(Radiology. 1999;212:811-816.)
© RSNA, 1999
Brain Tumor Volume Measurement: Comparison of Manual and Semiautomated Methods1
Bonnie N. Joe, MD, PhD,
Melanie B. Fukui, MD,
Carolyn Cidis Meltzer, MD,
Qing-shou Huang, MS,
Roger S. Day, ScD,
Phil J. Greer, BS and
Michael E. Bozik, MD
1 From the Departments of Radiology, Division of Neuroradiology (B.N.J., M.B.F., C.C.M., P.J.G.), Psychiatry (C.C.M.), Neurosurgery (M.E.B.), Neurology (M.E.B.), and Medicine (M.E.B.), and the Pittsburgh Cancer Institute (Q.H., R.S.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa. Received May 29, 1998; revision requested July 22; revision received November 11; accepted March 29, 1999. Address reprint requests to M.B.F., Department of Radiology, Presbyterian University Hospital, Rm D-132, 200 Lothrop St, Pittsburgh, PA 15213-2582 (e-mail: fukuimb@radserv.arad.upmc.edu).
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Abstract
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PURPOSE: To compare the reliability of two approaches to measuring enhancing brain tumor volumesthe conventional manual trace method and a threshold-based, semiautomated computer software method.
MATERIALS AND METHODS: Two operators rated contrast materialenhanced, T1-weighted axial magnetic resonance (MR) image data sets from 16 patients aged 2171 years with high-grade gliomas. Each MR data set was rated twice by using manual tracing and twice by using the semiautomated method. The semiautomated measurement method involved a thresholding algorithm based on mixture modeling. The data collection time for each method was recorded. Reliability was measured by using inter- and intraoperator agreement indexes.
RESULTS: Mean intraoperator agreement indexes (± SD) were 0.90 ± 0.09 (operator 1) and 0.83 ± 0.15 (operator 2) for the manual trace method and 0.83 ± 0.17 (operator 1) and 0.84 ± 0.16 (operator 2) for the semiautomated measurement method. The mean interoperator agreement was 0.85 ± 0.14 for the manual method and 0.82 ± 0.18 for the semiautomated method. The semiautomated method was faster than the manual trace method by an average of 4.6 minutes per patient.
CONCLUSION: The semiautomated computer method of measuring tumor volume was faster than the manual trace method. Semiautomated computer approaches offer an alternative to manual tracing for measuring serial tumor volumes in patients with high-grade brain neoplasms.
Index terms: Brain neoplasms, 10.363, 10.3634 Brain neoplasms, MR, 10.12141, 10.12143 Magnetic resonance (MR), volume measurement, 10.12141, 10.12143 Technology assessment
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Introduction
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Brain tumor volumes measured from diameters on computed tomographic (CT) and magnetic resonance (MR) images have been commonly used in the evaluation of intracerebral tumors and have implications for patient prognosis and treatment. Tracing the enhancing margin could potentially provide a more representative measurement of tumor size and has been used in clinical trials to assess treatment response (1). At many institutions, brain tumor volume measurements are obtained by the MR technologist, who manually traces the enhancing tissue on each image by using widely available imaging software. This approach is potentially subjective and prone to large variations in intra- and interoperator performance. Such variations affect the validity of serial measurements used in the planning of therapy, because a single technologist does not necessarily perform all tumor volume measurements in a given patient. Variability in serial volume measurements and inconsistency between observers have been noted by others (25) in studies involving tumor volume measurement methods used to follow tumor response to treatment or to plan treatment. Although previous studies (2,3) have involved limited evaluations of the reliability of tumor volumetrics, detailed comparisons of alternative semiautomated methods versus the conventional manual trace method have not been performed. To our knowledge, the reliability of manual tracing has not been considered in the more extensive studies (6,7) of inter- and intraoperator reliability of tumor volume measurement methods.
In this study, we quantitatively compared two methods of measuring enhancing tumor volumes from MR image datathe conventional manual trace method and a threshold-based semiautomated computer segmentation method. To compare the inter-and intraoperator reliability of the two methods, two operators performed tumor volume determinations twice with each method in the same subjects. Our hypotheses were that (a) the manual trace method would be more user dependentthat is, have low interoperator reliability, and (b) the semiautomated method would provide more reproducible measurementsthat is, have high intraoperator reliability.
