A Rosetta Stone for Coronary Calcium Risk Stratification: Agatston, Volume, and Mass Scores in 11,490 Individuals

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1 Downloaded from by on 0/2/8 from IP address Copyright ARRS. For personal use only; all rights reserved John A. Rumberger Leon Kaufman 2,3 Received January, 2003; accepted after revision March 5, The Ohio State University, Columbus, OH AccuImage Diagnostics Corporation, 400 Grandview Dr., South San Francisco, CA Present address: 6 4th Ave., San Francisco, CA 948. Address correspondence to L. Kaufman (leonkaufman.com). AJR 2003;8: X/03/ American Roentgen Ray Society A Rosetta Stone for Coronary Calcium Risk Stratification: Agatston, Volume, and Mass Scores in,490 Individuals OBJECTIVE. We introduce stratification data for three methods (Agatston, volume, mass) obtained from one single patient population. MATERIALS AND METHODS. Measurements in,490 individuals scanned from 999 to 2002 with electron-beam CT were used for this study. RESULTS. Our Agatston score ranges agree reasonably well with the Kondos values except for measurements in patients at the extreme ages, at which we sampled a wider age range and consequently had different biases of averages. Neither method is preferable because except for a small percentage of individuals near the dividing lines, stratification is the same for the three methods. When we matched them against a known lesion phantom, the Agatston and volume scores behave nonlinearly, and the latter grossly overestimates volume. The mass method is linear except for lesions near the edge of detectability and matches known volumes to within a small percentage. CONCLUSION. We provide validated risk stratification data for use with mass scoring methods. C oronary calcium scoring has become ubiquitous as a means of assessing coronary heart disease risk and as means of studying the progression of atherosclerotic plaque burden in the coronary arteries. Coronary artery calcium is observed in varying degrees of atherosclerotic involvement, can denote an active process of plaque development, and is regulated in a manner similar to that of bone mineralization []. Its role in disease remains unclear, but coronary artery calcium likely appears in response to the inflammatory cascade of developing coronary disease. CT can noninvasively detect and quantify coronary calcification. Histologic [], sonographic [2], and angiographic [] studies have confirmed that coronary calcium quantified on CT is related to the extent of atherosclerotic disease in a direct fashion, regardless of age or sex. Numerous angiographic studies during the past 25 years have shown that the extent of coronary disease is directly related to prognosis. The presence of moderate amounts of coronary calcium on CT (i.e., scores >) has been shown in several studies to predict cardiac events in symptomatic [3] and asymptomatic [4 6] individuals. The actual calcium score, although an indicator of overall disease extent [7], may not be as useful for predicting coronary events as its percentile ranking. Recent studies have emphasized that a calcium score above the 75th percentile for age and sex may increase heart risk an order of magnitude above that for individuals with scores below the 25th percentile [8, 9]. Thus, even small scores that are much higher than those anticipated for age and sex may be better predictors of risk. For instance, a calcium score of 40 in a 40-year-old man would place him well above the 95th percentile and engender a risk of a cardiac event during the next 3 6 years that may well exceed that of a 70-year-old with a similar score, who would rank for that age group below the th percentile. To stratify risk, we compared the score, which represents a measure of the calcium burden, with the scores from a database developed by Hoff et al. []. This database is in the Agatston scale []. The Agatston scale calculates a calcium burden by multiplying the area of the lesion above a 30-H threshold (obtained from 3-mm-thick nonoverlapped slices) by a weighting factor that is dependent on the peak signal anywhere in the lesion. Because of the discrete nature of the weighting, the Agat- AJR:8, September

2 Rumberger and Kaufman Downloaded from by on 0/2/8 from IP address Copyright ARRS. For personal use only; all rights reserved ston score is sensitive to noise when the peak signal is near one of the threshold values and completely insensitive away from them. More recently, the volume score was introduced by Callister et al. [2]. The volume score linearly interpolates the data set to isotropic volumes and, as its name implies, computes the volume of the lesion above a 30-H threshold (the nominal threshold for calcification derived from observational studies). The Kondos database was accumulated using an electron-beam CT scanner operated at the University of Illinois at Chicago and is based on an asymptomatic middle- and upper middle-class mostly white local population. For a long time in the development of this field, work was done essentially exclusively with electron beam CT scanners operated under a set of standard conditions. As the speed of mechanical CT scanners improved, they started to be used for calcium scoring, both in prospective and retrospective gating modes [3 5]. This use accelerated with the introduction of multidetector CT (MDCT) scanners, in