Currently, the global population continues to bear the enormous burden of coronary artery disease (CAD). Gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is a widely used noninvasive method for diagnosing CAD (1,2). SPECT MPI can show the location, extent, and severity of myocardial ischemia or infarction and provide information on myocardial perfusion and global and regional function (3-5). Nonetheless, the results of SPECT MPI may be incorrectly negative in patients with multivessel CAD, particularly those with 3-vessel diffuse illness, due to “balanced ischemia”, resulting in a missed diagnosis of severe CAD (6-8). At the same time, obstructive CAD increases with coronary artery calcium score (CACS), which reflects the burden of coronary atherosclerotic plaque (9,10). Previous research has shown that adding CACS to stress MPI improves the diagnosis of CAD (11).
Artificial intelligence (AI) is a growing and powerful technology in healthcare. In recent years, the application of AI in nuclear cardiology has become increasingly extensive (12-17). An interpretable algorithm based on deep learning was used to diagnose obstructive CAD in stress or stress/rest MPI (15,18). However, stress MPI is not suitable for all patients, as stress tests are contraindicated in patients with suspected acute coronary syndrome (ACS) (19). Previous studies found that, despite the addition of wall motion, rest-only MPI had limited value in detecting CAD, with a sensitivity of less than 50% (20,21). To date, there have been no studies of resting MPI combined with CACS and cardiovascular risk factors using machine learning (ML) to detect obstructive CAD. Therefore, the purpose of this study was to use ML to evaluate the value of rest-only MPI combined with CACS and cardiovascular risk factors for detecting obstructive CAD in suspected CAD patients. We present the following article in accordance with the TRIPOD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-22-758/rc).
Study cohort and population
We recruited a retrospective cohort of suspected CAD patients who underwent gated SPECT MPI at the Third Affiliated Hospital of Soochow University from February 2016 to April 2020. The following were the inclusion criteria: (I) no history of a definite myocardial infarction, (II) a contraindication to stress test, (III) no history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and (IV) coronary angiography was completed within 3 months of the examination. Severe valvular disease, hypertrophic or dilated cardiomyopathy, severe arrhythmias, poor image quality due to motion artifacts, and a lack of CACS scan data were the exclusion criteria. Finally, 253 patients were included in the study, including 61 with suspected ACS, 39 with decompensated heart failure, 41 with bradycardia combined with restricted physical activity, 54 with uncontrolled hypertension (systolic blood pressure >200 mmHg), and 58 with asthma. The detailed process of patient recruitment and study design is shown in Figure 1. The Ethics Committee of the Third Affiliated Hospital of Soochow University approved the research protocol, which complied with the Declaration of Helsinki (as revised in 2013). The requirement for informed consent was waived since the study was retrospective.
Resting image acquisition and analysis
99mTechnetium-sestamibi (99mTc-MIBI) (740–925 MBq) was administered intravenously at rest. Scanning was started after 60–90 min of rest. A dual-head 90o gamma camera (Symbia T16; Siemens Medical Systems, Erlangen, Germany) equipped with a parallel-hole collimator with low energy and high resolution was used for image acquisition. Detailed scan parameters are provided in our previous study (22). All SPECT image acquisition procedures followed the recommendations of the relevant guidelines (23). Perfusion images were analyzed using an international 17-segment model (24), which was divided into territories of the left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX), and right coronary artery (RCA). Quantitative perfusion SPECT + quantitative gated SPECT (QPS + QGS) 2009 automated analysis software (Cedars-Sinai Medical Center, Los Angeles, CA, USA) were used for semi-quantification of perfusion and wall motion, which scored perfusion (0–4) and wall motion (0–5) according to the degree of abnormality. The detailed meaning of the scores can be found in the relevant studies (25,26). Quantitative analysis of images was performed by a nuclear cardiologist. The summed rest score (SRS) or summed motion score (SMS) was the sum of the 17-segment resting perfusion or wall motion scores. An SRS ≥4 or SMS ≥2 exhibited in 2 consecutive segments in 1 territory was considered abnormal (20,25).
