Lung cancer is the most common cancer and the leading cause of cancer death in China. It is estimated to be responsible for more than 0.61 million deaths in 2015 (1). With the advent of widely available computed tomography (CT) scanning, the number of discovered pulmonary nodules has significantly increased. The National Lung Cancer Screening Test (NLST) revealed a relative 20% reduction in mortality from lung cancer with low-dose CT screening when compared with chest radiography (2). However, more than 90% of the nodules detected in CT screening were benign lesions. It is thus crucial for surgeons and physicians to accurately evaluate the lesion, as mischaracterization can either lead to unjustified surgery of benign lesions or delayed treatment of malignancy nodules (3).
A solitary pulmonary nodule (SPN) is defined as an approximately round lesion that is less than 3 cm in diameter and is completely surrounded by pulmonary parenchyma, without any associated atelectasis, lymphadenopathy or pleural effusion (4-6). SPNs can be classified into solid or subsolid types according to CT manifestation. Data from lung cancer screening tests have revealed that subsolid nodules have a significantly greater likelihood of being malignant than solid nodules on first screening CT (7,8). Of the patients who received surgical resections, the malignant ratio for subsolid nodules can be above 90% (9,10), while the malignant ratio for solid nodules ranges from 53% to 75% (11-14). This highlights the necessity of differentiating the nature of solid SPNs in an accurate and timely manner.
Although surgeons routinely make such judgments in the day to day practice, a standardized management approach has been established to estimate the malignancy of SPNs (3,7,11-13,15,16). The most extensively used model was established by Swensen et al. in the 1990s (15). However, 12% of the patients did not have a final diagnosis in their study. Another widely used approach is the Brock model established by McWilliams et al. (7), although both solid and subsolid SPNs were mixed together in that model. In addition, most of the previously proposed models were based on logistic regression (LR) analysis. Data mining, also known as knowledge-discovery in databases (KDD), is a new interdisciplinary branch of science which combines automated methods and statistical knowledge (17,18). The process tries to discover potential relationships and establish appropriate models of data and is considered as an effective method of discovering useful information from data. In our previous study (10), we tested the ability of certain data mining methods to differentiate between benign and malignant pulmonary ground-glass nodules (GGNs) and to predict invasiveness of malignant nodules. We found a good diagnostic value in predicting the malignancy and invasiveness of pulmonary GGNs by random forest (RF). The purpose of this study is to identify the clinical and radiological features that may help decide the malignancy of solid SPNs and to develop an effective and efficient model by data mining methods.
Retrospective data of 588 consecutive patients with solid SPNs who received surgical resection from 2013 to 2016 at Shanghai Chest Hospital were analyzed. All of the patients had a definite pathological diagnosis. CT scans were conducted using a 64-detector CT row scanner (Brilliance 64; Philips, Eindhoven, The Netherlands). The images were reconstructed using soft tissue and lung algorithms with a thickness of 1 mm. The CT features were evaluated in the following settings: lung window center, −520 HU/lung window width, 1,450 HU; mediastinal window center, 40 HU/mediastinal window width, 350 HU. The description of CT imagines and data collection were conducted by three thoracic radiologists (X Ye, L Zhu and Q Chen) and two thoracic surgeons (Y Sun and Y Xiang).
The clinical data included patients’ gender, age, smoking history, smoking quantity, previous malignancy and position of the lesion. The radiologic characters included the nodule diameter, the presence of spiculation, calcification, pleural indentation, lobulation and vascular convergence. Specific patterns of calcification manifesting as diffuse solid, laminated, concentric or popcorn were excluded from this study as they often suggest a benign lesion (6). The tumor biomarkers include carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), cytokeratin-19-fragment, (CYFRA21-1), neuron-specific enolase (NSE), and squamous cell carcinoma antigen (SCC).
Statistical analysis and model construction
Patients who received surgery from January 2013 to December 2015 were assigned to the training cohort (n=388). Those who received surgery from January 2016 to December 2016 were assigned to the validation cohort (n=200). The clinical, radiological and tumor biomarkers were analyzed by SPSS Statistics 19.0 software to compare the baseline demographic features of the train cohort against the validation cohort. Quantitative variables were evaluated by the Student’s t-test, while qualitative variables were examined with the Chi-square test.
