(Stroke. 1997;28:1972-1980.)
© 1997 American Heart Association, Inc.
Articles |
Reproducibility of Ultrasonographically Determined Intima-Media Thickness Is Dependent on Arterial Wall Thickness
The Tromsø Study
From the Institute of Community Medicine, University of Tromsø (Norway).
Correspondence to Eva Stensland-Bugge, Institute of Community Medicine, University of Tromsø, N-9037 Tromsø, Norway. E-mail eva.stensland-bugge{at}ism.uit.no
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose We compared the reproducibility of B-mode ultrasonographic measurements of intima-media thickness (IMT) in various segments of the right carotid artery and examined whether measurement error was associated with IMT or cardiovascular risk factor levels.
Methods In 1994/1995 a total of 6676 participants in the Tromsø Study underwent ultrasound examination of common carotid artery IMT. Reproducibility of measurements was assessed by inviting 111 participants to a second ultrasound scan within 3 weeks of the first scan. On each occasion the subjects were examined by three sonographers.
Results The mean between-observer absolute differences in IMT in the far wall of the bifurcation and the near and far walls of the common carotid artery were 0.15, 0.10, and 0.08 mm, respectively. The corresponding within-observer differences were 0.15, 0.10, and 0.06 mm, respectively. Approximately 70% to 80% of total measurement variability was due to differences among sonographers; the rest was attributable to within-reader variability. Measurement error increased significantly with increasing IMT: the increase was more than twofold over the range of measurements. Cardiovascular risk factor levels were not associated with measurement variability when we controlled for IMT.
Conclusions We conclude that B-mode ultrasound provides reproducible estimates of the IMT in both the near and far walls of the carotid artery. Although measurement error is generally small, it increases proportionally with the level of IMT.
Key Words: atherosclerosis • carotid arteries • ultrasonics
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Measurements of carotid artery IMT by use of ultrasound are increasingly used to assess the extent and severity of atherosclerosis in the carotid arteries,1 2 3 4 and several lines of evidence suggest that ultrasonographically determined IMT is a valid way to study early atherosclerosis.5 6 7 8 9 Ultrasound is preferable to arteriography because it is noninvasive, carries no risk for the examined subject, and can detect atherosclerosis as an increase in arterial wall thickness before a reduction in lumen diameter occurs. The usefulness of ultrasound therefore appears to depend critically on the precision with which the IMT can be measured. A number of factors contribute to measurement reliability, including ultrasound instrumentation and reader performance, but the dependence of B-mode image quality on interrogation angle and fine adjustment of instrument controls makes the role of the sonographer crucial to the measurement process.
Previous studies have reported that the IMT of the far wall of the CCA can be measured with mean absolute differences on repeated measurements ranging from 0.09 to 0.18 mm, and there is a general agreement in the literature that ultrasound provides highly reproducible data.10 11 12 13 However, reproducibility studies on the ultrasound method have mainly looked at average performance and with a few exceptions have not examined the possibility of patient factors being associated with measurement error. Results from the Rotterdam Study indicate that the scatter of the differences increases with increasing thickness of the carotid far wall intima-media complex.14 Reproducibility of ultrasonography may therefore critically depend on the characteristics of the study population.
The Tromsø Study was started in 1974 and is a prospective population-based study with repeated assessment of cardiovascular risk factor levels in the population.15 16 17 In 1994/1995 ultrasonography of the carotid artery was performed on 6720 subjects. High-quality images of the CCA and the carotid bifurcation were obtained in 6676 (99.3%) and 6314 subjects (94.0%), respectively. To determine the effect of sonographer and reader performance on IMT measurements, we assessed both within- and between-observer reproducibility in different locations of the carotid artery. We also examined the determinants of measurement variability. All images were analyzed in Gothenburg (Chalmers University of Technology) with the aid of a newly developed computerized automatic reading system developed at the Wallenberg Laboratory for Cardiovascular Research.18 19
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Design and Subjects
The Tromsø study was started in 1974 and is a single center prospective follow-up study of inhabitants in the municipality of Tromsø, Norway. The aims of the study are to investigate, by means of epidemiological, clinical, and basic research, determinants of chronic diseases to assess etiologic significance and to investigate potentially modifiable determinants that may be developed into preventive or therapeutic strategies. The main focus is on cardiovascular diseases. The study design includes repeated population health surveys to which total birth cohorts and random samples are invited. The study was approved by the regional board of research ethics, and each subject gave informed consent.
