Abstract
Objective: A working group (WG) of the Japanese Society of Nuclear Cardiology (JSNC) determined Japanese normal databases of myocardial perfusion single-photon emission computed tomography (SPECT) on semi-conductor gamma camera (D-SPECT), and the aim of this study was to validate its clinical utility.
Materials and methods: The normal myocardial perfusion SPECT (MPS) databases of Japanese patients in the 201Tl stress/redistribution protocol (201Tl protocol), 99mTc stress/rest or rest/stress protocol (99mTc protocol), and rest 99mTc/stress 201Tl simultaneous acquisition dual-isotope protocol (SDI protocol) were created by JSNC WG. The WG collected clinical cases for the 201Tl protocol (male/female [m/f], 8/8), 99mTc protocol (m/f, 9/7), and SDI protocol (m/f, 10/10) from WG participating hospitals. Four WG members read those clinical cases on a 17-segment and 5-point scale (0-4). Using the most frequent values as the score for each segment, weighted κ values were calculated with the scores obtained from quantitative perfusion software (QPS).
Results: Weighted κ values were as follows; 201Tl stress/female, 0.77; 201Tl rest/female, 0.74; 201Tl stress/male, 0.81; 201Tl rest/male, 0.68; 99mTc stress/female, 0.77; 99mTc rest/female, 0.62; 99mTc stress/male, 0.77; 99mTc rest/male, 0.75; SDI stress/female, 0.87; SDI rest/female, 0.82; SDI stress/male, 0.87; SDI rest/male, 0.85.
Conclusions: The diagnostic accuracy of Japanese MPS normal databases on D-SPECT were comparable with nuclear cardiology expert reading and further clinical applications are expected.
Stress myocardial perfusion single-photon emission computed tomography (SPECT) has been well validated as a useful diagnostic tool to detect significant coronary artery disease (CAD) (1–3). Semi-conductor gamma camera (D-SPECT, Spectrum Dynamics Medical, Israel) is one of paradigm shifts from conventional gamma camera including outstanding technical features of high spatial resolution, high sensitivity and high energy resolution.
Automatic scoring of myocardial perfusion SPECT (MPS) on polar map has clinically been used conveniently not only for beginners but also expert readers. Two methods of defect scoring have been utilized for myocardial perfusion analysis, one with the normal database (quantitative perfusion software; QPS, Cedars Sinai Medical Center, Los Angeles, CA, USA) and the other without it (serial change analysis) (4–6). The latter, serial variation analysis, does not require a comparison of normal database, but QPS has the advantage that analysis using a normal database can be used with any version of on-board software. Usually, specific normal databases are established according to gender (male, female), radioisotope agents (201Tl, 99mTc-sestamibi, 99mTc-tetrofosmin), conditions during SPECT imaging (stress, rest), and SPECT acquisition ranges (180°or 360° acquisition). However, normal MPS databases fitted for D-SPECT Japanese population had not been created and Japanese Society of Nuclear Cardiology (JSNC) Working Group (WG) was established in 2018 for the purpose of making Japanese normal perfusion databases including 1) 201Tl stress-redistribution protocol, 2) 99mTc-sestamibi or tetrofosmin rest/stress or stress/rest protocol, and 3) simultaneous acquisition dual-isotope protocol (rest 99mTc/stress 201Tl: SDI protocol). Regarding the SDI protocol, its clinical utility and validation detecting significant CAD has been already reported by Makita et al (7).
The aim of this study was to validate relationships between WG experts’ reading scores and automated quantitative scores by QPS from the Japanese MPS normal database.
Materials and methods
JSNC WG
The members of JSNC WG and collaborated hospitals were depicted in Table 1.
Creating normal database
In determining the normal range for Japanese MPS normal database, patients between the ages of 20 and 90 years with suspected having CAD were included in the study. Patients in the normal subjects in the study are as defined, 1) apparently low pretest likelihood of CAD (<5%), 2) no electrocardiogram (ECG) abnormality suspected of having cardiac disease or ischemia, 3) neither hypertension nor diabetic mellitus requiring medical treatment, 4) no arrhythmia causing electrocardiography (ECG)-gating errors, 5) normal wall motion and ejection fraction (EF) of >50% on quantitative gated SPECT software (QGS, Cedars Sinai Medical Center, Los Angeles, CA, USA), 6) no stenosis on coronary computed tomography (CT) angiography or coronary angiography diagnosed as normal, 7) visual SPECT imaging determined to be normal, 8) no underlying cardiac diseases, 9) no chronic kidney disease (eGFR<45ml/min/1.73m2) and 10) no significant body motion during acquisition.
The collected data from collaborative hospitals for creating Japanese MPS normal database were summarized in Table 2. Each normal database (201Tl stress-redistribution protocol [201Tl protocol], 99mTc rest/stress or stress/rest protocol [99mTc protocol] and simultaneous acquisition dual-isotope protocol [rest 99mTc/stress 201Tl: SDI protocol]) was created by different number of cases. MPS findings were based on a comparison between stress and rest imaging using relative myocardial counts after the normalization; therefore, we treated equally 99mTc isotopes (99mTc-sestamibi or 99mTc-tetrofosmin), stress protocols (rest/stress or stress/rest 99mTc protocol) and stress types (exercise or adenosine stress) in this study.