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MATERIALS AND METHODS
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Patient Population
The study group consisted of 16 adult patients (13 men, three women; mean age, 53 years; age range, 2271 years) with histologically proved, unresected high-grade gliomas, who were randomly selected from an ongoing treatment protocol conducted by the University of Pittsburgh Medical Center Neuro-Oncology Service. The inclusion criterion was the presence of an enhancing tumor on more than one MR image obtained by using routine imaging parameters.
MR Image Acquisition
From images obtained by using the routine clinical imaging protocol performed with a Signa 1.5-T imaging unit (GE Medical Systems, Milwaukee, Wis), we selected the contrast materialenhanced (0.1 mmol/kg gadoteridol [Prohance; Bracco Diagnostics, Princeton, NJ] or gadopentetate dimeglumine [Magnevist; Berlex Laboratories, Wayne, NJ]), T1-weighted axial MR series for the tumor volume measurements. The following parameters were used to obtain the T1-weighted images: 450650/1635 (repetition time range msec/echo time range msec), 256 x 192 matrix, 24-cm field of view, 5-mm section thickness with a 1-mm intersection gap, and one signal acquired.
Tumor Volume Measurement
Two nonradiologists (B.N.J., who was a medical student at the time of the study, and P.J.G., a research assistant in our positron emission tomography [PET] center) independently rated each MR image twice by using each of the two measurement methodsthat is, manual tracing and semiautomated segmentation. Operator 1 followed the order ABBA, whereas operator 2 followed the order ABAB, where method A was the semiautomated segmentation method and method B was the manual trace method. The images obtained in all 16 subjects were rated in one batch for each manual or semiautomated measurement trial. The rationale for using the two nonradiologists in this study was that tumor volume measurements are typically performed by MR technologists rather than radiologists in our radiology department. To compare inter- and intraoperator reliability, we needed two individuals who were available to perform the repetitive measurements. Because our technologists were not available to obtain these measurements, we chose a medical student and a PET research assistant, because their familiarity with imaging approached that of an imaging technologist but not that of a radiologist.
The image processing time for both methods was recorded by both operators during the second trial. In each patient, the total processing time included two componentsthe time required to generate tumor contours and the time required to load and save image data.
For both methods, only the enhancing portions of the tumor were included in the volume calculation. The nonenhancing portions within the tumor (ie, areas of tumor necrosis) were traced, and their volumes were excluded from the total tumor volume.
Manual trace method.Tumor volume measurements were determined by manually outlining, with a track ball, the enhancing portion of the mass on each image by using standard software on the imager console (GE Medical Systems). Nonenhancing regions within the tumor also were outlined and subtracted so that only the enhancing tumor area was measured. An example of manual tracing is shown in Figure 1. The area measurements were automatically calculated and multiplied by the MR image section thickness plus the intersection gap to calculate a per-section tumor volume. The total tumor volume was obtained by summing the volume calculations for all sections. Each image, along with its traced contours, was saved by using the "screen save" function on the console and then stored on optical disks.

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Figure 1a. (a, b) Axial T1-weighted MR images (repetition time msec/echo time msec, 466/11) demonstrate the manual trace method in two areas of tumor enhancement (arrows in a) in the left temporal lobe of a patient with glioblastoma multiforme. In b, the contours generated by manually tracing the enhancing portions of the tumor are shown.
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Figure 1b. (a, b) Axial T1-weighted MR images (repetition time msec/echo time msec, 466/11) demonstrate the manual trace method in two areas of tumor enhancement (arrows in a) in the left temporal lobe of a patient with glioblastoma multiforme. In b, the contours generated by manually tracing the enhancing portions of the tumor are shown.
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Semiautomated segmentation method.For the semiautomated segmentation method, threshold-based segmentation software (Morph; Silicon Graphics, Mountain View, Calif) was used. This software, which has not yet been released for general use (Thulborn K., personal communication, September 1998) (8), was operated on an SGI workstation (Silicon Graphics). For each image, the operator selected a point just within the enhancing border of the mass (Fig 2a) and a point just outside the enhancing border of the mass (Fig 2b). These two points defined the threshold used to generate the contour surrounding the enhancing area (Fig 2c). Similarly, nonenhancing regions within the tumor were excluded by choosing a point inside the nonenhancing (necrotic) region (Fig 2d) and a point outside the nonenhancing region (Fig 2e) to generate the contour surrounding the nonenhancing area. Figure 2f shows the result after all enhancing areas have been segmented. As with the manual trace method, the calculated tumor volume reflects the enhancing area only. A similar method, which involves the same mixture modeling algorithm for contour derivation, was previously validated for volume measurements in a phantom, with errors of 4%6% (9). With the semiautomated method, the contours were linked to the original images, and only the contour information plus the linking information was stored.