The fourth survey of the Tromsø population started in September 1994
and was completed in October 1995. The survey was conducted by the
University of Tromsø in cooperation with the National Health Screening
Service and comprised two screening visits with an interval of 4 to 12
weeks. All inhabitants older than 24 years were invited to the first
visit, and 27161 subjects (77% of the eligible population)
participated. A protocol similar to that used in the previous surveys
in this population15 16 17 and the Norwegian county
studies20 was followed. The examination included
standardized measurements of height, weight, blood pressure, nonfasting
serum lipids, serum calcium, 
-glutamyltransferase, hemoglobin and
blood cell counts, and a 20-second ECG of lead I. Two questionnaires
covered previous and present diseases and symptoms, use of drugs,
lifestyle (physical activity, smoking, alcohol intake) and dietary
habits, and socioeconomic situation. All subjects aged 55 to 74 and
random 5% to 10% samples in the other age groups were invited to the
second visit. A total of 6891 subjects (98% of those who came to the
first visit and were eligible for the second visit) attended. The
second visit comprised ultrasonographic examination of the carotid
artery and the abdominal aorta, echocardiography, a
12-lead resting ECG, a 90-second eight-lead rhythm ECG during
standardized deep breathing, measurements of bone density, body fat
composition, waist and hip circumference, sitting and standing blood
pressures, and urine and blood sampling.
The Reproducibility Study
The reproducibility study was designed to study variability in
IMT measurements between sonographers (different sonographers on the
same occasion), within sonographers (same sonographer on two separate
occasions), and within reader (same reader on two separate occasions)
in the beginning (first reproducibility study) and the end (second
reproducibility study) of the survey period. We use the term
"observer" variability to describe the sum of measurement error
due to sonographers (ie, the scanning process) and the reader (ie, the
off-line reading of images). A total of 111 subjects were invited to
the two reproducibility studies. All of them participated, but some met
only once. The total number of subjects with paired measurements was
101 (75 in the first and 26 in the second reproducibility study).
The subjects were examined by the same three sonographers on two occasions with an interval of 1 week (weeks 10 and 11) in the first and 3 weeks (weeks 37 and 40) in the second reproducibility study. The sonographers were blinded to each other's results and to medical information about the participants. One of the sonographers was a neurologist with 10 years' experience in ultrasound examination of the carotid artery, the second was a physician, and the third was a specially trained technician. A 2-month training session during which the neurologist instructed the other sonographers according to a protocol described by Wendelhag et al10 was completed before the survey started. In addition, the first 200 survey examinations conducted by the physician and the technician were supervised by the neurologist.
To assess the within-reader variability, images from the first scanning of the 80 subjects in our first reproducibility study were reread by the same reader who performed the initial reading. He was blinded to the participants' characteristics and the results of previous readings. A separate comparison study has been performed at the Wallenberg Laboratory to compare this reader with other experienced readers. The coefficients of variation for IMT measurements in the far walls of the CCA and the carotid bifurcation were 1.3% and 2.3%, respectively, indicating satisfactory agreement.
Ultrasonographic Scanning
IMT measurements of the right carotid artery were obtained with
the use of a high-resolution ultrasound Acuson 128 XP/10 c scanner
equipped with a linear transducer with 7 MHz in B-mode and 5 MHz in
pulsed-Doppler mode. The system provides an optimal axial
resolution of approximately 0.20 mm. The subjects were examined in
the supine position with the head turned approximately 45 degrees to
the left. The angle of examination was mainly antero-oblique and
lateral, occasionally postero-oblique, depending on which angle gave
optimal visibility of the thickest part of the arterial
wall. The scanning procedure lasted 15 to 20 minutes.