CACS acquisition and analysis
A chest CT for obtaining CACS was performed after the completion of the MPI acquisition. Scan details were as follows: tube voltage, 120 kV; tube current, 100 mA; thickness, 3 mm; 60–80% of the R-R interval, and completed with 1 breath-hold after inhalation. The scanning range was from the plane below the tracheal carina to 1–2 cm below the heart’s diaphragmatic surface. Coronary artery calcifications were identified as dense areas in coronary arteries that exceeded the 130 Hounsfield unit (HU) threshold using the Agatston algorithm (27). CACS was measured independently by a nuclear cardiologist. The sum of the calcium scores of left main coronary artery (LM), LAD, LCX, RCA, and their branches was defined as CACS, and then CACS was divided into 4 categories: 0, 1–100, 101–399, and ≥400 (28,29).
Invasive coronary angiography
All coronary angiograms were visually interpreted on-site by 2 cardiologists. Obstructive CAD was defined as ≥70% narrowing of the inner diameter of the LAD, LCX, RCA, or their main branches and ≥50% narrowing of the LM (30). If 2 physicians disagreed on the results, a third senior physician was invited to read the angiograms, and the final decision was the opinion with the most votes.
We performed feature selection based on clinical experience and actual situations before ML. Combining variable selection from our previous study (22) and clinical experience, we finally identified the following 8 variables: age, gender, hypertension, diabetes, hyperlipidemia, SRS, SMS, and CACS. The correlation between variables was analyzed using Spearman correlation (R package: corrplot). The study population included 253 suspected CAD patients who underwent rest-only MPI due to stress contraindications. Participants were divided at random into 2 groups: the training (70%) and test (30%) groups. We selected supervised ML algorithms developed in R statistical software (version 4.1.0, R Foundation for Statistical Computing, Vienna, Austria). A total of 8 ML algorithms were used: Logistic (31), recursive partitioning and regression trees (Rpart) (R package: rpart), random forest (32), extreme gradient boosting (XGBoost) (R package: xgboost), Naïve Bayes (R package: naivebayes), K-nearest neighbor (KNN) (R package: kknn), support vector machine (SVM) (R package: e1071), and adaptive boosting (AdaBoost) (33). Except for tree-based ML algorithms, we performed feature normalization. We used a 10-fold cross-validation approach, conducted twice, for the training data. We tuned the free parameters for each algorithm using this subset. For both the training and test groups, we computed accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver operator characteristic curve (AUC).
All statistical analysis was performed using the R software. Continuous variables that conformed to the normal distribution were expressed as the mean ± SD, and continuous variables that did not conform to the normal distribution were expressed as the median P50 (P25, P75). Chi-square tests were used for categorical variable comparisons between groups. The unpaired t-test for normal continuous variables or Mann–Whitney U test for skewed continuous variables were used for comparisons between 2 groups. The receiver operator characteristic curve (ROC) analysis was used to assess the discrimination of models. The best cutoff value was calculated using Youden index. A 2-sided P value less than 0.05 was considered statistically significant.
Among 253 patients with suspected CAD, 94 (37.2%, 94/253) were diagnosed with obstructive CAD by coronary angiography. Participants were divided randomly into 2 groups: the training (70%, n=178) and test (30%, n=75) groups. A total of 8 ML algorithms were used and validated, with detailed results presented below.
Demographics and clinical characteristics
The mean age was 62.7±9.0 years in the obstructive CAD group and 60.9±9.3 years in the nonobstructive CAD group (P=0.131). There was a higher proportion of males in the obstructive CAD group compared with the nonobstructive CAD group (76.6% vs. 61.0%; P=0.011). There were no significant differences in body mass index (BMI) and smoking history between the 2 groups. Cardiovascular risk factors, including hypertension, diabetes, and hyperlipidemia, were more prevalent in patients with obstructive CAD. There was no significant difference in medication history, such as angiotensin-converting enzyme inhibitors, beta-blockers, or calcium channel blockers, between the 2 groups. The clinical characteristics are displayed in Table 1.
|Variables||Without obstructive CAD (n=159)||With obstructive CAD (n=94)||P value|
|Age (years old)||60.9±9.3||62.7±9.0||0.131|
|Male||97 (61.0)||72 (76.6)||0.011|
|Hypertension||102 (64.2)||72 (76.6)||0.039|
|Diabetes||26 (16.4)||35 (37.2)||<0.001|
|Hyperlipidemia||92 (57.9)||74 (78.7)||0.001|
|Smoking >1 year||58 (36.5)||41 (43.6)||0.261|
|ACEI||81 (50.9)||58 (61.7)||0.097|
|Beta-blockers||98 (61.6)||66 (70.2)||0.167|
|Calcium channel blockers||95 (59.7)||54 (57.4)||0.719|
Data are shown as mean ± standard deviation or number (percentage). CAD, coronary artery disease; BMI, body mass index; ACEI, angiotensin-converting enzyme inhibitor.
