for future review. Aortic and mitral valve calcification was
simply assessed as present or absent without applying any
quantification method. All echocardiograms were read by two
experienced investigators (PR and AB) and a consensus was reached
on the interpretation of all tests.
Aorta PWV measurement
PWV was assessed by applanation tonometry with the Sphygmocor
Vx software (AtCor Medical, Sydney, Australia). We measured PWV
within 24 h from the midweek dialysis section after 5 min of bed
resting and this was done systematically in all patients. PWV was
derived using a standard methodology. The first step consisted of
measuring the distance between the sternal notch and the carotid
pulse. We proceeded to measure the distance between the sternal
notch and the femoral artery pulse, and subtracted the first from the
latter measurement. This provided an approximation of the distance
between the heart and the femoral artery. With the tonometer, we
then assessed the timing of the carotid and femoral arterial pulse
upstroke in relation to the R-wave on a simultaneously acquired
electrocardiogram. The time difference between the R-wave and
pressure upstroke at each arterial site was then computed by the
Sphygmocor Vx software and used in the calculation of conduction
velocity (velocity distance between the heart and femoral artery
divided by the time difference between R-wave and pressure
upstroke at each site). As no standard definition for elevated PWV
exists, high PWV was defined as the highest quartile of the
distribution (i.e., PWVX12 m/s). This cut point is consistent with a
finding by Blacher et al.,17 who showed a PWVX12 m/s to have a
significant negative prognostic impact on the survival of CKD-5
patients.
Statistical analyses
The characteristics of the study population are presented as means
for continuous variable and percentages, for the overall population,
and for participants with PWVo12 and X12 m/s, separately. Also,
the distribution of concomitant medication use for these groups was
calculated. Differences across PWV categories were obtained after
adjustment for age by linear regression and binomial regression for
continuous and dichotomous variables, respectively. The median
coronary artery and thoracic aorta calcium scores, separately, were
calculated for persons with PWVo12 and X12 m/s. Coronary
artery calcium scores were divided into three levels (o100, 100999,
Kidney International (2007) 71, 802807

original article

P Raggi et al.: Vascular calcification and PWV

and X1000) based on cut points that have been shown to be


associated with increased cardiovascular disease incidence in general
population studies. As no accepted cut points exist, thoracic aorta
calcium scores were divided into tertiles (o135, 1351924, and
X1925). The abdominal aorta calcification score was divided into
approximate tertiles (scores of 0, 16, and X7). Approximate tertiles
were utilized because 44% of the study population had scores of 0.
Mean PWV was calculated by level of abdominal aorta, thoracic
aorta, and coronary artery calcium score and number of valves with
calcification. Next, age and multivariate-adjusted differences in
PWV across levels of abdominal aorta, thoracic aorta, and coronary
artery calcium score were determined using the lowest level as the
reference. Similar analysis was also performed for the number of
valves with calcification. Variables associated with PWV (Po0.20;
age, race, diabetes mellitus, systolic blood pressure, pulse pressure,
use of calcium acetate, serum phosphate, and the product Ca  P)
were included in the multivariate-adjusted regression model. Finally,
the multivariate-adjusted prevalence rate ratio of PWV X12 m/s
associated with each calcification measure was calculated as a ratio
of the predicted marginals obtained from a logistic regression
model. This method has been shown to provide an accurate estimate
of the relative risk for cross-sectional studies. Standard errors of the
prevalence rate ratio were calculated using Taylor series approximation methods. Data analysis was performed using SAS version 9.1
(SAS Corporation, Cary, NC, USA).

12.

13.

14.
15.
16.

17.
18.

19.

20.

21.

22.

23.

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