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Figure 2a. (a-d) Axial T1-weighted MR images (466/11) obtained in the same patient and same image section as those in Figure 1 illustrate the semiautomated computer tracing method. (a-c) First, a point just inside the enhancing border (blue dot at tip of arrow in a) is selected. (b, c) Next, a point just outside the enhancing border (yellow dot at tip of arrow in b) is selected. In c, the enhancing area is automatically outlined (shown in red). (d, e) By selecting a point inside the nonenhancing (necrotic) region (blue dot at tip of arrow in d) and a point outside the nonenhancing region (yellow dot at tip of arrow in e), the contour surrounding the nonenhancing area (outlined in red in e) is generated and excluded from the final tumor volume measurement. (In a-e, all dots have been increased from 1 pixel to 4 pixels in width for clarity of reproduction.) (f) The final result after all enhancing areas have been segmented is shown.
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Figure 2b. (a-d) Axial T1-weighted MR images (466/11) obtained in the same patient and same image section as those in Figure 1 illustrate the semiautomated computer tracing method. (a-c) First, a point just inside the enhancing border (blue dot at tip of arrow in a) is selected. (b, c) Next, a point just outside the enhancing border (yellow dot at tip of arrow in b) is selected. In c, the enhancing area is automatically outlined (shown in red). (d, e) By selecting a point inside the nonenhancing (necrotic) region (blue dot at tip of arrow in d) and a point outside the nonenhancing region (yellow dot at tip of arrow in e), the contour surrounding the nonenhancing area (outlined in red in e) is generated and excluded from the final tumor volume measurement. (In a-e, all dots have been increased from 1 pixel to 4 pixels in width for clarity of reproduction.) (f) The final result after all enhancing areas have been segmented is shown.
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Figure 2c. (a-d) Axial T1-weighted MR images (466/11) obtained in the same patient and same image section as those in Figure 1 illustrate the semiautomated computer tracing method. (a-c) First, a point just inside the enhancing border (blue dot at tip of arrow in a) is selected. (b, c) Next, a point just outside the enhancing border (yellow dot at tip of arrow in b) is selected. In c, the enhancing area is automatically outlined (shown in red). (d, e) By selecting a point inside the nonenhancing (necrotic) region (blue dot at tip of arrow in d) and a point outside the nonenhancing region (yellow dot at tip of arrow in e), the contour surrounding the nonenhancing area (outlined in red in e) is generated and excluded from the final tumor volume measurement. (In a-e, all dots have been increased from 1 pixel to 4 pixels in width for clarity of reproduction.) (f) The final result after all enhancing areas have been segmented is shown.
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Figure 2d. (a-d) Axial T1-weighted MR images (466/11) obtained in the same patient and same image section as those in Figure 1 illustrate the semiautomated computer tracing method. (a-c) First, a point just inside the enhancing border (blue dot at tip of arrow in a) is selected. (b, c) Next, a point just outside the enhancing border (yellow dot at tip of arrow in b) is selected. In c, the enhancing area is automatically outlined (shown in red). (d, e) By selecting a point inside the nonenhancing (necrotic) region (blue dot at tip of arrow in d) and a point outside the nonenhancing region (yellow dot at tip of arrow in e), the contour surrounding the nonenhancing area (outlined in red in e) is generated and excluded from the final tumor volume measurement. (In a-e, all dots have been increased from 1 pixel to 4 pixels in width for clarity of reproduction.) (f) The final result after all enhancing areas have been segmented is shown.