Characteristics of gated SPECT MPI and CACS
Participants with obstructive CAD had lower left ventricular ejection fraction (LVEF) and a peak filling rate (PFR) compared to the group without obstructive CAD. End-diastolic volume (EDV), end-systolic volume (ESV), SRS, and SMS were higher in the obstructive CAD group than in the nonobstructive CAD group. In the group without obstructive CAD, 111 (69.8%, 111/159) patients had a CACS of 0 and 33 (20.8%, 33/159) had a CACS between 1 and 100. In the obstructive CAD group, 36 (38.3%, 36/94) patients had a CACS between 101 and 399, and 25 (26.6%, 25/94) had a CACS ≥400. The characteristics of gated SPECT MPI and CACS are displayed in Table 2. Figure 2 shows the distribution and probability density of continuous variables in patient characteristics.
|Variables||Without obstructive CAD (n=159)||With obstructive CAD (n=94)||P value|
|EDV (mL)||83.0 (67.0–105.0)||89.0 (71.0–114.3)||0.075|
|ESV (mL)||30.0 (21.0–41.0)||33.5 (25.8–48.3)||0.003|
|SRS||0.0 (0.0–1.0)||2.0 (0.0–7.0)||<0.001|
|SMS||0.0 (0.0–0.0)||1.0 (0.0–9.3)||<0.001|
|CACS||0.0 (0.0–9.1)||152.9 (47.7–442.5)||<0.001|
|CACS: 0 (%)||111 (69.8)||12 (12.8)||<0.001|
|CACS: 1–100 (%)||33 (20.8)||21 (22.3)||0.766|
|CACS: 101–399 (%)||11 (6.9)||36 (38.3)||<0.001|
|CACS ≥400 (%)||4 (2.5)||25 (26.6)||<0.001|
Data are shown as mean ± standard deviation, median (interquartile range) or number (percentage). SPECT, single photon emission computerized tomography; MPI, myocardial perfusion imaging; CACS, coronary artery calcium score; CAD, coronary artery disease; EDV, end diastolic volume; ESV, end systolic volume; LVEF, left ventricular ejection fraction; SRS, summed rest score; SMS, summed motion score; PFR, peak filling rate.
Diagnostic efficacy of 8 ML algorithms for predicting obstructive CAD in the training group
The Spearman correlation coefficients of the included features were calculated (Figure 3). Most features had weak correlations with absolute values less than 0.25. The correlation between SMS and SRS was moderate (ρ=0.58) and was the highest correlation among the features. The lower correlation values shown by the heatmap indicated the absence of redundant features.
As shown in Figure 4, The AUCs of Logistic, Rpart, random forest, XGBoost, Naïve Bayes, KNN, SVM, and AdaBoost in the training group were 0.905 [95% confidence interval (CI): 0.861–0.949], 0.893 (95% CI: 0.841–0.944), 1.000 (95% CI: 1.000–1.000), 0.922 (95% CI: 0.878–0.965), 0.897 (95% CI: 0.853–0.942), 0.874 (95% CI: 0.819–0.929), 0.925 (95% CI: 0.883–0.967), and 0.953 (95% CI: 0.926–0.979), respectively. The AUC of the random forest was the highest, and the AUCs of Logistic, XGBoost, SVM, and AdaBoost were all above 0.9. The accuracy, sensitivity, specificity, PPV, and NPV of each algorithm for diagnosing obstructive CAD are shown in Table 3 and Figure 5. Random forest, SVM, AdaBoost, and XGBoost techniques exhibited high accuracy, although each had advantages in terms of sensitivity or specificity.
|ML techniques||Training group (n=178)||Test group (n=75)|
ML, machine learning; PPV, positive predictive value; NPV, negative predictive value; Rpart, recursive partitioning and regression trees; KNN, K-nearest neighbor; SVM, support vector machine; XGBoost, extreme gradient boosting; AdaBoost, adaptive boosting.