The boundaries of the different layers of the carotid artery wall can
be visualized with high-resolution B-mode ultrasonography. On a
longitudinal ultrasound image of the carotid artery, both the near and
the far walls have a double-line pattern with two parallel echogenic
lines separated by a small hypoechogenic space (Fig 1
). The first echo on the far wall arises
from the lumen-intima interface, while the second arises from the
media-adventitia interface. The upper demarcation line of an echo is
defined as the "leading edge" (near edge) and the lower
demarcation line as the "trailing edge" (far edge). The distance
between the leading edge of the first line (line 4 in Fig 1) and the
leading edge of the second line (line 5 in Fig 1) of the far wall
corresponds to the combined IMT.
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Initial cross-sectional and longitudinal scans of the common, the external, and the internal carotid arteries were made to investigate anatomic relations. The carotid artery was then scanned for the presence of plaques (defined as a focal widening of the IMT relative to adjacent segments) starting approximately 3 cm proximally to the bifurcation and extending approximately 2 cm distally to the tip of the flow divider into the internal carotid artery. Atherosclerotic plaques in the near or far wall of the internal carotid artery (the starting point of the internal artery was defined as the tip of the flow divider), the bifurcation, and the CCA were recorded, and the maximal plaque thickness was measured on-line by use of electronic calipers.
The carotid artery was then scanned to find optimal images for IMT
measurements. If possible, plaques were included in the images of the
IMT. We attempted to visualize both the near and the far walls of the
artery simultaneously. To guarantee true proportions of the
IMT and lumen diameter, we aligned the ultrasound transducer so that it
crossed the axis of the vessel, since only in this projection are
the inner echoes of both the near and far walls clearly visible. The
loss of parallel configuration of the near and far walls of the CCA
served as a reference point for the start of the carotid bifurcation.
This point was marked on-line by an arrow (Fig 1
). Three frozen images
of IMT from both the bifurcation and the CCA were stored on
high-resolution S-VHS videotape for off-line analysis. To
minimize variability in IMT during the cardiac cycle, image capturing
was standardized by recording images at the top of the R wave
in an ECG signal. A short sequence of real-time images from the
bifurcation and the CCA was also stored on videotape.
Automated Measurement of IMT and Lumen Diameter
The stored ultrasonic images were analyzed off-line by a
newly developed computerized technique for automated ultrasonic image
analysis.18 19 The video images were digitized by
a frame grabber (VideoRaptor, BitFlow Inc) attached to a personal
computer and stored on disk for subsequent automated analysis.
The automated analysis system combines echo density, edge
strength, and edge continuity of the boundaries to decide the exact
location of the boundaries.18 Estimated values of the
boundary features are included as weighted terms in a cost function.
The boundary detection algorithm inspects all points (pixel) in the
image and gives favor to those boundary pixels that minimize the cost
function. The precision with which an individual cursor line can be
placed on a boundary is defined by the pixel dimension (approximately
0.07 mm) of the digitized image. The interfaces were marked
automatically and were, if necessary, manually modified (Fig 1). The
real-time images were available on a second monitor so that
interpretation of the static images could be integrated with the moving
images on tape.
A 10-mm wall segment on both sides of the demarcation arrow separating
the CCA and the bifurcation was measured, including the near and far
walls of the CCA and the far wall of the bifurcation. IMT of the far
wall is defined as the distance between the leading edge of the
lumen-intima interface and the leading edge of the media-adventitia
interface (Fig 1, lines 4 and 5). In the near wall the adventitia-media
interface is not easily identifiable because it interferes with the
periadventitia-adventitia interface.10 To try to get an
estimate of IMT in the near wall, we measured IMT as the distance
between the trailing edge of the periadventitia-adventitia interface
and the trailing edge of the intima-lumen interface (Fig 1, lines 1 and
3). The computer program estimated the maximum, minimum, and average
IMT along the 10-mm segment. The mean of the average, maximum, and
minimum IMT of the three frozen images was calculated and used in the
analysis. We also measured the lumen diameter of the CCA,
defined as the distance between the leading edge of the near wall
intima-lumen interface and the leading edge of the far wall
lumen-intima interface (Fig 1, lines 2 and 4).