Clinical validation group
The number of validation cases was targeted to accumulate at least 2 male and 2 female cases for four categories of summed stress score (SSS) normal (0–3), mildly abnormal (4–8), moderately abnormal (9–13), and highly abnormal (13<) from each WG participating hospitals. Four WG members (NM, YS, NI, and MN) read all cases using a 17-segment and 5-point scale scoring system (0, normal; 1, mildly reduced; 2, moderately reduced; 3, severely reduced; and 4, nearly no uptake) (8, 9). Four WG readers of the MPS were all certified specialists of Japanese Society of Nuclear Medicine. However, weighted κ values in the SDI protocol were obtained from four WG readers to verify inter-reader variability. SDI protocol includes both 201Tl and 99mTc images, therefore it would be appropriate to verify it. The most frequent score among 4 WG readers in each 17-segment was obtained from each case. Weighted κ values were calculated between the visual segmental scores by 4 WG readers and automated segment scores obtained from QPS software based on various kinds of Japanese MPS normal databases.
Statistical analysis
Numbers are expressed as mean ± SD. Statistical analyses were performed using MedCalc for Windows, version 19.2.1 (MedCalc Software, Ostend, Belgium). Inter-rater agreement of κ statistics was applied.
Approval of ethics committees
This retrospective study was registered as UMIN 000035757 and approved by an independent review board committee of the Nihon University Hospital (IRB No. 150102 for creating normal database and IRB No. 20190301 for this validation study). Ethics committees approved the study in all participating hospitals.
Results
Creation of normal databases
Patient numbers from WG member’s hospitals were as follows: 201Tl protocol, female 58 and male 72; 99mTc protocol, female 97 and male 127; and SDI protocol, female 34 and male 38 (Table 2). 201Tl data came from institutions 1, 2, 5 and 7. 99mTc data came from institutions 1-6 and 8. SDI data came from institution 6. Japanese MPS normal databases for various isotopes and gender were depicted in Figure 1. Figure 1A–C showed 201Tl protocol, 99mTc protocol, and SDI protocol, respectively.
Validation group
Weighted κ values of SDI protocol at rest and stress among 4 WG readers were as follows; MN-NI, 0.51; MN-NM, 0.69; MN-YS, 0.67; NI-NM, 0.57; NI-YS, 0.59; and NM-YS, 0.93 at resting 99mTc images. At stress 201Tl images; MN-NI, 0.60; MN-NM, 0.75; MN-YS, 0.72; NI-NM, 0.66; NI-YS, 0.64; and NM-YS, 0.94 were observed. Patient population and background in validation group were depicted in Table 3. Table 3A-C showed 201Tl protocol, 99mTc protocol, and SDI protocol, respectively. Weighted κ values for various combinations of methods and gender were as follows; 201Tl stress/female, 0.77; 201Tl rest/female, 0.74; 201Tl stress/male, 0.81; 201Tl rest/male, 0.68; 99mTc stress/female, 0.77; 99mTc rest/female, 0.62; 99mTc stress/male, 0.77; 99mTc rest/male, 0.75; SDI stress/female, 0.87; SDI rest/female, 0.82; SDI stress/male, 0.87; SDI rest/male, 0.85 (Figure 2).
Discussion
An appropriate normal database is one of the essential factors for reliable and reproducible quantification of MPS. The normal database is known to vary by gender, body size, tracer, and camera types. Since D-SPECT is a new generation gamma camera with a semiconductor detector, the normal database on board has been made only by foreign subjects. With the spread of D-SPECT in Japan, the normal database for Japanese subjects became necessary, as the type of population-specific databases significantly influenced the diagnostic accuracy (10). In comparison to the Japanese MPS normal databases created by Japanese Society of Nuclear Medicine WG, Japanese MPS normal database on D-SPECT showed basically uniform distribution of myocardial counts (11). Anger-type conventional gamma camera sometimes includes breast attenuation in the anterior wall in female patients and subdiaphragmatic attenuation in the inferior wall in male subjects. However, D-SPECT provides uniform count distribution compared with Anger camera, probably because effects of attenuation is relatively small using upright-position imaging. Moreover, the %count in the basal segments was relatively higher by D-SPECT compared with that by Anger camera (12). Figure 1A–C showed relatively reduced tracer uptake in the distal inferior wall to inferoapex in the left ventricle in each tracer.
Inter reader agreement using inter-rater agreement (κ statistics) among 4 WG readers showed moderate to good reproducibility. This would be explained by only MPI assessment without the information of ECG-gated wall motion study. Usually, the fixed perfusion defects without wall motion abnormality are considered to be attenuation. However, WG member evaluated MPS with only severity of tracer uptake without QGS study. Therefore, use of the frequent scores in each segment should be appropriate.