Diagnostic efficacy of ML algorithms in the test group
The AUCs of Logistic, Rpart, random forest, XGBoost, Naïve Bayes, KNN, SVM, and AdaBoost in the test group were 0.896 (95% CI: 0.817–0.975), 0.911 (95% CI: 0.846–0.976), 0.888 (95% CI: 0.802–0.974), 0.899 (95% CI: 0.832–0.965), 0.866 (95% CI: 0.768–0.964), 0.859 (95% CI: 0.768–0.950), 0.874 (95% CI: 0.784–0.964), and 0.845 (95% CI: 0.754–0.937), respectively (Figure 4). The AUC of Rpart was the highest (0.911). In the test group, Rpart and Naïve Bayes had the highest accuracy (0.840). The sensitivity and specificity of Rpart were 0.851 and 0.821, respectively. The sensitivity and specificity of Naïve Bayes were 0.809 and 0.893, respectively. The algorithm with the next highest accuracy was Logistic, with an accuracy of 0.827, a sensitivity of 0.872, and a specificity of 0.750. A high accuracy of 0.813 was also demonstrated by the random forest and XGBoost algorithms. Figure 6 shows the importance of features in the random forest, XGBoost, Logistic, and Rpart algorithms.
This study demonstrated the role of ML in detecting obstructive CAD with rest-only MPI combined with CACS and cardiovascular risk factors. In the training group, the AUC of random forest was the highest, and the AUCs of Logistic, XGBoost, SVM, and AdaBoost were all above 0.9. In the test group, the AUC of Rpart was the highest (0.911). Rpart and Naïve Bayes had the highest accuracy (0.840). The algorithm with the next highest accuracy was Logistic, with an accuracy of 0.827, a sensitivity of 0.872, and a specificity of 0.750. This present study demonstrated that combining CACS and cardiovascular risk factors using ML algorithms can improve the performance of resting-gated SPECT MPI for detecting obstructive CAD.
The most common cause of CAD is coronary artery stenosis due to coronary atherosclerotic plaque. As the degree of stenosis increases, the risk of myocardial ischemia also increases, with myocardial ischemia reaching more than 80% in over 70% of stenotic coronary arteries (34). Gated SPECT MPI is a widely used, well-validated, noninvasive method for detecting myocardial ischemia and obstructive CAD (5,15,35). The value of stress SPECT MPI in the diagnosis and risk stratification of CAD has been widely confirmed (36). Usually, if the SRS is high and obstructive CAD exists, it is myocardial infarction. If the SRS is high yet there is no obstructive CAD, it is pseudo-positive by artifacts. If the SRS is low and there is no obstructive CAD, it is true normal. If the SRS is low and obstructive CAD is present, it is demand ischemia, which is difficult to detect without conventional stress MPI. A previous study found that the combination of CACS on the basis of stress MPI improved the sensitivity for detecting CAD from 76% to 86%, with no significant difference in specificity (11). However, many patients can still only choose resting MPI due to the contraindication of stress, such as ACS. In addition, rest-only MPI is less effective for detecting CAD, with a sensitivity of approximately 30% (20). Improving the ability of rest-only MPI to diagnose CAD is an urgent clinical issue, and ML is increasingly used in cardiovascular imaging. The present study demonstrated that the combination of resting MPI, CACS, and cardiovascular risk factors improved the diagnosis of obstructive CAD by using ML algorithms. We showed the importance of features in 4 algorithms in the test set. Overall, the importance of SRS was relatively low among the 4 algorithms. A possible reason for this might have been that, at rest, even if the coronary arteries significantly narrowed, the myocardial blood flow could still be normal due to coronary compensation. Meanwhile, a previous study confirmed that the sensitivity of rest-only perfusion abnormalities for diagnosing CAD was low (20). Therefore, we believe that SRS still plays a role in different algorithms.