By using the SPSS Modeler 18.0, five classifiers including LR, artificial neural network (ANN), k-nearest neighbor (KNN), RF, and support vector machines (SVM) were used to establish the model. A brief description of these data mining methods and the Mayo model is shown in Table 1.
The parameters of classifiers play an important role in the classification performance and we set the parameters as follows to enhance the performance of each classifier: the radial basis function kernel as the kernel of the SVM, with the parameter C=16, γ=0.06 (1/number of features); Euclidean distance function as the distance metric in KNN, with the number of nearest neighbor ranging from 3 to 5; a multilayer perceptron neural network for the ANN model consisting of one input layer, one or more hidden layers and an output layer; one hundred decision tree number in RF model with the max feature including all the features input; binomial LR in the LR model with forward selection.
To prospectively evaluate the diagnostic efficiency, the data of the validation cohort was input into the five models by SPSS Modeler. Predictive performance was evaluated using the area under the receiver operating characteristic (ROC) curve. The Mayo model (15) was also evaluated by the validation cohort. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of each model were evaluated.
Matthews correlation coefficient (MCC) is typically used in machine learning as a measure of the quality of binary (two class) classifications introduced by the biochemist Brian W. Matthews in 1975 (23). The MCC is in essence a correlation coefficient between the observed and predicted binary classifications; it returns a value between −1 and +1. A coefficient of +1 represents a perfect prediction, 0 represents no better than a random prediction and −1 represents a total disagreement between prediction and observation. The formula can be expressed as the following:
Tp is the number of true positives; Tn is the number of true negatives; Fp is the number of false positives; Fn is the number of false negatives.
The characteristics of 588 participants with solid SPNs are described in Table 2. The patient group was comprised of 339 (57.7%) males and 249 (42.3%) females with an average age of 59.98±10.21 years. Overall, 462 (78.6%) patients were pathologically proven to have a malignant lesion and 126 (21.4%) patients had a benign lesion. The 462 malignant tumors consisted of 381 (82.5%) cases of adenocarcinoma, 35 (7.6%) cases of squamous cell carcinoma, 5 (1%) cases of adenosquamous carcinoma, 6 (1.3%) cases of small cell carcinoma, 9 (1.9%) cases of large cell carcinoma, 3 (0.6%) cases of carcinoid, 20 (4.3%) cases of metastatic tumor, 1 (0.2%) case of sarcomatoid carcinoma and 2 (0.4%) cases of lymphoepithelioma. There was no significant difference between the training cohort and the validation cohort in terms of patient or tumor characteristics.
Predictive performance of the five models
Predictive performance of the five models for the validation cohort is shown by the ROC curves in Figure 1. SVM model achieved the highest AUC of 0.890±0.0323. The AUC of LR, ANN, KNN, RF and the Mayo model was 0.874±0.0280, 0.833±0.0351, 0.792±0.0418, 0.775±0.0400, and 0.793±0.0416, respectively (Figure 1). The SVM model had a better predictive performance than the Mayo model (P=0.030) (Table 3). SVM showed equivalent sensitivity to LR, but had the best specificity, PPV, NPV, accuracy and MCC for the validation cohort. A detailed comparison of the performance of each model in predicting the malignancy of solid SPNs is summarized in Table 4.
The ten most important variables in the SVM model included lobulation, calcification, spiculation, pleural indentation, diameter, age, vascular convergence, CEA, previous malignancy and smoking history. The relative importance of these variables can be seen in Figure 2.
Evaluating the probability of malignancy is an important step in the management decision making for SPNs, since timely treatment is associated with more favorable prognosis and over diagnosis may cause unnecessary biopsies, radiation exposure, and other secondary costs of screening. Differential diagnosis of solid SPNs has proven to be more difficult than subsolid nodules and thus, has become a pressing problem in daily practice. A comprehensive evaluation of clinical and radiological characteristics is needed to establish the probability of malignancy before treatment (16,24). With a sole focus on the solid nodules, our study made an initial effort in exploring the potential of diagnosing SPNs by using data mining methods.
