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Published online before print February 21, 2008, 10.1148/radiol.2471062190
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(Radiology 2008;247:241-250.)
© RSNA, 2008


Technical Developments

Semiautomated Quantification of the Mass and Distribution of Vascular Calcification with Multidetector CT: Method and Evaluation1

Raghav Raman, MD, Bhargav Raman, BSc, Sandy Napel, PhD, and Geoffrey D. Rubin, MD

1 From the Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, S-072B, Stanford, CA 94305. Received January 8, 2007; revision requested March 1; revision received July 30; accepted August 27; final version accepted September 28. Supported by National Institutes of Health grants 1RO1HL58915 and 1RO1HL67194. Address correspondence to G.D.R. (e-mail: grubin{at}stanford.edu).


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Institutional review board approval was obtained for this HIPAA-compliant study. Informed consent was obtained for prospective evaluation in 21 asymptomatic volunteers (10 women, 11 men; mean age, 60 years) but waived for retrospective (10 patients with and five patients without disease) evaluation. Prospective validation was in phantoms. Quantification of mass and calcium distribution was performed with fast semiautomated method, without calibration. For actual versus measured mass in phantoms, R2 was 0.98; absolute and percentage errors were 1.2 mg and 9.1%, respectively. In asymptomatic volunteers, mean interscan variability for calcium mass quantification in extracoronary arteries was 24.9 mg; mean was 991 units for Agatston scoring. In coronary arteries, mean variability was 5.5 mg; mean Agatston variability was 27.7 units. At retrospective computed tomography, mean total calcified mass was 321.3 mg. Accurate quantification of mass and distribution of calcification in simulated arteries with this method can be applied in vivo, with low interscan variability.

© RSNA, 2008


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Arterial calcification as a manifestation of atherosclerosis has been found in a variety of vascular beds and appears to be an independent predictor of morbidity and mortality from coronary, cerebrovascular, and peripheral arterial disease (110). The distribution of calcification in the aortoiliac system has been shown to vary considerably, depending on age, sex, and comorbidities such as diabetes (6).

The speed and coverage of multi–detector row computed tomography (CT) allows imaging of most of the arterial system in a single scan (1113), presenting a unique opportunity to quantify arterial calcification as a measure of atherosclerotic burden. Determining the quantity and distribution of calcium in each blood vessel could allow the investigation of the relationships between the distribution of arterial calcium and a variety of behavioral, physiologic, pathologic, and genotypic conditions.

Among the methods that have been proposed for quantifying coronary calcium, quantification of the mass of calcium is reported to be more accurate and less variable than the classic Agatston score or the volume score (1418). Reported methods for the quantification of coronary calcium mass have been both threshold specific and scan protocol specific (17,18). For example, one method requires separate calibration scans by using a complex phantom that simulates small calcium fragments. Calibration is performed for each scanner and scan protocol and is used to obtain comparable measurements across different scanners and protocols. With the calibration scans, a correction factor is also calculated for each level of arterial contrast enhancement following intravenous contrast medium administration and is used to obtain comparable measurements that are independent of the level of arterial contrast enhancement (17). In addition, although these methods allow total mass quantification per vessel and per scan, they do not provide a detailed analysis of the size and distribution patterns of the calcium fragments.

Moreover, these methods for coronary arterial calcium quantification require the manual identification of individual calcium fragments. Thus, scaling these methods to the extracoronary arteries presents a challenge of practicality. CT studies currently performed for the quantification of calcification of the coronary arteries include less than 100 sections and take 10–15 minutes to process manually. Systemic arterial CT angiograms currently consist of hundreds to more than 1000 sections and, therefore, require substantially longer to process.

Our study purpose was to prospectively validate in phantoms and to prospectively and retrospectively evaluate in volunteers and patients, respectively, a fast semiautomated method we developed for quantification of the true mass and distribution of calcium in the systemic arteries, without the need for separate calibration scans for each level of arterial contrast enhancement and without the need for calibration with complex phantoms.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Semiautomated Method
We developed a semiautomated system that measures calcium mass on multi–detector row CT scans obtained by using contrast enhancement of the arterial lumen. Our algorithm consists of three stages. First, the lumen of the vessel is segmented. Second, all mural calcium fragments in the vessel wall are detected and localized to the arterial wall. Finally, the mass of each fragment is quantified.

Selection of arteries of interest.—Our algorithm first requires the user to identify the start and end points of vessels to be processed. This serves two purposes. It enables the bones to be excluded by using a previously developed algorithm that identifies and deletes structures that possess a shape and density distribution characteristic of bone (19). It then extracts median centerlines of the vessels of interest by using a previously published method (20) that has been shown in subsequent studies to be reliable (21,22). From the user-defined seed points, this algorithm automatically produces an initial branching path on the surface of the artery, from the start to the end points. The path then undergoes midline extraction and smoothing to produce branched median centerlines through the selected arteries.