Cardiovascular Risk Factors
Height and weight were measured with the subjects in light
clothing without shoes. Blood pressure was recorded by a specially
trained technician using an automatic device (Dinamap Vital Signs
Monitor 1846, Critikon Inc) before the ultrasound examination and blood
sampling. Nonfasting serum total cholesterol and
triglycerides were analyzed by enzymatic
colorimetric methods with commercial kits (CHOD-PAP for
cholesterol and GPO-PAP for triglycerides;
Boehringer-Mannheim). Serum HDL cholesterol was
measured after the precipitation of lower-density lipoprotein with
heparin and manganese chloride. The analyses were done at the
Department of Clinical Chemistry, University Hospital of Tromsø.
Information about current cigarette smoking was obtained from a
self-administered questionnaire.
Statistical Analysis
Between- and within-observer variability was estimated by
calculating the mean arithmetic difference and the mean absolute
difference between repeated measurements on the same subject. ANOVA
(the GLM-procedure in SAS21 ) with IMT as dependent
variable and subject (n=111), time (two levels), observer (three
levels), and interaction terms of time by subject and observer by
subject was used to determine the SDs of between- and within-observer
differences (Tables 2 and 3). This procedure was used to exclude
intersubject variability from variability caused by measurement error.
To examine whether the mean and SD of the arithmetic difference were
reasonably constant throughout the range of measurements, we plotted
the arithmetic difference between repeated measurements against their
average according to Bland and Altman.22 If the
differences are normally distributed, 95% of the differences will lie
within a range of ±1.96 SD of the mean arithmetic difference. This
range will be referred to as "the limits of agreement". The CV
describes measurement error as a percentage of the pooled mean value
(¯x) and is calculated according to the formula
CV=(s*100/¯x)%. The standard deviation (s) of the
measurement error is calculated according to the formula
s=SD/
. Variance component analysis was used to
determine which part of the variability could be attributed to between
subject variability and which part to measurement imprecision. The
association between measurement error (mean absolute difference in IMT)
and cardiovascular risk factor levels was examined by
computing Spearman rank order correlation coefficients. Means were
compared by ANCOVA with age as covariate. Two-sided values of
P<.05 were considered to indicate significance. The SAS
software package21 was used.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Measurements of IMT of the CCA and the bifurcation could be obtained in all subjects participating in the reproducibility study. The mean (range) IMT in the reproducibility-study was 0.71 mm (0.44 to 1.74 mm) in the far wall of the CCA, 0.77 mm (0.45 to 1.70 mm) in the near wall of the CCA, and 1.00 mm (0.46 to 2.23 mm) in the far wall of the carotid bifurcation (Table 1
). Participants in the reproducibility
study were slightly younger than the total study population (Table 1).
The reason is that very old persons were not invited to participate in
the reproducibility study because the subjects had to undergo two
extensive examinations. When we controlled for age there were no
significant differences across the two groups.
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Between-Observer Variability
The mean arithmetic differences among observers were generally
small and showed little variation between vessel wall locations or
between the two reproducibility studies (Table 2). The mean (SD) arithmetic differences
in IMT, computed as the average of three locations, for the three pair
of observers were -0.02 (0.17 ) (technician versus physician), 0.01
(0.17 ) (physician versus neurologist) and -0.01 (0.16) mm
(technician versus neurologist), indicating that there were no
systematic differences between observers. The mean absolute difference
and the SD were higher in the bifurcation than in the CCA (Table 2),
suggesting greater scattering (ie, lower precision) of the measurements
with increasing IMT. Interestingly, the measurement precision values of
the near and far walls of the CCA were similar. Lumen diameter was
measured with low between-observer variability. Absolute differences
between observers in measurements of lumen diameter were significantly
correlated with mean lumen diameter, but this association disappeared
with logarithmic transformation of the lumen diameter values (data not
shown).