Five classifiers were utilized in our study among which SVM achieved the best predictive performance with the top AUC of 0.890 for the validation cohort. LR is a traditional and prevalent algorithm which has been widely used in industrial scale problems and health research (25). Previous studies of evaluating the malignancy of pulmonary nodules were mainly based on the LR algorithm (11-13,15). The heuristic behind SVM is quite different from LR. The LR algorithm uses a weighted least squares algorithm (26). SVM is based on the structural risk minimization criterion and the Vapnik-Chervonenkis concept (22), which directly finds the best dividing hyperplane regardless of the actual probability of class membership. In the classification problems, SVM generally showed equal or superior performance than LR (27). Examples of applications using SVM include image recognition (28), medical diagnostics (10), survival prediction (29), and analysis of bioinformatics and genetics (30). In our study, SVM showed equivalent sensitivity to LR, but outperformed LR in specificity, PPV, NPV and accuracy for the validation cohort.
In the present study, three clinical variables (age, previous malignancy and smoking history), six radiological characteristics (diameter, lobulation, calcification, spiculation, pleural indentation, vascular convergence) and one serum tumor marker (CEA) were adopted as important predictors in the SVM model. Comparing with other models based on the LR algorithm, the SVM model contained more predictors of malignancy for patients with solid SPNs. Pleural indentation, vascular convergence and CEA have seldom been reported as independent predictors in the LR algorithm. However, it has been widely recognized that the presence of pleural indentation sign and vascular convergence sign were associated with malignant SPNs (31). CEA has been demonstrated as an effective marker for a wide range of malignancies (32). As reported by Yonemori et al. (14), the mean serum CEA was significantly higher in malignant SPNs compared to benign SPNs. By combing more variables, it is not surprising that the SVM algorithm achieved better predictive performance than the LR algorithm. In other words, more hidden risk factors associated with the diagnosis of SPNs were discovered by data mining methods. We suggest that data mining methods can be applied in more medical fields to explore risk factors, discover hidden relationships, establish appropriate models and improve management outcomes.
The clinical and radiological data we collected were easily available in daily work. The five serum tumor makers are routinely examined before operation. SPSS Statistics 19.0 and SPSS Modeler 18.0 were the software programs we used to construct the five models. SPSS Statistics is widely used in medical record and statistical analysis. SPSS Modeler allows data mining to be a highly accessible approach for clinicians. As expected, data mining methods such as SVM showed greater accuracy with the combination of more variables than the conventional LR algorithm. However, this is just an initial attempt which awaits for further validation in a wider range of study. When the data series become more complicated, such as if the radiomics features are used to describe the SPNs, the advantages of data mining methods over traditional algorithms may be more comprehensively verified. In terms of making the diagnosis of SPNs more efficient and accurate, it is still worth exploring more complicated machine learning techniques even though the predictive performance of SVM is only slightly better than the LR algorithm in our current study. The problem is that data mining methods are usually connected with complicated statistical methods and the formulas are expressed as a very abstruse pattern. How to implement these models in the clinical practice is an important question we need to solve in the future.
There were several limitations in our study. First, the radiologic features of SPNs that we collected in our study were described by radiologists and surgeons instead of being captured directly as information from the CT images. Future research will use the imaging dataset directly to develop deep learning algorithms for similar purposes. Second, positron emission tomography (PET) scan was not adopted as a differential feature in our study. PET scan is helpful in the differential diagnosis of lung cancer. However, it has not been a routine examination due to its high expense and its inability to provide useful information in SPNs smaller than 8 mm (33). Third, there was a relatively small cohort of patients included in our study which may limit the generalizability of our results. We speculate that the strengths of applying data mining algorithms to the diagnosis of solid SPNs may be more fully verified in a larger population since data mining, when compared to traditional statistical methods, has advantages in handling large scale and high dimensional data sets.
In conclusion, our study compared five data mining algorithms to predict the malignancy of solid SPNs, and SVM achieved the best predictive performance. We expect that data mining methods such as SVM could serve as an effective alternative to conventional LR in identifying the key variables and evaluating the malignancy of solid SPNs in a more accurate and timely manner.
Funding: This work is supported by the Shanghai Science and Technology Commission Foundation Project (No. 14411950800) (W Gao).
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The study was approved by the Institutional Review Board of the hospital (Number/ID of the Ethics Approval is ks14029). Informed consent was waived because of the retrospective nature of the study.
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