Vessel segmentation.—From the centerlines, we define the volume occupied by the selected arteries, excluding other vessels and surrounding soft tissue. To accomplish this task, a list of centerline points is obtained by sampling the median centerlines at subvoxel intervals. The perpendicular vessel cross section through each of these points is then segmented by using the point as a seed for region growing, which is based on an adaptive threshold level computed from the voxel attenuation statistics near the seed point. The average size and shape of the previous five segmentations are used to constrain the subsequent segmentation from extending into adjacent veins or arterial branches. The segmented cross sections are then combined to obtain one composite vessel segmentation. To ensure inclusion of the wall of the vessel in the segmentation, all voxels within 10 mm of the surface of the segmentation that are not classified as bone (the "vessel surround") are added to the segmentation (Fig 1). Because the bony structures have already been excluded by a previous processing step, bone that is within 10 mm of the vessel is not included in the segmentation. Calcium fragments that are within 10 mm of the surface of the segmentation are included in the segmentation.


Figure 1
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Figure 1: Diagram depicts how calcium is localized. Fragment A protrudes into vessel lumen and is contained within segmentation of vessel lumen. All voxels within 10 mm of vessel segmentation not classified as bone (vessel surround) are added to vessel segmentation. Fragment B is in vessel wall but is still contained within vessel surround.

 
Calcium fragment detection.—To detect calcium fragments, a calcium detection threshold level is calculated. If one assumes a normal distribution of luminal voxel attenuation, a threshold level set at 1.64 standard deviations would theoretically exclude 90% of luminal voxels. Therefore, the calcium detection threshold level is set empirically at 1.64 standard deviations higher than the mean central vessel attenuation. Voxels within the segmentation that have attenuation higher than the calcium detection threshold level are extracted as mural calcium-containing voxels. All extracted voxels are then subjected to a connected-component analysis to group them into discrete calcium fragments. Large calcium fragments that partially extend beyond the volume defined by the segmentation will initially be only partially extracted.

In the process of connected-component analysis, these fragments are resegmented by using the same calcium detection threshold level to include the whole fragment. For this resegmentation step, voxels that are outside the vessel segmentation, higher than the calcium detection threshold level, and in continuity with the partially segmented fragment are also included as part of the fragment. Because only voxels higher than the calcium detection threshold level are selected, no soft-tissue voxels or luminal voxels are segmented as part of the calcium fragment. The user is then prompted to review the detected calcium fragments; delete any erroneously included fragments such as venous phleboliths, osteophytes, or dystrophic extravascular soft-tissue calcifications; and also add any fragments missed by the algorithm.

Mass quantification.—Mass quantification by using our algorithm is designed to be independent of the calcium detection threshold level and is the result of an extrapolation of the brightness-volume product (BVP) of individual calcium fragments at a series of attenuation threshold levels. The BVP of a fragment is defined as the average attenuation of the voxels in the fragment in Hounsfield units multiplied by the volume of the fragment in cubic millimeters. Since the average Hounsfield unit value of the fragment is used to calculate BVP, the various densities of calcium that compose the calcium fragment all contribute to the calculation of the average Hounsfield unit value. Therefore, the heterogeneity of the fragment does not affect the calculation of the BVP.

The following is performed for each fragment. An initial BVP is calculated at the calcium detection threshold value that is higher than the attenuation of surrounding soft tissue and contrast medium. This calculation excludes all soft-tissue voxels from the segmentation of the fragment. Then, the threshold level is increased iteratively by 10 HU, and the BVP is recalculated at each threshold level. This procedure is conducted until the BVP is 10% of the initial BVP. From the series of BVP measurements thus obtained, a best-fit line is calculated and extrapolated to calculate the theoretic BVP that would be obtained at a threshold level of 0 HU (Fig 2). At least five BVP measurements are used to calculate the slope of the best-fit line. If fewer than five measurements are obtained, the fragment is marked as unquantifiable.


Figure 2
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Figure 2: Transverse CT image of a 31-mg calcium fragment (arrows) on surface of aortic phantom. A, Phantom filled with water. B, Phantom filled with contrast medium (attenuation, 230 HU). Graph shows threshold level used to segment calcium fragment versus BVP measured at that threshold level. BVP values are calculated and plotted for threshold levels every 10 HU starting at calcium detection threshold level. C, Best-fit line is calculated and projected back to determine the theoretic BVP of the fragment at threshold level of 0 HU (BVP0). D, Line calculated with repetition of process for same fragment in contrast medium–filled phantom. Higher luminal contrast (attenuation, 230 HU) necessitates a higher minimum threshold level of 270 HU. Extrapolated BVP that would be obtained at 0 HU threshold level shows little mean relative variation (1.3%) between unenhanced and contrast-enhanced scans. HU-mm^3 = attenuation per unit volume.

 
The threshold level of 0 HU corresponds to material that has 0 mg/mL of calcium. If a threshold level of 0 HU is used, the BVP that is calculated can be used to calculate the actual mass of the fragment. However, because of the density of surrounding soft tissue and contrast medium, the minimum threshold level that allows exclusion of surrounding tissue is higher than 0 HU. With this method, we estimate that the BVP would be obtained at a threshold level of 0 HU by extrapolating data from the BVPs obtained at higher threshold levels.