Figs 2 and 3 show that
between-observer variability is skewed and increases with increasing
level of IMT. For the far wall of the CCA the CV is 4.8 when IMT is
below the median value (0.68 mm), whereas the CV is 8.4 at IMT
above the median value (Fig 2, top panel). The limits of agreement,
defined as the range around the mean arithmetic difference where 95%
of the differences lie, are ±0.08 mm when IMT is below the median
value, whereas they are ±0.20 mm when IMT is greater than the
median value (Table 4). The same trends are found with measurements in
other locations. Generally the limits of agreement for measurements of
IMT thicker than the median value were about twice as large as when IMT
was thinner than the median value (Fig 2, Table 4). The strong
relationship between measurement error and the level of IMT is further
illustrated in Fig 3, which shows that the absolute difference between
observers increases significantly with IMT (top panel). The association
remained significant after we standardized the measurement error by
taking the absolute difference as a percentage of the average IMT
(bottom panel). Also, the measurement error remained significantly
associated with the level of IMT after logarithmic transformation of
the IMT values (r=.33, P=.0001) (data not shown).
The between-observer limits of agreement for IMT in the far wall of the
carotid bifurcation were ±0.35 mm in subjects with
atherosclerotic plaque(s) and ±0.20 mm in subjects without
plaque(s).
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Within-Observer Variability
Within-observer variability tended to be lower than
between-observer variability, and the mean arithmetic differences
between repeated measurements of the same subject by the same observer
were small (Table 3). The mean (SD)
arithmetic differences in IMT (average of three locations) were -0.01
(0.18), -0.02 (0.15), and -0.02 (0.15) mm for the neurologist,
the physician, and the technician, respectively, indicating that there
was no systematic difference between measurements by the same observer
on two occasions. Within-observer variability was similar in the
beginning and end of the survey period (Table 3). All measures of
scatter, such as the mean absolute difference and the SD, increase with
increasing IMT (Table 3, Fig 4). In Fig 4
the within-observer difference is plotted against the mean of replicate
measurements for each observer. For the far wall of the CCA the CV is
3.6 when IMT is below the median value, whereas the CV is 5.9 when IMT
is above the median value (Fig 4, top panel). The limits of agreement
increase from ±0.06 mm for IMT below the median value to
±0.14 mm for IMT above the median value (Table 4). The same trends are found with
measurements in other locations. Generally the limits of agreement for
measurements of IMT thicker than the median value were approximately
twice as large as for when IMT was thinner than the median value (Fig 4, Table 4). There was a significant association between
within-observer measurement error and the level of IMT before
(r=.32; P=.0001) and after (r=.26;
P=.0002) logarithmic transformation of the IMT values. The
within-observer limits of agreement for IMT in the far wall of the
carotid bifurcation were ±0.41 mm in subjects with
atherosclerotic plaque(s) and ±0.21 mm in subjects without
plaque(s).
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Maximum IMT
The mean (SD) maximum IMT was 0.89 (0.24) mm in the far wall
of the CCA and 1.41 (0.66) mm in the far wall of the bifurcation.
The mean absolute difference between observers was 0.13 and 0.24
mm for the CCA and the bifurcation, respectively. The corresponding CVs
were 12.6 and 13.6, respectively. The within-observer CVs for
measurements of maximum IMT were 9.1 and 15.6 for the CCA and the
bifurcation, respectively.
Within-Reader Variability
The mean (SD) absolute within-reader differences for measurements
of IMT in the far and near walls of the CCA and the far wall of the
carotid bifurcation were 0.02 (0.02), 0.02 (0.03), and 0.03 (0.03)
mm, respectively (n=80). These values may be subtracted from the mean
absolute differences shown in Tables 2 and 3 to obtain the proportion
of measurement error that is attributable to the sonographers. The
within-reader variability did not increase with increasing IMT in the
CCA, but in the carotid bifurcation there was a statistically
significant correlation between mean absolute difference and mean IMT
(r=.49, P=.0001).
Measurement Variability and Cardiovascular Risk
Factor Levels
Measurement variability was not associated with
cardiovascular risk factors (age, sex, smoking
(yes/no), total cholesterol, HDL, systolic blood
pressure, body mass index, waist-hip ratio) in any location of the
carotid artery when we controlled for mean IMT (data not shown).
