An integrated nomogram combined semantic-radiomic features to predict invasive pulmonary adenocarcinomas in subjects with persistent subsolid nodules
Original Article

An integrated nomogram combined semantic-radiomic features to predict invasive pulmonary adenocarcinomas in subjects with persistent subsolid nodules

Fu-Zong Wu1,2,3, Yun-Ju Wu1,4, EnKuei Tang5

1Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung; 2Faculty of Medicine, School of Medicine, National Yang Ming University, Taipei; 3School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung; 4Department of Software Engineering and Management, National Kaohsiung Normal University, Kaohsiung; 5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung

Contributions: (I) Conception and design: FZ Wu; (II) Administrative support: FZ Wu; (III) Provision of study materials or patients: FZ Wu; (IV) Collection and assembly of data: FZ Wu, EK Tang; (V) Data analysis and interpretation: FZ Wu, YJ Wu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Fu-Zong Wu, MD. Section of Thoracic and Circulation Imaging Department of Radiology, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Road, Kaohsiung 813414. Email: cmvwu1029@gmail.com.

Background: Patients with persistent pulmonary subsolid nodules have a relatively high incidence of lung adenocarcinoma. Preoperative early diagnosis of invasive pulmonary adenocarcinoma spectrum lesions could help avoid extensive advanced cancer management and overdiagnosis in lung cancer screening programs.

Methods: In total, 260 consecutive patients with persistent subsolid nodules ≤30 mm (n=260) confirmed by surgical pathology were retrospectively investigated from February 2016 to August 2020 at the Kaohsiung Veterans General Hospital. All patients underwent surgical resection within 3 months of the chest CT exam. The study subjects were divided into a training cohort (N=195) and a validation cohort (N=65) at a ratio of 3:1. The purpose of our study was to develop and validate a least absolute shrinkage and selection operator-derived nomogram integrating semantic-radiomic features in differentiating preinvasive and invasive pulmonary adenocarcinoma lesions, and compare its predictive value with clinical-semantic, semantic, and radiologist’s performance.

Results: In the training cohort of 195 subsolid nodules, 106 invasive lesions and 89 preinvasive lesions were identified. We developed a least absolute shrinkage and selection operator-derived combined nomogram prediction model based on six predictors (nodular size, CTR, roundness, GLCM_Entropy_log10, HISTO_Entropy_log10, and CONVENTIONAL_Humean) to predict the invasive pulmonary adenocarcinoma lesions. Compared with other predictive models, the least absolute shrinkage and selection operator-derived model showed better diagnostic performance with an area under the curve of 0.957 (95% CI: 0.918 to 0.981) for detecting invasive pulmonary adenocarcinoma lesions with balanced sensitivity (92.45%) and specificity (88.64%). The results of Hosmer-Lemeshow test showed P values of 0.394 and 0.787 in the training and validation cohorts, respectively, indicating good calibration power.

Conclusions: We developed a least absolute shrinkage and selection operator-derived model integrating semantic-radiomic features with good calibration. This nomogram may help physicians to identify invasive pulmonary adenocarcinoma lesions for guidance in personalized medicine and make more informed decisions on managing subsolid nodules.

Keywords: Nomogram; invasive pulmonary adenocarcinomas; subsolid nodules; diagnosis


Submitted Apr 04, 2022. Accepted for publication Nov 07, 2022. Published online Nov 30 2022.

doi: 10.21037/qims-22-308


Introduction

The prevalence and detection rate of pulmonary subsolid nodules (SSNs) has increased in recent years due to the high utilization of low-dose lung computed tomography (CT) for lung cancer screening worldwide, especially in Asian populations with a high prevalence of non-smoking-related lung cancer (1-6). Lung adenocarcinoma spectrum lesions are the most common histological subtype of lung cancer in Asian populations. They are divided into atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIAs), and invasive pulmonary adenocarcinomas (IPAs) according to the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011 (7,8). This classification has important prognostic implications because preinvasive lesions like AAH, AIS, and MIA have a more favorable prognostic outcome than IPA lesions (9-11). As persistent SSNs have a higher likelihood of lung adenocarcinoma spectrum lesions with heterogeneous growth or aggressive behavior, it is important for radiologists and clinical physicians to correctly identify these indolent preinvasive lesions from IPAs preoperatively (12-16).

Given the inconsistent diagnosis by radiologists, an increasing number of studies have attempted to incorporate clinical profiles, CT features, and radiomic biomarkers to predict IPA lesions in persistent pulmonary SSNs, such as part-solid nodules (PSNs) or pure ground-glass nodules (GGNs) (17-24). However, previous studies have demonstrated inconclusive results regarding the benefit of combined clinical, semantic, or radiomic CT features to improve IPAs prediction in different study settings (17,19-26). In this study, we hypothesized that combined semantic-radiomic features in thin-slice CT settings have superior diagnostic performance in differentiating IPAs from preinvasive lesions in patients with persistent SSNs, which is important in guiding surgical decision-making. This study tests the hypothesis that combination of semantic-radiomic features has a better classification ability than traditional models. This study aimed to develop and validate the least absolute shrinkage and selection operator (LASSO)-derived nomogram integrating semantic-radiomic features in differentiating preinvasive and IPA lesions, and to compare the predictive ability of the other six prediction models, including the clinical-semantic model (model 2), radiologist’s performance (model 3–4), and semantic model (model 5–7). We present the following article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-22-308/rc).