To calculate the fragment mass from BVP that would be obtained at a threshold level of 0 HU, we used four homogeneous cylindric standards of known calcium density of 0 mg/mL (water attenuation), 50 mg/mL, 100 mg/mL, and 200 mg/mL. These were placed under the patient and included in the scan field. The densities of the standards expressed in milligrams per cubic millimeter were plotted against the attenuation of each standard in Hounsfield units. A line of best fit was computed by using these four measurements. The gradient G of the line of best fit was used to derive the mass of each fragment from the BVP that would be obtained at a threshold level of 0 HU (BVP0). Mass (in milligrams) was calculated as follows: G[mg/(HU · mm3)] · BVP0(HU · mm3).

This method of derivation of mass has two major elements that potentially reduce error and improve precision and simplicity. First, BVP is not calculated at any one threshold level; it is calculated at many threshold levels. We extrapolated these measurements to calculate the BVP at a threshold level of 0 HU (water attenuation). Second, simple in-scan density standards are used to calculate the gradient G. There is no need to obtain separate calibration scans by using complex phantoms that simulate small calcium fragments and there is no need to repeat these calibration scans for a range of arterial contrast enhancement levels. The algorithm is therefore designed to be both threshold level and protocol independent.

Calcium distribution.—For analysis of arterial calcium distribution, radial rays are projected from the median centerline to produce a flattened image map of the vascular surface, with the positions and shapes of the calcium fragments as seen from the centerline superimposed on the image (Fig 3). The first radial ray is projected in an anteroposterior orientation, and the subsequent rays are projected 360° around the center of the vessel, in a clockwise direction. The surface area of the vessel is calculated from the length and angular separation of the radial rays when they intersect with the luminal surface of the vessel.


Figure 3
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Figure 3: M, Calcium map along aorta and right iliac, femoral, and popliteal arteries. Vascular surface is virtually cut and laid flat and calcium fragments are visualized projected onto surface. Shade of gray of calcium fragments depicted on map is proportional to their Hounsfield unit value, with higher Hounsfield unit values yielding lighter shades of gray. N, Calcium distribution graph. Mass values are smoothed by a 10-mm moving average. Direct correspondence is observed between longitudinal position of aortoiliac through popliteal arteries on calcium map and x-axis of this graph. The y-axis indicates the total mass summed over arterial circumference relative to longitudinal position. A = start of aortic arch, B = start of descending thoracic aorta,C = celiac artery origin, D = superior mesenteric artery origin, E = origins of renal arteries, F = inferior mesenteric artery origin, G = aortic bifurcation, H = right common iliac bifurcation, and I = start of popliteal artery.

 
All data and images are stored in a relational database to allow statistical analysis and Web-based review. An interactive Web interface allows the image map to be presented with automatically generated graphs of calcium mass as a function of median centerline position. To facilitate interpretation, the user is able to point and click on the graph or the image map, allowing comparison of the graphic output and the image data (Fig 3). We implemented our system at a workstation that we built with two 1.67-GHz processors (Advanced Micro Devices, Sunnyvale, Calif) and 2 GB of RAM, running a commercial operating system (Windows XP; Microsoft, Redmond, Wash).

Validation
Physical phantom studies.—Because there is no noninvasive reference standard available for live subjects, we used a physical phantom to verify accuracy. Physical phantoms also allowed us to carefully control calcium mass. Three homogeneous solids with elemental calcium densities of 0.15, 0.30, and 0.45 mg/mm3 were created with calcium oxide and an epoxy resin base. The materials were mixed thoroughly before curing and were constantly shaken during the curing process to ensure homogeneity. Three cylindric standards were machined from each of the homogeneous solids. A fourth standard was made from epoxy resin that contained no calcium (attenuation, 40 HU).

To simulate the irregular fragment geometries encountered in vivo, irregular fragments were randomly chipped from the three solids. Twenty-four fragments representing a range in mass of 0.4–50 mg were selected to obtain a spectrum of mass value. The smallest fragment that could be accurately measured with our scale was 0.4 mg. The mean mass of all fragments was 15.12 mg. The fragments were then placed on the walls of four aortic phantoms. The walls of these cylindric phantoms were composed of low-density polyethylene (attenuation, –50 HU) with a thickness of less than 0.5 mm and were manufactured with a diameter of 35 mm. The phantoms were filled alternately with water and then with a dilute iodine solution (1:30 dilution of iohexol [Omnipaque; GE Healthcare, Milwaukee, Wis], 300 mg/mL, 200–250 HU). The phantoms were sealed at both ends with cork (attenuation, –800 HU) and made watertight by using polymer glue (attenuation, –50 HU).

The four phantoms and four standards were placed in a 25-cm-diameter water bath, with the phantoms positioned near the isocenter of the CT gantry (Fig 4). The standards were placed at the bottom of the phantom, adjacent to the CT table, to mimic the geometry used for patient scanning and, thereby, to generate similar artifact-causing conditions, such as scatter and beam hardening, that occur during patient scanning. The water bath was treated with a small amount of silicone solution to decrease bubble formation.


Figure 4
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Figure 4: Four cylindric standards (A–D) with known elemental calcium densities (A, 0.15 mg/mm3; B, 0.30 mg/mm3; C, 0.45 mg/mm3; and D, 0 mg/mm3). Eight fragments were chipped from each of the three solids used to create the standards containing calcium (A–C) and were placed in four aortic phantoms (1–4).