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Figure 2e. (a-d) Axial T1-weighted MR images (466/11) obtained in the same patient and same image section as those in Figure 1 illustrate the semiautomated computer tracing method. (a-c) First, a point just inside the enhancing border (blue dot at tip of arrow in a) is selected. (b, c) Next, a point just outside the enhancing border (yellow dot at tip of arrow in b) is selected. In c, the enhancing area is automatically outlined (shown in red). (d, e) By selecting a point inside the nonenhancing (necrotic) region (blue dot at tip of arrow in d) and a point outside the nonenhancing region (yellow dot at tip of arrow in e), the contour surrounding the nonenhancing area (outlined in red in e) is generated and excluded from the final tumor volume measurement. (In a-e, all dots have been increased from 1 pixel to 4 pixels in width for clarity of reproduction.) (f) The final result after all enhancing areas have been segmented is shown.
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Figure 2f. (a-d) Axial T1-weighted MR images (466/11) obtained in the same patient and same image section as those in Figure 1 illustrate the semiautomated computer tracing method. (a-c) First, a point just inside the enhancing border (blue dot at tip of arrow in a) is selected. (b, c) Next, a point just outside the enhancing border (yellow dot at tip of arrow in b) is selected. In c, the enhancing area is automatically outlined (shown in red). (d, e) By selecting a point inside the nonenhancing (necrotic) region (blue dot at tip of arrow in d) and a point outside the nonenhancing region (yellow dot at tip of arrow in e), the contour surrounding the nonenhancing area (outlined in red in e) is generated and excluded from the final tumor volume measurement. (In a-e, all dots have been increased from 1 pixel to 4 pixels in width for clarity of reproduction.) (f) The final result after all enhancing areas have been segmented is shown.
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Each operator underwent a training and validation exercise before beginning the tumor volume measurements. This involved using the semiautomated method to measure the volume of a cadaverous brain hemisphere that was imaged with a volumetric spoiled gradient-recalled-echo sequence (25/5, 40° flip angle, one signal acquired, 256 x 192 matrix, 1.5-mm section thickness, 24-cm field of view). Both operators obtained measurements within 2% of the actual brain volume (as measured by the displacement of water by a brain fixed in a preservative substance) before proceeding with the tumor volume measurement study (8).
Statistical Considerations and Data Analyses
To compare the intra- and interoperator reliability of the two measurement methods, we used the following agreement index, AI, equation (10):
For interoperator agreement calculations, xa was the measurement obtained by operator 1 and xb, the measurement obtained by operator 2 with the same technique on the same image. For intraoperator agreement calculations, xa was the measurement made during the first trial, and xb, the measurement made during the second trial by the same operator with the same technique on the same image.
Intraoperator and interoperator agreement indexes were calculated for each image, because the tumor contours were generated on a section-by-section basis and represented independent observations. Making the agreement comparisons on a section-by-section basis also increased the statistical power of the study, because the tumors in the 16 patients spanned about 100 sections in total and consequently provided about 100 comparison data points.
An agreement index was calculated for each instance in which both volume measurements (ie, xa and xb) were greater than 0. (There were instances at the extreme inferior and superior tumor margins on the axial images in which very small contours [generally representing 2%5% of the total tumor volume] were generated by one observer and not the other. The results of statistical analyses of these instances by means of the McNemar test showed no significant difference between the semiautomated method and manual trace method and no significant difference between operators in terms of the tendency to find tumor in a particular section.) A value of 1.0 indicated perfect agreement, and a value of 0 indicated no agreement. The measurements made by each operator during the second trial were used in the interoperator agreement calculations. A paired Student t test was used to evaluate differences in interoperator agreement between the semiautomated and manual trace methods. Intraoperator reliability was similarly assessed by evaluating the intraoperator agreement between operators and between methods. Statistical significance was determined by a P value of less than .05. A paired Student t test was also used to look for systematic bias in volume measurements between the two approaches.
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RESULTS
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Tumor Volume Measurements
A total of 384 axial images obtained in the 16 patients were evaluated; approximately 100 of these images demonstrated enhancing tumor. Tumor enhancement was seen on approximately four to 10 (mean, 6.2) images per patient. The range of tumor volume measurements is presented in Table 1. In 49 (77%) of 64 volume measurements, the volume measurement obtained with the semiautomated method was lower (mean difference ± SD, 12.1% ± 11.6) than that obtained with the manual method (P = .001).