Methods

Study cohort

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was reviewed and approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (IRB number: VGHKS19-CT2–09). And patient consent was waived owing to the retrospective design of the study.

The inclusion criteria for the study participants were specified as follows: (I) patients with persistent SSNs ≤30 mm in the longest diameter, (II) patients not receiving preoperative therapy or treatment before surgical resection, (III) patients underwent surgical resection within 3 months of thin-slice CT, (IV) patients who underwent preoperative chest CT scan with thin-slice thickness setting before the surgical intervention (slice thickness: ≤2.5 mm), and (V) patients with a pathologically confirmed diagnosis of pulmonary adenocarcinoma spectrum lesions based on the IASLC/ATS/ERS classification. The training and validation cohorts were grouped according to the time of enrollment, and the research design followed the validation rules (27). The study participants (n=260) were divided into two groups: a training cohort (n=195) and validation cohort (n=65) in a 3:1 ratio (Figure 1). The study population consisted of 195 patients including 195 SSNs with surgical pathology from February 2016 to March 2020 in the training cohort, and 65 patients including 65 SSNs with surgical pathology from April 2020 to August 2020 in the validation cohort.

Figure 1 Overall study design process for the training and validation cohorts and diagnostic performance by each model for predicting invasive pulmonary adenocarcinoma lesions. AIC, Akaike information criterion; AUC, area under the ROC curve; BIC, Bayesian information criterion, CTR, consolidation to tumor ratio; IPA, invasive pulmonary adenocarcinoma.

CT image acquisition

All patients underwent thin-slice chest CT within 3 months of surgical resection at our hospital. All preoperative thin-slice chest CT scans were performed using a 16-slice CT scanner (Somatom Sensation 16, Siemens Healthcare, Erlangen, Germany), 64-slice CT scanner (Aquilion 64; Toshiba Medical Systems), 64-slice CT scanner (Discovery CT750 HD, GE Healthcare, Milwaukee, USA), and 256-slice CT scanner (Revolution CT, GE Healthcare, Milwaukee, USA) from the lung apex to the lung base. CT scans were acquired at full inspiration without contrast agent administration. The details of the scanning protocol for different vendors are listed as follows: tube voltage of 120 kVp; slice thickness, 1–2.5 mm; and reconstruction algorithm, soft tissue kernel.

Clinical and semantic features

The clinical information of the study participants, including age, sex, and smoking history, was collected from the electronic medical record system at the Kaohsiung Veterans General Hospital. In this study, nine CT radiologic semantic features were identified to characterize pulmonary subsolid nodules. Semantic CT features included the following: (I) lesion location, (II) nodular size along the longest axis, (III) nodular type according to the Fleischer classification (SSNs categorized as GGNs or PSNs) (28) (IV) solid part in the lung window setting with a window level of 1,500 Hounsfield units (HU) and a window width of −430 HU in the picture archiving system; (V) cystic change (defined as a low attenuation area within the SSNs), (VI) air-bronchogram (defined as small dilated, distorted bronchi passing through the SSNs), (VII) shape (smooth, lobulated, and spiculated border), (VIII) roundness (oval or irregular), and (IX) consolidation to tumor ratio (CTR). The CTR was defined as the ratio of the maximum size of consolidation (solid part in the lung window) to the maximum tumor size in the lung window. Each semantic CT feature was reviewed and defined by a consensus between two experienced thoracic radiologists (15 and 6 years of experience, respectively). The selection of the three clinical features and nine semantic features were extracted through LASSO regression to construct the clinical-semantic predictive model for differentiating preinvasive and IPA lesions according to the rationale design (29).

Radiomic feature extraction

The LifeX package open-source software (http://www.lifesoft.org) for nodule segmentation and volume of interest (VOI)-based radiomic analysis was employed to extract thin-slice CT imaging features manually by an experienced thoracic radiologist (30). A total of 41 radiomic features were grouped and extracted according to the LifeX package and previous studies. The following features were extracted for the histogram of the grey-level distribution: minimum, maximum, mean, and standard deviation of the HU distribution. The following features were extracted for the first-order metrics extracted from the histogram: SkewnessH, KurtosisH, EntropyH, and EnergyH. The following features were extracted for the second-order metrics calculated from the co-occurrence matrices: homogeneity, energy, contrast, correlation, entropy, and dissimilarity. For higher-order metrics extracted from the grey-level histogram, the parameters included features of neighborhood grey-level dependence matrix (NGLDM), grey-level co-occurrence matrix (GLCM), grey-level zone length matrix (GLZLM), and grey-level run length matrix (GLRLM).

Radiologist interpretation and predictive performance

Two experienced thoracic radiologists (with 15 and 6 years of experience, respectively) independently interpreted the pulmonary adenocarcinoma spectrum lesion subclassification of 260 SSNs according to the IASLC/ATS/ERS classification using blind evaluation methods. In addition, the pulmonary adenocarcinoma spectrum lesions were subclassified into the preinvasive lesion group (AAH, AIS, and MIA) and invasive lesion group (IPA).