 
The phantoms were imaged with a 16–detector row CT scanner (Somatom 16; GE Healthcare), with 1.25-mm section thickness, 0.625-mm section spacing, pitch of 1.7, and 0.5-second rotation at 120 kV and 440 mA. The mass for each fragment on each scan was quantified by using the algorithm described previously and was compared with the actual mass of each fragment.

Prospective scans.—We quantified the precision of our algorithm and compared it with the traditional Agatston score by conducting a prospective study in volunteers who reported no history of vascular disease or symptoms attributable to vascular disease. According to a protocol approved by our institutional review board, 21 asymptomatic volunteers (11 men, 10 women; mean age, 60 years; range, 50–80 years) were recruited among employees and families of employees at Stanford University, Stanford, Calif. Identification information of volunteers was removed from all images to achieve compliance with the Health Insurance Portability and Accountability Act (HIPAA). The risks associated with the radiation from the CT scans were discussed with volunteers, and full informed consent was obtained. Because arterial calcium tends to develop 10 years later in women than it does in men, the women were selected to be 10 years older than the men to increase the likelihood that arterial calcium would be present in most of the subjects.

Each volunteer was positioned supine on the CT table over a body-contoured phantom containing three calcium hydroxyapatite reference samples (phantom density of 50, 100, and 200 mg/mL) and one water-equivalent reference (Image Analysis, Columbia, Ky). In the first 10 volunteers, two unenhanced CT scans were obtained, followed by the acquisition of a single contrast material–enhanced CT scan. In the subsequent 11 volunteers, one unenhanced CT scan was obtained, followed by the acquisition of two contrast-enhanced CT scans, to enable quantification of interscan variability on both unenhanced and contrast-enhanced scans. Depending on subject weight, 35–60 mL of nonionic iodinated contrast medium (concentration, 300 milligrams of iodine per milliliter) was delivered through an antecubital intravenous catheter, with the goal of achieving uniform arterial opacification during the entire scan duration.

On the basis of preliminary work performed by one of the authors (G.D.R.), a biphasic injection was delivered with an initial 5-second phase at a flow rate of 2–3 mL/sec and a subsequent 15–20-second phase at a flow rate of 1–2 mL/sec. Contrast-enhanced CT scans were triggered by using a bolus-monitoring algorithm. Once the enhancement in the aortic arch reached 100 HU, helical scanning was initiated with 16 detector rows and 1.25-mm section thickness (16 x 1.25), pitch of 1.3, 0.5-second rotation, 120 kV, and 100 mA, which resulted in a CT dose index of 5.34 mGy and a radiation dose of 5.9 mSv. The scan was initiated at the angle of the mandible and extended inferiorly to the proximal tibial diaphysis. Sections were reconstructed at 0.7-mm intervals, corresponding to approximately 50% of the full width at half maximum of the section sensitivity profile. These scans were used to quantify calcium in the extracoronary arteries.

In addition, a prospectively electrocardiographically triggered breath-hold CT scan was obtained through the heart with 16 x 1.25, which was electrocardiographically gated to 80% of the R-R interval. The scan was obtained with an x-ray tube potential and current of 120 kV and 100 mA, respectively, and a gantry rotation of 0.5 second, resulting in a CT dose index of 5.8 mGy and a radiation dose of 1.05 mSv. The data were reconstructed by using a half-scan reconstruction algorithm to give an effective temporal resolution of 250 msec per section. These scans were used to assess coronary calcium. To assess intrasubject variability of coronary artery calcium measurements, scanning was repeated once. The total dose to each volunteer from all five scans by using our low-dose protocol was approximately 19.8 mSv. This dose was smaller than the estimated dose of 27.5 mSv for a nonelectrocardiographically gated CT angiogram of the same territory by using our standard diagnostic protocol, which includes acquisition of an unenhanced scan followed by that of a contrast-enhanced scan.

On these scans, calcium mass was quantified by using our algorithm, and the Agatston score was calculated by using the published method (23). Calcium was quantified in the coronary arteries, the carotid arteries, the thoracoabdominal aorta, the renal arteries, the common and external iliac arteries, the femoral arteries, and the popliteal arteries. To simplify reporting, results were coalesced into the coronary and extracoronary arterial beds.

Retrospective patient assessment: feasibility in patients with disease.—This study was conducted with an approved protocol of our institutional review board; informed consent was waived, as patient images were collected retrospectively and identification information was removed to achieve compliance with HIPAA. To demonstrate the feasibility of our algorithm in patient data sets, we quantified the amount and distribution of abdominal aortic and iliac calcium on CT angiograms in 15 patients (nine men, six women; mean age, 52 years). Ten consecutive patients (mean age, 61 years) underwent CT angiography for preoperative evaluation of aortic aneurysms, and five consecutive patients (mean age, 30 years) underwent CT angiography to rule out traumatic aortic injury or aortic dissection and did not have known clinical manifestations of systemic atherosclerosis.

For all scan protocols, section thickness was 1.25 mm and section spacing was 0.8 mm, with 120 kV and 390–440 mA. In all cases, 100–150 mL of iodinated contrast medium (iohexol), 350 mg of iodine per milliliter, was injected at a rate of 4–5 mL/sec. All CT angiograms encompassed the entirety of the chest, abdomen, and pelvis. The mean aortic attenuation within the CT scans was 220 HU (range, 150–270 HU).