The variance component analysis revealed that 83.5% of the total variance in the IMT in the far wall of the CCA was caused by differences between subjects, whereas 16.5% was caused by between- and within-observer variability.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study shows that the IMT of the carotid artery can be measured without systematic difference between observers, whereas the precision of the measurements appears to be highly dependent on the level of IMT. The trend of poorer precision with increasing IMT was present in all segments of the carotid artery and was found both for between- and within-observer variability. In the carotid bifurcation, where the severity of atherosclerotic involvement is more advanced, there was a more than twofold increase in measurement error over the range of measurements. We studied a fairly large number of subjects in the setting of a population survey. The sonographers completed an extensive standardization program before the start of the reproducibility study and were blinded to each other's results, and the images were read with the use of an automatic program. The generalizability of the results therefore appears sound.
The measurement variability in our reproducibility study was small in relation to the biological variability between subjects. The values of the mean absolute difference between repeated measurements in the far wall of the CCA ranged between 0.06 and 0.10 mm, whereas IMT ranged between 0.44 and 1.74 mm in the same location. Reproducibility, measured in terms of both absolute difference and CV, was better for the CCA than for the carotid bifurcation. The arterial walls in the bifurcation are thicker and more prone to plaque development than in the CCA, and this apparently creates a higher degree of measurement variability. In addition, the arterial walls in the bifurcation are curved and therefore may create more scattering of the ultrasound beams. This leads to darker and less detailed images and occasionally nonvisualized interfaces. Within-observer variability was only slightly smaller than between-observer variability. This indicates that in our single center study with three sonographers, the variability in IMT on repeated measurement to a small extent is influenced by different sonographers.
There are several sources of measurement error. The most important
factor is probably the use of different interrogation angles during
sonography, which can lead to different judgments of where the vessel
wall is thickest. Another source of error is different opinions among
sonographers regarding the location of the beginning of the bifurcation
(Fig 1). This may be difficult to decide when the bifurcation shows
little divergence of the near and far walls. Since the
arterial wall in the carotid bifurcation is thicker than in
the CCA and plaques are more often located in the bifurcation,
misinterpretation of the beginning of the bifurcation can lead to
measurement variability. This is exemplified in the top panel of Fig 2.
The outlier at the lower right quadrant is caused by different opinions
among two sonographers about the location of the start of the
bifurcation in a subject with little divergence of the near and far
walls.
Reproducibility of IMT measurements in the near wall of the CCA has to
our knowledge previously only been presented in one
study.13 Interestingly, both that and the present
study indicate that reproducibility of the near and far walls is quite
similar. Prior studies have shown that the ultrasound-measured IMT of
the far wall reflects the anatomic intima-media layer.5 23
The IMT of the far wall is measured by using the leading edges of an
echo, and the location of the leading edge is on the same level as the
level of the interface that creates the echo.10 The IMT of
the near wall, on the other hand, is measured using the trailing edges
of an ultrasound echo. Prior studies have shown that the trailing edge
of an echo is not dependent on the anatomic structure only but also
depends on gain setting and other properties of the reading
system.10 24 Gamble et al24 showed that a
10-fold increase in gain (from 0.2% to 2% of maximum gain) resulted
in a 50% increase in the width of an ultrasound echo in the carotid
artery but did not affect the position of the leading edges. In our
study gain setting was continuously changed during the scanning
procedure to obtain optimal images, but despite this the
reproducibility of the near wall IMT measurements was good. We kept the
gain setting at the lowest possible level maintaining good-quality
images, and it is possible that our small changes in gain did not
affect the width of the ultrasound echo. An alternative explanation is
that the two trailing edges in the near wall (lines 1 and 3 in Fig 1)
are displaced parallel when gain is varied, so that the thickness of
the intima-media complex is not altered significantly. The present
study suggests that the influence of gain setting on near wall IMT
measurements may not be as important as previously thought. However,
since the measurements of IMT in the near wall lack an anatomic
substrate, near and far wall measurements should be analyzed
separately. A multiple regression analysis of the present
data showed that age, sex, systolic blood pressure, smoking
(yes/no), and total cholesterol accounted for 31% and 34%
of the explained variability in mean IMT of the far and near walls of
the CCA, respectively. The present results as well as findings
showing that the variability of IMT progression estimates may be
lowered by 30% to 40% by using near wall measurements,25
indicate that examination of the near wall may provide additional
information and should be considered for inclusion in future
studies.