which the time resolution is considerably increased by the manipulation of data from different detector rows [6] and the concomitant decrease in rotational speed compared with single-detector devices. Controversy arose as to the accuracy with which these scanners could reproduce the coronary calcium scores of the scanner used to accumulate the database of Hoff et al. [] and as to whether risk stratification could be assessed using this database as a reference, with the literature suggesting both agreement and disagreement [4, 7 20]. These articles were generated while the technology of helical scanners was changing; this timing of their research makes reference to this material difficult to evaluate. Much attention was paid in these evaluations to two factors: speed or time resolution and scanner calibration. Blurring and motion artifacts due to heart motion can either increase or decrease the calcium score, depending on the particulars of the lesion and its motion. Heart motion and partial volume averaging seem to account for a 50% change in score when patients are imaged twice within a short interval, with 30% variability seemingly the most common value, depending on lesion size [2, 20 28]. As time resolution improves and slices become thinner, this variability is decreasing. Scanner calibration ensures the Hounsfield scale and is well handled by the calibration procedures implemented by manufacturers. What has received less attention is spatial resolution. For lesions that have a dimension even a few times larger than the fullwidth at half-maximum of the scanner point spread function, both peak intensity and the apparent area of the lesion will be affected by spatial resolution of the imaging device. Much of the controversy is due to the measurement method itself. The Agatston scoring scale is rule-based: calculate an area for all pixels above a threshold of 30 H, do so every 3 mm (the slice thickness and spacing used by Agatston et al. []), and multiply it by a weight. Because the method is rule-based, it does not address what should be done if the slice parameters are changed. For instance, for a 2.5-mm spacing between slices, calculating an area for every slice oversamples compared with doing so every 3 mm. This oversampling can be mathematically corrected by an appropriate scaling factor (2.5/3 in this case) if this were the only issue. For instance, partial volume effects would lead to higher peak values for small lesions (but not for large ones). If the change in peak value happens to be such that it changes the weighting factor, then it can, theoretically, change the score by a factor of four. In other ranges, the effect may be trivial. The finite spatial resolution of the scanner (typically between and.7 mm full-width at half-maximum) [29] will spread a small lesion over a larger area for a larger peak value. Considering that newer 6-slice MDCT scanners can image the heart with less than -mm slice thickness, we believe that these effects become important and that nothing in the Agatston rules allows for a consistent computational method to translate a measurement from one scanner to another in a consistent fashion. In other words, the Agatston method is not portable. At first sight, the volume method of Callister et al. [2] resolves the issue of slice thickness and spacing by computing a volume above threshold. Over- or undersampling for slice parameters is automatically accounted for. Nevertheless, this method has some important and poorly appreciated limitations. First, it does not compute a volume or even a number that is independent of the calcium content of the lesion. Because of the finite point spread function of any CT scanner, the signal is spread in the imaging plane. It is intuitively obvious that if two lesions of equal area have different amounts of calcium, the one with more calcium will show a larger area above threshold than the one with less calcium. The process is easily modeled and is significant: the volume measured is the same for a lesion of mm 3 consisting of % hydroxy apatite and another lesion of.4.4 mm 3 with a content of 66% hydroxy apatite. This is further distorted by the linear interpolation used to create isotropic pixels before measuring volume. Consider a lesion with high calcium content contained fully within a slice. Its signal will be spread by the linear interpolation to other slices, and the volume will be artifactually increased. Conversely, a lesion fully within a slice that has low calcium content may appear artifactually smaller. Thus, the volume method, contrary to what its name implies, does not measure a value purely dependent on volume; it is affected by calcium content and by scanner operating parameters. Even when the latter are held fixed, the volume score reflects both lesion volume and calcium content. Its portability is affected by the same issues that affect the Agatston method. The recent literature has seen a discussion of mass measurement methods [29, 30]. Basically, these consist of integration of the signal for pixels above a given threshold. For a wellcalibrated CT scanner, in the absence of noise, this integration (scaled by pixel volume) gives the total mineral content independently of slice thickness and spatial resolution. In practice, the threshold necessary to avoid the inclusion of false-positive pixels changes