Because the scans were retrospectively chosen, calcium standards were not included in the scan field. As a result, the mass conversion factor was estimated from the density standards on other scans that were obtained with a similar scan protocol. These scans were obtained by searching our picture archiving and communication system for scans from other patients that had density standards included as part of other related research projects. These scans were obtained with the same scanner and the same scanning protocol and were used only to calculate calibration factors. Calibration was not performed on a section-by-section basis because the density standards were shorter than the scan range. Identification information was removed from all scans to meet HIPAA requirements.

Calcium mass statistics in patient studies were calculated per patient and per anatomic vascular segment by a single operator (R.R.), who is a radiology resident with 6 years of experience in cardiovascular CT research. The thoracic aorta was divided into three segments: ascending, arch, and descending. The abdominal aorta was divided into four segments, demarcated by the origins of the celiac artery, the most inferior renal artery, the inferior mesenteric artery, and the aortic bifurcation. In the pelvis, the left and right common and external iliac arteries were analyzed independently. The calcium content of each segment was determined, with and without normalization, by the total surface area of the segment.

The user interaction time, computer processing time, and review time required to analyze these images was recorded. To assess measurement precision relative to user-selected inputs, for each patient study, the effect of variation in user-selected points was simulated by selecting points within the volume of a sphere with a radius equal to the vessel radius, centered at each initially selected user point. The points were chosen along the radial direction, with each set of radial points 60° from the next set and spaced 1 mm apart in the radial direction. In so doing, we generated between 60 and 220 points, depending on the size of the vessel, and simulated variation in user input; the calcium quantification algorithm was repeated for each of these points. The number and mass of fragments detected by the algorithm for each pair of start and end points was recorded, and results were compared to quantify the effect of variation in the initial user inputs.

Statistical Analysis
In phantom studies, the relationship between the measured and actual mass of each fragment was quantified by using linear regression. Error was quantified in milligrams per fragment and as a percentage of fragment mass. The variability of mass measurement between unenhanced and contrast-enhanced scans was quantified in milligrams per fragment and as a percentage of fragment mass. Because fragment masses were not normally distributed, Wilcoxon signed rank tests were used to test the hypothesis that there was no difference between error on unenhanced scans and error on contrast-enhanced scans. A Wilcoxon signed rank test was also used to test the hypothesis that there was no difference in measured mass on unenhanced versus contrast-enhanced scans.

A two-tailed unpaired t test was used to test the hypothesis that there was no difference in percentage variability between small (mass, <4 mg) and large (mass, >4 mg) fragments. A large fragment was defined as a fragment with a mass of more than 4 mg because approximately one-half of the fragments (13) had actual masses of more than 4 mg, and the other half (11) had actual masses of less than 4 mg. Measurement bias was quantified by determining the signed error and signed percentage error for fragments on both the unenhanced and contrast-enhanced scans.

In prospective volunteer studies, interscan variability between paired unenhanced scans, between paired contrast-enhanced scans, and between paired unenhanced and contrast-enhanced scans for calcium mass was quantified in milligrams and as a percentage of mean calcium mass. For Agatston scores, this interscan variability was quantified in units and as a percentage of mean Agatston score. A two-tailed unpaired t test was used to test the hypothesis that there was no difference in percentage interscan variability for Agatston scores and for calcium mass.

In retrospective patient studies, the mean calcium content of each vascular segment was compared with the calcium content of the other segments by using a randomized block analysis, with each patient as a block. The null hypothesis was that the mean calcium content of each vascular segment was equal. Post hoc analyses were performed by using the Bonferroni method to compare the mean calcium content of each vascular segment with the calcium content of the other segments to test the hypothesis that the calcium content was significantly greater in one segment. Both these analyses were repeated after calcium mass was normalized to the surface area of each segment. For analysis of the effect of variation in user-selected points, error was quantified in milligrams per fragment and per scan. The statistical package (Analyze-It, version 1.73; Analyze-It Software, Leeds, England) for spreadsheet software (Excel; Microsoft) and statistical software (SPSS; SPSS, Chicago, Ill) was used for all statistical tests.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Phantom Studies
When our algorithm was used to calculate fragment mass, the R2, mean absolute error, and mean percentage error for measured versus actual mass for all scans were 0.98, 1.2 mg ± 1.6 (standard deviation), and 9.1% ± 5.9, respectively. The R2, mean absolute error, and mean percentage error for measured versus actual mass for the unenhanced scans were 0.99, 1.0 mg ± 1.4, and 9.1% ± 5.1, respectively, and the R2, mean absolute error, and mean percentage error for measured versus actual mass for contrast-enhanced scans were 0.95, 1.4 mg ± 1.9, and 9.1% ± 7.0, respectively. The difference in the absolute mass error and percentage mass error between contrast-enhanced and unenhanced scans was not significant across all calcium fragments (P = .845 and .948, respectively). Fragments more than 4 mg in mass had a mean absolute error of 1.7 mg ± 1.8 (mean percentage error, 8.6% ± 4.5), whereas fragments less than 4 mg in mass had a mean absolute error of 0.21 mg ± 0.26 (mean percentage error, 9.8% ± 7.8). The difference in mean percentage error between large and small fragments was not significant (P = .58).