Previous studies have used different summary statistics to present the reproducibility of the data, such as the mean arithmetic or absolute differences, the correlation coefficient, or the CV. Comparison of results is therefore complicated. Also, the use of a single summary statistic provides limited information on the amount of agreement and may be misleading if the differences vary systematically over the range of measurements, as shown in the present study. The mean arithmetic differences will, if there is no systematic difference in measurement levels between repeated examinations, add up to a value near zero. However, the SDs of the mean arithmetic differences combined with the absolute differences provide a good estimate of the range of measurement error. The correlation coefficient measures the strength of a linear relationship between replicate measurements, not the agreement between them,22 and is therefore not a suitable indicator of reproducibility.
Table 5 shows a comparison of
reproducibility studies of carotid artery IMT. The CVs of the IMT of
the far wall and lumen diameter of the CCA are quite similar among the
studies. This indicates that the variability of measurements of IMT
only to a limited degree depends on differences in ultrasound equipment
and protocols across studies. In Table 5 the Tromsø values include
within-reader variability. In our study 70% to 80% of total
variability is due to sonographers, and the rest is attributable to the
reading process. The within-reader mean (SD) absolute difference of the
average of three locations in the present study was 0.02
(0.03) mm compared with 0.06 (0.05) mm in the
Asymptomatic Carotid Artery Plaque Study,26
and 85% of the differences in maximum IMT in the carotid bifurcation
were less than 0.13 mm, whereas in the
Atherosclerosis Risk in Communities study 85% of the
differences were less than 0.20 mm.27 This may
indicate that the automated computerized image analyzing system
developed by the group at the Wallenberg Laboratory at Sahlgrenska
University Hospital, Gothenburg, Sweden, presents less variability
than other reading systems.
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IMT is being used both as an exposure variable to predict cardiovascular disease and as an outcome variable to study the determinants of atherosclerosis. When measurement imprecision of the exposure variable occurs randomly (ie, independent of the outcome under study), the magnitude of an association between exposure and outcome may be underestimated. Statistical methods can to some degree correct for measurement error in the exposure to obtain more reliable estimates.28 29 In the present study measurement error did not occur completely at random but increased with increasing level of IMT and was associated with the presence of atherosclerotic plaques. Thus, our data show that when IMT is used as an exposure to predict atherosclerotic cardiovascular disease, errors in the classification of individuals by exposure produce a differential accuracy depending on disease status. Unfortunately, it is difficult to estimate the precise effect of nonrandom misclassification; it can result in a biased risk estimate that is an overestimate, an underestimate, or, by chance, the same as the true measure of association.30 It has been suggested that IMT values be transformed logarithmically,14 but our data indicate that this will not remove the association between measurement error and IMT level. When IMT is used as an outcome variable, measurement imprecision may lead to misclassification of subjects. In the present study measurement imprecision was not associated with risk factor levels, and misclassification will therefore be nondifferential and tend to weaken the association between risk factor and outcome.
In conclusion, our findings suggest that reproducibility of IMT measurements of the carotid artery is acceptable, but measurement error increases considerably with increasing IMT. Computer algorithms for automatic reading of images may be used to minimize reading error and improve reliability. Ultrasound may be a useful tool in epidemiological studies on the determinants of atherosclerosis and cardiovascular disease. However, the precision of the method must be improved before it can be used in the monitoring of atherosclerosis on an individual level. Performing replicate measurements and/or using a fixed angle of interrogation during sonography can do this, although the use of a fixed angle will probably lead to more missing values.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Norwegian Research Council. We are indebted to John Wikstrand and Inger Wendelhag at the Wallenberg Laboratory for Cardiovascular Research, Gothenburg University, Sweden, for introducing us to their ultrasound scanning methods. We are also indebted to Tomas Gustavsson and Quan Liang, Department of Applied Electronics, Chalmers University of Technology, Gothenburg, Sweden, for valuable help with the reading of the ultrasound images.
Received February 28, 1997; revision received May 12, 1997; accepted June 24, 1997.
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