the measurement. Another issue of mass methods is what mass is being expressed; calcified lesions include a complex of different calcium bone ash equivalent or calcium equivalent. Whereas each will give a different result, all these are different scaling factors for the integral of the Hounsfield values so that the different measures are easily related to each other. If the scaling factor is given, translation is possible. With suitably low threshold settings, the mass methods come closest to being portable. The retention of the Agatston score has been predicated on the availability of a database for these scores []. Without it, stratification of risk is not possible. Adoption of other methods will depend on the availability of similar stratification data. Materials and Methods Eleven thousand four hundred ninety patients were scanned from 999 to 2002 using an electron beam CT scanner (Imatron, General Electric Medical Systems, South San Francisco, CA) operating with a slice thickness of 3 mm, spatial resolution of.3 mm full-width at half-maximum, field of view of 26 cm, threshold of 30 H, and image acquisition of msec, prospectively triggered at 60 80% of the R-R (ECG) interval. The age range of patients was from 25 to 84 years, and 63% were men (Fig. ). All patients were in normal (regular) heart rhythm. 744 AJR:8, September 2003

3 Coronary Calcium Risk Stratification Downloaded from by on 0/2/8 from IP address Copyright ARRS. For personal use only; all rights reserved No. of Individuals Fig.. Chart shows age distribution for men (black bars) and women (white bars) of patients in this study. There were,490 patients, 63% male. All measurements were performed using AccuScore (AccuImage Diagnostics, South San Francisco, CA). Agatston and volume scores were computed as described previously [, 2]. Mass was computed as the integral (sum) of all Hounsfield values in a lesion multiplied by the voxel volume in millimeters cubed. A scaling factor of H/mg was chosen to yield a mass that approximately represents bone ash equivalent. Results Agatston scores from our population were compared with published results from Hoff et al. [] (also known as the Kondos database). We found substantial equivalence for men and women, except at the youngest and oldest ranges, in which we showed lower and higher Agatston Score,000 0 th Percentile Agatston Score,,000 0 values, respectively. This could have been due to our using a broader age range, so that more younger people were included (this reduced the average score for the young) and more older individuals at the high age end (this increased the average score). Results of the comparison for the 75th percentile range are shown in Figure 2. Figures 3 5 and 6 8 show Agatston, volume, and mass scores for men and women, respectively. We examined whether stratification results would be the same irrespective of the scoring scheme used. We found for instance that for men years old, 35 of 79 men were misclassified as to their position around the 50th percentile point when comparing Agatston and Men (present study) Men (Kondos []) Women (present study) Women (Kondos []) Fig. 2. Graph shows comparison of results for 75th percentile range for men and women as reported in Hoff et al. [] (Kondos database). Volume Score (mm 3 ),000 0 volume scores, 20 were misclassified when comparing Agatston and mass scores, and 23, when comparing volume and mass scores (equal above and below the point). For women years old, just one was misclassified in any comparison around the 50th percentile point. All the misclassifications were close to the dividing lines. Except in a few cases, risk stratification seems to be reasonably the same for any of the three calcium scoring methods. Furthermore, we did not find much variability or difference when comparing consecutive scans obtained on a given patient. For all three methods in 35 patients, each imaged on the same day, the average variability was approximately 38%, and approximately half the cases could be reproduced with better than 25% vari- th Percentile Fig. 3. Graph shows Agatston scores for men. Fig. 4. Graph shows volume scores for men. AJR:8, September

4 Rumberger and Kaufman 0 th Percentile,000 0 Downloaded from by on 0/2/8 from IP address Copyright ARRS. For personal use only; all rights reserved Mass (mg) Fig. 5. Graph shows mass scores (bone ash equivalent) for men. ability (Fig. 9). These results are consistent with those in the literature, in which average deviations of 30 50% in repeated studies are commonly reported [2, 20 28]. Thus, under the conditions of this study, neither method recommends itself as superior to another for stratification of reproducibility on a patient-by-patient basis. We do not mean to imply that the volume and mass methods simply differ by a scale factor: The ratio (a pseudodensity) varies from mg/mm 3 to.4 mg/mm 3 (a dynamic range of 20), with 78% in the mg/mm 3 range. We call this a pseudodensity because the volume score overestimates true volume so that the ratio underestimates density. The largest value should be.44 mg/mm 3, pure bone ash, and none of the measured values exceeds it. Volume Score (mm 3 ) 0 Agatston Score The single advantage of the mass method is its better reflection of the physical properties of the lesion and, consequently, better adaptation to portability across and between CT