All fragments were detected and quantified on the unenhanced scans. On the contrast-enhanced scans, six small fragments (mean mass, 1.08 mg ± 0.47; maximum mass, 1.50 mg) were not identified because their maximum Hounsfield unit value was lower than the mean attenuation of the opacified lumen of the phantom (attenuation, 275 HU). For statistical analysis, fragments that could not be detected were recorded as having a measurement error equal to the mass of the fragment. When we compared mass measurements between unenhanced and contrast-enhanced scans, the mean absolute variability for the 18 fragments detected on both unenhanced and contrast-enhanced scans was 1.8 mg ± 2.0 (mean percentage variability, 13.0% ± 7.2). The difference between mass measured by using unenhanced scans and that measured by using contrast-enhanced scans was not significant (P = .35). Mean absolute variability in mass measured between unenhanced and contrast-enhanced scans for fragments more than 4 mg was 2.3 mg ± 2.2 (mean percentage variability, 11.9% ± 7.1), and mean absolute variability for fragments less than 4 mg was 0.5 mg ± 0.3 (mean percentage variability, 16.1% ± 7.3). The difference in percentage measurement variability between large and small fragments was not significant (P = .28).

Mean signed error for measured versus actual mass for both unenhanced and contrast-enhanced scans was 0.35 mg ± 2.0 (mean percentage signed error, 0.61% ± 10.9). The mean signed error for measured versus actual mass for the unenhanced scans and the contrast-enhanced scans was 0.56 mg ± 1.6 (mean percentage signed error, 2.6% ± 10.2) and 0.08 mg ± 2.4 (mean percentage signed error, –2.1% ± 11.5), respectively. Fragments more than 4 mg in mass had a mean signed error of 0.64 mg ± 2.5 (mean percentage signed error, 2.0% ± 9.7), whereas fragments less than 4 mg in mass had a mean signed error of –0.10 mg ± 0.32 (mean percentage signed error, 1.6% ± 12.7). All confidence intervals for the signed errors included zero. Thus, a bias toward over- or underestimation of the mass was not found. The difference in percentage signed error between large and small fragments was not significant (P = .33).

Prospective Patient Scans
Five patients had no detectable extracoronary calcium on all scans, and three patients had no detectable coronary calcium on all scans. These patients were excluded from the analysis for interscan variability. The 16 patients with detectable extracoronary calcium had a mean calcium mass of 472.9 mg ± 688 and a mean Agatston Score of 1633 units ± 2276. Unenhanced scans had a mean absolute interscan variability of 9.6 mg ± 8.6 (mean percentage interscan variability, 5.6% ± 5.9). The Agatston score had a significantly higher mean variability of 129 units ± 184 (mean percentage variability, 11.6% ± 7.9; P < .01). Contrast-enhanced scans had a mean variability of 12.3 mg ± 9.3 (mean percentage variability, 5.7% ± 6.2), whereas the Agatston score had a significantly higher variability of 167 units ± 156 (mean percentage variability, 26.6% ± 34.8; P < .01). Unenhanced versus contrast-enhanced scans had a mean variability of 24.9 mg ± 33.4 (mean percentage variability, 6.3% ± 3.5), whereas the Agatston score had a significantly higher mean variability of 991 units ± 1820 (mean percentage variability, 45.2% ± 21.1; P < .01). The 18 patients with detectable coronary calcium had a mean calcium mass of 33.6 mg ± 87.5 and a mean Agatston score of 201 units ± 492. The mean variability in coronary calcium was 5.5 mg ± 14.2 (mean percentage variability, 10.9% ± 9.3), whereas the Agatston score had a significantly higher mean variability of 27.7 units ± 56.5 (mean percentage variability, 23.7% ± 32.3; P < .01).

Retrospective Patient Scans
Calcium mass.—On the five scans in patients without symptomatic atherosclerosis, a mean of two fragments (mean mass, 0.7 mg; range, 0–1.8 mg) of calcium were detected. No calcium was detected in two patients. Of a total of 10 fragments detected in the three remaining patients, seven fragments (mean mass, 2.46 mg) were located in the infrarenal aorta, two fragments (mean mass, 0.71 mg) were located at the common iliac artery bifurcations, and one fragment (mass, 0.33 mg) was located at the inferior aspect of the arch of the aorta. In patients with aortic aneurysms, the mean number of detected fragments was 21 (range, 6–254), the mean fragment size was 23.1 mm3 (mean mass, 15.3 mg), and the mean total calcium mass per patient was 321.3 mg (range, 45–1443 mg).

Calcium surface and mass distribution.—In patients with aortic aneurysms, 1.45% (range, 0.1%–3.3%) of the total surface area of the assessed arterial walls was calcified (Table). The abdominal aorta as a whole and the infrarenal aorta had significantly greater calcium than all other segments (P < .05). The subsegment of the infrarenal aorta between the inferior mesenteric artery and the aortic bifurcation also possessed significantly more calcium than all other segments (P < .01). There was no significant difference in the calcium content among all other segments and no significant difference between the calcium content of the right and left common and external iliac arteries. When the calcium content of each segment was normalized to the surface area of the segment, the results did not change.