Eight ML algorithms were used in this research. Rpart, Naïve Bayes, XGBoost, Logistic, and random forest were highly accurate for diagnosing obstructive CAD in the test group. Rpart is a decision tree algorithm that operates by recursively dividing the dataset into 2 parts. The features that best reduce the heterogeneity of the outcome variables are taken into account to determine the partition at each stage (37). XGBoost, a scalable end-to-end tree boosting technique, uses a weighted quantile sketch for approximate tree learning and a sparse-aware algorithm for sparse data (38). The Logistic algorithm used in this study is a part of generalized linear models (17). This classifier is widely used in clinical statistical analysis for dichotomous and multicategory outcome variables. The predictor variables and the log odds of the event were supposed to have a linear relationship by the equation. ADA is a classification tree that fits various stochastic boosting models using adaptive algorithms. A combination of this algorithm and other learning procedures can be used to enhance performance. The output of these procedures, known as weak learners, is merged into a weighted sum that reflects the boosted classifier’s final output (39). AdaBoost is a classifier that works similarly to ADA, but is not the same as ADA. Freund and Schapire implemented the M1 algorithm (40). Based on the Statistical Learning Theory, SVM is a powerful supervised ML model for binary and nonlinear classification issues (41). In this study, the sensitivity and specificity in the training set were calculated according to the optimal cutoff value found by Youden’s rule, and then the cutoff value was used in the test set to evaluate the sensitivity and specificity. The sensitivity and specificity of the 8 ML methods in the test set were inconsistent, showing different advantages. We used a 10-fold cross-validation approach for the training data (42-45). Ten-fold cross-validation divides the training set into 10 subsamples; 1 single subsample is retained as the data to validate the model, and the other 9 samples are used for training. Therefore, cross-validation can use more sample information to tune hyperparameters.
Computed tomography angiography (CTA) and SPECT MPI, according to the latest European Society of Cardiology (ESC) guidelines (46), are both class I recommendations for suspected CAD patients. CTA is an option for patients with contraindications to stress MPI. A previous study found that CTA had a sensitivity and specificity of 82% and 92%, respectively, for diagnosing ACS in patients with low-risk chest pain (47). The development of ML in CTA further expands its application (48). In this study, resting MPI combined with CACS and cardiovascular risk factors were over 80% accurate in diagnosing obstructive CAD based on the Logistic, Rpart, Naïve Bayes, XGBoost, and random forest algorithms. However, for patients with extensive coronary calcification, arrhythmia, severe obesity, and difficulty holding their breath, CTA may not be appropriate since the image quality will be compromised. Additionally, CTA can provide anatomical stenosis, whereas SPECT MPI combined with CACS can provide anatomical and functional information simultaneously. Our results show that ML can effectively improve the diagnosis of obstructive CAD by rest-only MPI and may be used for CAD screening, although there are still many limitations. ML and AI may be the direction of future development and deserve attention.
Several limitations of this study should be taken into account. First, this study was not externally validated, and its extrapolation still needs to be validated. Second, patients with stress-related contraindications did not undergo CTA, so it was impossible to compare their diagnostic efficacy. Third, we could not analyze subgroups due to size limitations in the included population, which included multiple contraindications to stress. This study also had a small sample size and needs to be carried out again in a prospective, large sample, multicenter study to validate its findings.
Rest-only SPECT MPI combined with CACS and cardiovascular risk factors using ML algorithms to diagnose obstructive CAD is feasible. Among the algorithms tested in the test group, Rpart, Naïve Bayes, XGBoost, Logistic, and random forest are highly accurate for diagnosing obstructive CAD. The application of ML in resting MPI and CACS may be used for screening obstructive CAD.
Funding: This research was partially supported by the National Natural Science Foundation of China (No. 81871381; PI: Yuetao Wang); the Key Laboratory of Changzhou High-tech Research Project (No. CM20193010; PI: Yuetao Wang); the Chinese National Natural Science Foundation for Young Scholars (No. 81901777; PI: Feifei Zhang); and the Science and Technology Project for Youth Talents of Changzhou Health Committee (No. QN201920; PI: Feifei Zhang).
Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-22-758/rc
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-758/coif). The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of the Third Affiliated Hospital of Soochow University approved the study protocol, and the requirement for informed consent was waived since the study was retrospective.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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