Relationship between semiquantitative visual scoring by WG readers on Japanese MPS normal database and automated segmental scores obtained from QPS software showed good to excellent association in all 3 protocols (0.62≤ κ ≤0.87). Notably, SDI protocol showed excellent association (all κ >0.8). There are two possible reasons for this good association. SDI protocol uses 201Tl which has higher extraction fraction than 99mTc without subdiaphragmatic activity. This might lead a good to excellent correlation between two scores. Another reason is the possibility of patient selection bias. Conversely, 99mTc rest/female showed a little bit lower κ value (0.62). Subdiaphragmatic extracardiac accumulation of 99mTc tracer in close proximity to the inferior wall of the left ventricle might affect the scoring of the inferior wall (13). Therefore, we mention to pay attention to the interpretation of the inferior wall in the right coronary artery territory. Since the diagnostic accuracy depends on the selection of patients for validations, we suppose these results were reasonable concordance with nuclear cardiology experts, and further clinical applications are expected.
Conclusions
The Japanese MPS normal databases on D-SPECT created by JSNC WG were verified and found to be comparable to expert readings.
Acknowledgments
We deeply appreciate clinical radiological technologists for their assistance to prepare this manuscript.
Sources of funding
None.
Conflicts of interest
N. Matsumoto received lecture fees from Nihon Medi-Physics, Tokyo, Japan and PDRadiopharma, Tokyo, Japan, and had a scholarship fund from PDRadiopharma.
K. Nakajima has collaborative research with Spectrum Dynamics Medical, Israel, and belongs to endowed department partly funded by PDRadiopharma, Tokyo, Japan; Nihon Medi-Physics, Tokyo, Japan; and Siemens Healthcare, Tokyo, Japan
References
1. Hachamovitch R, Berman DS, Kiat H, Cohen I, Cabico JA, Friedman J, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery disease: incremental prognostic value and use in risk stratification. Circulation 1996; 93: 905–14.
2. Tanaka H, Chikamori T, Tanaka N, Hida S, Igarashi Y, Yamashita J, et al. Diagnostic performance of a novel cadmium-zinc-telluride gamma camera system assessed using fractional flow reserve. Circ J 2014; 78: 2727–34.
3. Matsumoto N, Sato Y, Suzuki Y, Kunimasa T, Yoda S, Iida J, et al. Prognostic value of myocardial perfusion single-photon emission computed tomography for the prediction of future cardiac events in a Japanese population: a middle-term follow-up study. Circ J 2007; 71: 1580–5.
4. Sharir T, Germano G, Waechter PB, Kavanagh PB, Areeda JS, Gerlach J, et al. A new algorithm for the quantitation of myocardial perfusion SPECT. II: validation and diagnostic yield. J Nucl Med 2000; 41: 720–7.
5. Germano G, Kavanagh PB, Waechter P, Areeda J, Van Kriekinge S, Sharir T, et al. A new algorithm for the quantitation of myocardial perfusion SPECT. I: technical principles and reproducibility. J Nucl Med 2000; 41: 712–9.
6. Slomka PJ, Nishina H, Berman DS, Kang X, Friedman JD, Hayes SW, et al. Automatic quantification of myocardial perfusion stress-rest change: a new measure of ischemia. J Nucl Med 2004; 45: 183–91.
7. Makita A, Matsumoto N, Suzuki Y, Hori Y, Kuronuma K, Yoda S, et al. Clinical feasibility of simultaneous acquisition rest 99mTc/stress 201Tl dual-isotope myocardial perfusion single-photon emission computed tomography with semiconductor camera. Circ J 2016; 80: 689–95.
8. Berman DS, Kiat H, Friedman JD, Wang FP, van Train K, Matzer L, et al. Separate acquisition rest thallium-201/stress technetium-99m sestamibi dual-isotope myocardial perfusion single-photon emission computed tomography: a clinical validation study. J Am Coll Cardiol 1993; 22: 1455–64.
9. Berman DS, Abidov A, Kang X, Hayes SW, Friedman JD, Sciammarella MG, et al. Prognostic validation of a 17-segment score derived from a 20-segment score for myocardial perfusion SPECT interpretation. J Nucl Cardiol 2004; 11: 414–23.
10. Nakajima K, Okuda K, Kawano M, Matsuo S, Slomka P, Germano G, et al. The importance of population-specific normal database for quantification of myocardial ischemia: comparison between Japanese 360 and 180-degree databases and a US database. J Nucl Cardiol 2009; 16: 422–30.
11. Nakajima K, Matsumoto N, Kasai T, Matsuo S, Kiso K, Okuda K. Normal values and standardization of parameters in nuclear cardiology: Japanese Society of Nuclear Medicine working group database. Ann Nucl Med 2016; 30: 188–99.
12. Nakajima K, Kumita S, Ishida Y, Momose M, Hashimoto J, Morita K, et al. Creation and characterization of Japanese standards for myocardial perfusion SPECT: database from the Japanese Society of Nuclear Medicine Working Group. Ann Nucl Med 2007; 21: 505–11.
13. Johansen A, Lomsky M, Gerke O, Edenbrandt L, Johansson L, Hansen G, et al. When is reacquisition necessary due to high extra-cardiac uptake in myocardial perfusion scintigraphy? EJNMMI Res 2013; 3: 20.