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Summary of Findings in Patients with Aortic Aneurysms

 
Interaction, processing, and review time.—Calcium identification and quantification required a mean of 1.6 minutes ± 0.3 for user interaction to select the start points and end points of vessels of interest and a mean of 6.2 minutes ± 1.5 of computer processing time to detect and quantify calcified fragment mass and distribution. This included a mean of 0.4 minutes ± 0.2 for output of images and data to the relational database. A mean of 1.5 minutes ± 0.8 was required after computer processing to review the detected calcium fragments and delete erroneously included bony fragments such as osteophytes and venous phleboliths that were in close proximity to the arteries of interest. Specifically, two osteophytes and two venous phleboliths were erroneously detected in two patients, and these were manually deleted prior to statistical analysis. No calcium fragments were missed by the algorithm.

Dependence on user input.—The mean aortic radius at the user-defined start points was 12.1 mm, and the mean radius of the external iliac arteries at the user-defined end points was 3.4 mm. The measured mass of all detected fragments was identical when user points were varied and the calcium quantification algorithm was repeated. However, because the user-selected start and end points were varied within a spheric area, two fragments were missed in a proportion of the repeated computer runs of the algorithm. Specifically, one fragment (6.14 mg) was 4 mm proximal to the initial user-selected start point in the abdominal aorta and was missed when the start point was distal to the fragment. This occurred in 32.8% of the repeated computer runs. The other fragment (3.82 mg) was 5 mm distal to the user-selected end point in the external iliac artery and was missed when the end point was proximal to the fragment. This occurred in 71.4% of the repeated computer runs.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Early methods of calcium mass quantification were used to measure the BVP at a set threshold, and scanned calcium standards were used to derive a measurement of the mass of each fragment (14,1618,24). When vascular contrast enhancement was present, the threshold had to be increased to exclude the intravascular contrast, causing substantial underestimation of the BVP of the fragments (16). One author addressed this problem by calculating a correction factor for the measured mass to derive a more accurate mass for each fragment (17). However, the correction factor was specific to each scanner, scan protocol, and level of arterial contrast enhancement. The correction factor needed to be recalibrated as these conditions changed. The correction factor was calculated from calibration scans of small, regular cylindric phantoms with known mass. Because calcium fragments in vivo are of widely varying shapes, sizes, and homogeneity that result from partial volume effects, this calibration factor may not be optimal to minimize error. Our method does not require scan protocol–specific calibration by using separate scans of complex phantoms, and it inherently takes into account the level of arterial contrast enhancement. With it, no assumption is made that calcium fragments have a regular shape. Finally, our algorithm detects and quantifies calcium fragments automatically with minimal user input.

Our algorithm has limitations. When a high level of arterial contrast enhancement is present, small fragments of calcium may have a maximum Hounsfield unit value that is less than the level of arterial contrast enhancement and may therefore be excluded from the analysis. Thus, we recommend maintaining luminal opacification at reasonable levels. If the amount of noise in the scan is high, the calcium detection threshold level will be much higher than the level of arterial contrast enhancement. As a result, small low-attenuation calcium fragments may be missed. Calcium fragments that are completely outside the segmentation will be missed by the automated segmentation. This is most likely to occur in aortic aneurysms with substantial mural thrombus. However, these fragments should be included once the segmentation is reviewed by an experienced observer prior to analysis. If the calcium fragment is at least partially enclosed by the segmentation, it will be detected in the initial stages of our algorithm. The subsequent calculation of BVP will include the whole fragment, including the part that is outside the segmentation. Calcium fragments that are proximal to the initial start point entered by the user or distal to the end points will be missed by our algorithm. Therefore, care must be taken by the operator to assure that the start and end points encompass all mural calcium. Our algorithm may erroneously include some calcium that is located near the ostia of branch vessels that originate in the vessels of interest. Finally, as with all other algorithms, our method is dependent on the amount of error in the fabrication of the mass standards used to convert BVP to calcium mass.

Our method for automated quantification of calcium in the systemic arteries produced accurate and reproducible measurements on scans in phantoms. In a prospective study in a limited set of 21 asymptomatic volunteers, we demonstrated that this method exhibits a low variability on both unenhanced and contrast-enhanced scans. We demonstrated its feasibility for rapid quantification of calcium mass and distribution in patients with and without known vascular disease. These results are preliminary, but our algorithm showed promise for use as a tool to facilitate studies of the relationship between the quantity and distribution of systemic arterial calcification in a variety of patient subtypes.


    ADVANCE IN KNOWLEDGE
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 


    IMPLICATION FOR PATIENT CARE
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 


    ACKNOWLEDGMENTS
 
We thank Laura Pierce, MPA, RT (CT), Linda Novello, RT (MR), Marc Sofilos, RT, and Kala Raman, MSc, MS (Soft Eng), for support with image processing and computer applications.


    FOOTNOTES
 

Abbreviations: BVP = brightness-volume product • HIPAA = Health Insurance Portability and Accountability Act

Author contributions: Guarantor of integrity of entire study, G.D.R.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; clinical and experimental studies, all authors; statistical analysis, all authors; and manuscript editing, all authors

Authors stated no financial relationship to disclose.