scanners. For example, we have tested 3 units from different manufacturers, including helical, multidetector, and electron beam CT scanners using a phantom consisting of five aluminum wires of diameters between 0.3 and 3.2 mm [3]. Each wire was scored, and the peak intensities were used to measure spatial resolution with high precision. Spatial resolution affects calcium scoring in a predictable manner. We can compare the volume and mass scores to the known volume and mass of the aluminum (which has a density between that of bone ash and pure hydroxy apatite), using the appropriate scaling factor for aluminum (2400 H instead of Fig. 6. Graph shows Agatston scores for women. Mass (mg) 0 H). The results are shown in Figure for a scanner with a resolution of.02 mm full-width at half-maximum and another with.54 mm full-width at half-maximum. Two effects can be noted: For lesions under mm 3 in volume, the mass method is more closely reflective of the lesion volume, and the spread of values between the two scanners is much less for the mass method. Figure shows the same data in terms of percentage deviation from the wire volume. For the lower resolution scanner, the peak intensity of the signal from the small wire fell below 30 H and was not scored. Operating with a lower threshold (which is possible in newer scanners) significantly improves the mass method measurements for small volumes but paradoxically worsen the results from the volume method. 85 Fig. 7. Graph shows volume scores for women. Fig. 8. Graph shows mass scores (bone ash equivalent) for women. 746 AJR:8, September 2003

5 Coronary Calcium Risk Stratification 40 Downloaded from by on 0/2/8 from IP address Copyright ARRS. For personal use only; all rights reserved No. of Patients < % < 5% < % < 25% < 50% < 75% Total Agreement Among Successive Scans Fig. 9. Graph shows reproducibility of three scoring methods in 35 patients. Approximately 50% of all nonzero scores fall within 25% reproducibility. Mean is 38% for all three methods. There is no significant difference among them. Black bars = Agatston score, white bars = volume score, gray bars = mass score. Discussion Stratification of calcium scoring can be affected by any of the three methods that we presented insofar as they are consistently applied. Nevertheless, some methods are more translatable to CT scanners operating under different imaging conditions. One type of scanner could be operated with fixed imaging parameters and make translation unnecessary. From a practical point of view, it is not the nature of the market that only one machine will be bought by those interested in a particular application. Furthermore, technology evolves, and no scanner will Deviation from Volume (%) Measured Volume (mm 3 ) 0.0 remain static in its capabilities because it is difficult to argue that slices much thinner than 3 mm would be undesirable for objects as small as the coronary arteries or that improved time resolution would not be beneficial. As the methodology changes, it is desirable to have a measurement method that can grow with it. The mass method that we and others have described is best adapted to be compared among scanners and more closely reflects the physical properties of the target. In this study, we did not find any one method preferable to another in terms of reproducibility of results Wire Volume (mm 3 ) Mass,.02 mm Mass,.54 mm Volume,.02 mm Volume,.54 mm Fig.. Graph shows (for data in Fig.) percentage of deviation from known volume for same scanners. Wire Volume (mm 3 ) from consecutive scans in a patient. Differences may be noted as spatial resolution and slice thickness improvement [32]. References Mass,.02 mm Mass,.54 mm Volume,.02 mm Volume,.54 mm Wire volume 0 Fig.. Graph shows comparison of volume and mass scores in phantom consisting of five aluminum wires with diameters between 0.3 and 3.2 mm for two scanners with spatial resolution of.02 and.54 mm full-width at half-maximum. At resolution of.5 mm, smallest wire falls below detection threshold.. Wexler L, Brundage B, Crouse J, et al. Coronary artery calcification: pathophysiology, epidemiology, image methods and clinical implications a scientific statement from the American Heart Association. Circulation 996;94: Baumgart D, Schmermund A, Goerge G, et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 997;30: Detrano R, Tzung H, Wang S, et al. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 996;27: Agatston AS, Janowitz WR, Kaplan GS, et al. Electron beam CT coronary calcium predicts future coronary events. (abstr) Circulation 996;94:I Arad Y, Spadaro LA, Goodman K, et al. Predictive value of electron beam computed tomography of the coronary arteries: 9-month follow-up of 73 asymptomatic subjects. Circulation 996;93: Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron beam computed tomographic coronary calcium as a predictor of coronary events: comparison of two protocols. Circulation 997;96: Schmermund A, Bailey KR, Rumberger JA, Reed JE, Sheedy PF II, Schwartz RS. An algorithm for non-invasive identification of angiographic threevessel and/or left main coronary artery disease in symptomatic patients based on cardiac risk and electron-beam computed tomographic calcium scores. J Am Coll Cardiol 999;33: Raggi P, Cooil B, Callister TQ. Use of electron AJR:8, September

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