Intraoperator Agreement
The intraoperator agreement indexes for the two operators who used the two tumor volume measurement methods are summarized in Table 2. The difference in mean intraoperator agreement between the manual and semiautomated methods was significant for operator 1 (P = .003) but not for operator 2 (P = .74). Scatterplots of the intraoperator agreement indexes for the manual trace method versus the semiautomated segmentation method illustrate the superior reliability of operator 1 with the manual trace method compared with the reliability of this operator with the semiautomated method (Fig 3a). In contrast, for operator 2, there was no significant difference in intraoperator reliability between the two methods (Fig 3b). There was a significant difference in intraoperator reliability between operators when they used the manual trace method (P = .001), whereas there was no significant difference in intraoperator reliability between operators when they used the semiautomated method (P = .60).

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Figure 3a. Scatterplots of intraoperator agreement indexes for the manual versus semiautomated segmentation method. The dotted line is the line of equality, along which the agreement indexes for the manual and semiautomated methods are equal. Each data point represents one image. (a) Agreement indexes for operator 1. Note that there are more points clustered toward the manual axis; this indicates that operator 1 had better reliability with the manual trace method. (b) Agreement indexes for operator 2. In this case, the points are evenly distributed on both sides of the equality line; this indicates that operator 2 had comparable reliability with the two measurement methods.
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Figure 3b. Scatterplots of intraoperator agreement indexes for the manual versus semiautomated segmentation method. The dotted line is the line of equality, along which the agreement indexes for the manual and semiautomated methods are equal. Each data point represents one image. (a) Agreement indexes for operator 1. Note that there are more points clustered toward the manual axis; this indicates that operator 1 had better reliability with the manual trace method. (b) Agreement indexes for operator 2. In this case, the points are evenly distributed on both sides of the equality line; this indicates that operator 2 had comparable reliability with the two measurement methods.
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Interoperator Agreement
There was no significant difference (P = .20) in interoperator reliability between the two tumor volume measurement methods (Fig 4). The mean interoperator agreement index (± SD) was 0.85 ± 0.14 for the manual trace method and 0.82 ± 0.18 for the semiautomated segmentation method.

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Figure 4. Scatterplot of interoperator agreement indexes for the manual versus semiautomated segmentation method. The agreement indexes for the manual and semiautomated methods are equal along the dotted line. The points are evenly distributed on both sides of the equality line; this indicates similar interoperator reliability between the two measurement methods.
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Time Considerations
The mean time required to generate contours and the total tumor measurement timethat is, the time required to generate contours plus the time required to load and save image databy using the two measurement methods are presented in Table 3. There was no significant difference in the average time required to generate contours between the manual trace method and the semiautomated segmentation method (P = .24). However, a significant difference in the total processing time between the two methods was found; the semiautomated method required an average of 4.6 minutes less per patient than did the manual trace method (P = .001). A significant difference in the total processing time per image section also was found between the two methods; the semiautomated method required an average of 0.6 minutes less per image than did the manual trace method (P = .008).
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DISCUSSION
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In a study conducted by the Brain Tumor Cooperative Group (11), the tumor size at CT, as measured by using diameters, was determined to be of prognostic importance, independent of other known prognostic variables. In addition, Blankenberg et al (12) suggested that MR imaging or CT-determined volumetric tumor doubling time is superior to histologic grade in predicting the survival of patients with intracranial astrocytomas. Currently, MR imaging is considered to be superior to CT in determining the extent of tumor infiltration, although histologic evidence of malignancy may extend beyond the margin of enhancement (1315). In addition, surgery, steroids, and radiation therapy may substantially alter the enhancement characteristics of the tumor bed (16,17). Despite this, the extent of tumor enhancement at MR imaging or CT is routinely used to guide radiation therapy, and recent attention has been given to improving the accuracy of in vivo brain tumor volume measurements that are obtained with MR imaging and used in patient treatment and prognostic determinations (1,3,7,18).
In our study of the reliability of brain tumor volume measurements, we quantitatively compared the conventional manual trace method with a semiautomated computer segmentation method. We hypothesized that the semiautomated method would provide more reproducible measurementsthat is, have high inter- and intraoperator reliabilitywhereas the manual trace method would be more user dependent and have low interoperator reliability. As expected, we found no significant difference in intraoperator reliability between operator 1 and 2 (mean agreement index, 0.83) when they used the semiautomated measurement method. In addition, interoperator reliability (agreement index, 0.82) was comparable to intraoperator reliability when the semiautomated method was used. However, the manual trace method was more user dependent in that operator 1 had better intraoperator reliability (agreement index, 0.90) than did operator 2 (agreement index, 0.83). When we compared the interoperator reliability of the two methods, we found no significant difference between the manual and semiautomated measurement methods (agreement index, 0.85 vs 0.82, respectively).