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 

  1. Margolis JR, Chen JTT, Kong Y, Peter RH, Behar VS, Kisslo JA. The diagnostic and prognostic significance of coronary artery calcification: a report of 800 cases. Radiology 1980;137:609–616.[Abstract/Free Full Text]
  2. Danielsen R, Sigvaldason H, Thorgeirsson G, Sigfusson N. Predominance of aortic calcification as an atherosclerotic manifestation in women: the Reykjavik study. J Clin Epidemiol 1996;49:383–387.[CrossRef][Medline]
  3. Symeonidis G, Papanas N, Giannakis I, et al. Gravity of aortic arch calcification as evaluated in adult Greek patients. Int Angiol 2002;21:233–236.[Medline]
  4. Li J, Galvin HK, Johnson SC, Langston CS, Sclamberg J, Preston CA. Aortic calcification on plain chest radiography increases risk for coronary artery disease. Chest 2002;121:1468–1471.[CrossRef][Medline]
  5. Witteman JC, Kok FJ, van Saase JL, Valkenburg HA. Aortic calcification as a predictor of cardiovascular mortality. Lancet 1986;2:1120–1122.[Medline]
  6. Niskanen LK, Suhonen M, Siitonen O, Lehtinen JM, Uusitupa MI. Aortic and lower limb artery calcification in type 2 (non-insulin-dependent) diabetic patients and non-diabetic control subjects: a 5 year follow-up study. Atherosclerosis 1990;84:61–71.[CrossRef][Medline]
  7. Kauppila LI, Polak JF, Cupples LA, Hannan MT, Kiel DP, Wilson PW. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis 1997;132:245–250.[CrossRef][Medline]
  8. Wilson PW, Kauppila LI, O'Donnell CJ, et al. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation 2001;103:1529–1534.[Abstract/Free Full Text]
  9. Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:2810–2815.[Abstract/Free Full Text]
  10. Iribarren C, Go AS, Tolstykh I, Sidney S, Johnston SC, Spring DB. Breast vascular calcification and risk of coronary heart disease, stroke, and heart failure. J Womens Health (Larchmt) 2004;13:381–389.[CrossRef][Medline]
  11. Rubin GD. MDCT imaging of the aorta and peripheral vessels. Eur J Radiol 2003;45(suppl 1):S42–S49.[CrossRef][Medline]
  12. Rubin GD, Schmidt AJ, Logan LJ, Sofilos MC. Multi-detector row CT angiography of lower extremity arterial inflow and runoff: initial experience. Radiology 2001;221:146–158.[Abstract/Free Full Text]
  13. Rubin GD, Shiau MC, Schmidt AJ, et al. Computed tomographic angiography: historical perspective and new state-of-the-art using multi detector-row helical computed tomography. J Comput Assist Tomogr 1999;23(suppl 1):S83–S90.
  14. Hoffmann U, Kwait DC, Handwerker J, Chan R, Lamuraglia G, Brady TJ. Vascular calcification in ex vivo carotid specimens: precision and accuracy of measurements with multi-detector row CT. Radiology 2003;229:375–381.[Abstract/Free Full Text]
  15. Hopper KD, Strollo DC, Mauger DT. Comparison of electron-beam and ungated helical CT in detecting coronary arterial calcification by using a working heart phantom and artificial coronary arteries. Radiology 2002;222:474–482.[Abstract/Free Full Text]
  16. Hong C, Bae KT, Pilgram TK. Coronary artery calcium: accuracy and reproducibility of measurements with multi-detector row CT—assessment of effects of different thresholds and quantification methods. Radiology 2003;227:795–801.[Abstract/Free Full Text]
  17. Hong C, Becker CR, Schoepf UJ, Ohnesorge B, Bruening R, Reiser MF. Coronary artery calcium: absolute quantification in nonenhanced and contrast-enhanced multi-detector row CT studies. Radiology 2002;223:474–480.[Abstract/Free Full Text]
  18. Rumberger JA, Kaufman L. A rosetta stone for coronary calcium risk stratification: Agatston, volume, and mass scores in 11,490 individuals. AJR Am J Roentgenol 2003;181:743–748.[Abstract/Free Full Text]
  19. Raman R, Raman B, Napel S, Rubin GD. Improved speed of bone removal in CT angiography (CTA) using automated targeted morphological separation: method and evaluation in CTA of lower extremity occlusive disease (LEOD). J Comput Assist Tomogr (in press).
  20. Paik DS, Beaulieu CF, Jeffrey RB, Rubin GD, Napel S. Automated flight path planning for virtual endoscopy. Med Phys 1998;25:629–637.[CrossRef][Medline]
  21. Raman R, Napel S, Rubin GD. Curved-slab maximum intensity projection: method and evaluation. Radiology 2003;229:255–260.[Abstract/Free Full Text]
  22. Raman R, Napel S, Beaulieu CF, Bain ES, Jeffrey RB Jr, Rubin GD. Automated generation of curved planar reformations from volume data: method and evaluation. Radiology 2002;223:275–280.[Abstract/Free Full Text]
  23. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–832.[Abstract]
  24. Hong C, Bae KT, Pilgram TK, Zhu F. Coronary artery calcium quantification at multi–detector row CT: influence of heart rate and measurement methods on interacquisition variability—initial experience. Radiology 2003;228:95–100.[Abstract/Free Full Text]




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