There was a highly significant difference in absolute volume measurements between the two methods; the semiautomated method resulted in lower volume measurements than did the manual tracing method 77% (49 of 64 measurements) of the time. We postulate that this may have resulted from the ability of the semiautomated method to provide a more detailed outline of the irregular edges of the tumor, whereas the manual trace method tends to approximate the tumor border with a smooth curve. Because the true histologic extent of these tumors is not delineated with contrast enhancement, it is impossible to determine which of the tumor volume measurement methods is more accurate (1315). Given the systematic differences, all serial volume measurements that are typically used to follow tumor response to treatment should be performed with the same method.
In some studies (19), attempts to correlate survival with volume of abnormal tissue at T2-weighted imaging have been made. The semiautomated method used in this study would be impractical to apply to T2-weighted images because of the lack of contrast and the inability to discern a complete border between the tumor-related signal intensity abnormality and the cerebrospinal fluid. However, the semiautomated method potentially could be used for volume measurement of abnormal signal intensity at T2-weighted imaging with fluid-attenuated inversion recovery sequences, because the contrast between tumor and cerebrospinal fluid would be increased and thus allow appropriate segmentation. Morph software is currently being used to measure white matter signal intensity abnormalities on fluid-attenuated inversion recovery images in an ongoing study (C.C.M., personal communication, September 1998).
The semiautomated method required less time to generate tumor volume measurements than did the manual trace method. This difference reflects the decreased time required to load and save image data with the semiautomated measurement method. In addition, the semiautomated method required less storage space than did the manual trace method.
The differences between the two measurement methods that were difficult to quantify included qualitative "ease of use" factors. Both operators subjectively believed that the manual trace method was highly labor intensive and required more concentration to do well than did the semiautomated method. Because editing functions were not available with the manual trace method, an image had to be completely retraced if a mistake was made. Also, the outputs of the manual trace method were area measurements, which then had to be multiplied by the section thickness to generate volume measurements. The semiautomated method enabled tumor volumes to be calculated automatically and allowed basic editing functions.
The tumor volume measurements calculated with standard manual tracing and a semiautomated computer program were comparable in interoperator reliability, but the semiautomated computer program was faster than manual tracing. The reliability of MR imagingdetermined tumor volume measurements potentially may be improved with decreased reliance on subjective image interpretation. Although the semiautomated method used in this study still requires an operator to choose the points that determine the threshold value used to outline the area of enhancement, generation of the tumor contour is based on consistent objective criteria. Several automated methods of MR image segmentation based on texture analysis (20), clustering techniques (eg, unsupervised fuzzy c-means) (21,22), or vector decomposition and probability techniques (23) have been reported on. These alternative approaches to MR image segmentation remain under development and retain problems with misclassification. Ultimately, by improving the reliability of MR imagingbased tumor volume measurements, these types of analyses may be used to follow tumor response to therapy and thus potentially influence patient care and treatment planning.
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Acknowledgments
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We thank Keith Thulborn for supplying the Morph software before its completion.
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Footnotes
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Author contributions: Guarantors of integrity of entire study, B.N.J., M.B.F., C.C.M.; study concepts, B.N.J., M.B.F., C.C.M., R.S.D., M.E.B.; study design, B.N.J., M.B.F., C.C.M., R.S.D.; definition of intellectual content, B.N.J., M.B.F., C.C.M.; literature research, B.N.J., M.B.F., C.C.M.; clinical studies, M.E.B.; experimental studies, M.B.F., B.N.J., C.C.M., P.J.G.; data acquisition, M.B.F., B.N.J., P.J.G., C.C.M.; data analysis, B.N.J., M.B.F., C.C.M., P.J.G., Q.H., R.S.D.; statistical analysis, B.N.J., Q.H., R.S.D.; manuscript preparation, B.N.J.; manuscript editing, B.N.J., M.B.F., C.C.M.; manuscript review, all authors.
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