Histological evaluation

All surgical specimens were routinely fixed in formalin and embedded in paraffin using hematoxylin and eosin staining for histopathological diagnosis. Two pathologists histopathologically analyzed the surgically resected specimens at a consensus conference to establish a final diagnosis. They were subclassified as AAH, AIS, MIA, and IPA lesions according to the revised lung adenocarcinoma (IASLC/ATS/ERS) classification of 2011. All 260 participants with 260 SSNs were categorized into preinvasive (AAH, AIS, and MIA lesions) and invasive lesion groups (invasive pulmonary adenocarcinoma lesions) according to the revised lung adenocarcinoma (IASLC/ATS/ERS) classification. Of all 260 patients with surgical proof, 78 (30%) patients underwent lobectomy, 24 (9.2%) underwent segmentectomy, and 158 (60.8%) underwent wedge resection.

LASSO-derived predictive model building and model comparison

A LASSO classifier was conducted using tenfold cross-validation on the training cohort to choose the optimized features and to build semantic-radiomic and clinical-semantic predictive models for IPA prediction. Six features were extracted through LASSO regression to construct a semantic-radiomic predictive model with the optimal lambda value that minimizes the error in cross-validation. Its predictive accuracy and discriminatory ability were compared with other predictive models, such as the clinical-semantic model, semantic model, or radiologist’s performance. A personalized nomogram based on the semantic-radiomic model in the training cohort was constructed to predict the degree of invasiveness of pulmonary adenocarcinoma spectrum lesions. Calibration plots with the Hosmer-Lemeshow test were used to evaluate the goodness of fit of this predictive model. The following seven predictive models were compared: combined semantic-radiomic model (Model 1); clinical-semantic model (Model 2), radiologist 1 performance (Model 3), radiologist 2 performance (Model 4), CTR model (Model 5), nodular size (Model 6), and roundness (Model 7). The discriminatory ability of these seven predictive models was evaluated and compared using C-statistics [area under the receiver operating characteristic (ROC) curve (AUC)], Akaike information criterion (AIC), and Bayesian information criterion (BIC). Higher c-statistics and lower AIC/BIC values indicated a more discriminatory model.

Statistical analyses

All statistical analyses were performed using SPSS 22.0 for Windows (SPSS Inc., Chicago, IL, USA), Stata version 13.1 (StataCorp, College Station, Texas, USA), and MedCalc 15.8 (MedCalc Software, Acacialaan 22, Ostend, Belgium). For the estimated sample size, sample size was determined by “rule of thumb” formula (31). An independent Student’s t-test was used to test the mean differences between the two groups if continuous variables are normally distributed under the null hypothesis. Continuous variables were presented as mean ± standard deviation (SD). Categorical variables were summarized as frequencies and percentages and compared using the chi-square or Fisher’s exact test to examine proportion differences between the two groups. A LASSO classifier was conducted using tenfold cross-validation on the training cohort to choose the optimized features and to build semantic-radiomic and clinical-semantic predictive models for IPA prediction. Therefore, univariate and multivariate logistic regressions were used to build a LASSO-derived predictive model/nomogram based on the selected semantic-radiomic features to differentiate IPA lesions from preinvasive lesions.

The logistic results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). ROC curves for these predictive models were constructed, and the difference between AUCs was calculated to compare the diagnostic performance of these predictive models using DeLong’s method (32). Moreover, regarding the PPV, NPV, sensitivity, specificity, positive LR (LR+), and negative LR (LR−), the diagnostic accuracy was calculated to measure the overall accuracy of these predictive models.

The Hosmer-Lemeshow test was used to estimate and validate the goodness-of-fit of the combined semantic-radiomic predictive model (33). Calibration was evaluated using Hosmer-Lemeshow goodness-of-fit statistics and calibration graphs plotting predicted IPA lesions against the observed rates in deciles of predicted risk. A prediction nomogram was established based on the LASSO-derived combined semantic-radiomics model in the training cohort. Statistical significance for all tests was set at P value of less than 0.05.


Results

The study population characteristics

In total, 260 participants with pathologically confirmed SSNs were enrolled in this study, with 66.6% (n=195) in the training cohort and 33.3% (n=65) in the validation cohort. Of the 195 participants with pathologically confirmed pulmonary adenocarcinoma spectrum lesions in the training cohort, 56 (28.7%) were men and 139 (71.3%) were women; 106 had IPA lesions, and 89 had preinvasive lesions. The prevalence of IPA lesions in the training cohort was 54.35%. Of the 65 participants with pathologically confirmed pulmonary adenocarcinoma spectrum lesions in the validation cohort, 33 had IPA lesions, and 32 had preinvasive lesions. In the validation cohort, the prevalence of IPA lesions was 50.76%. Summary of cross tubulation of model 1 for diagnosis of invasive pulmonary adenocarcinomas in training and validation cohorts are shown in Figure S1. Table 1 summarizes the clinical and semantic characteristic features of the training cohort and validation cohort participants. For the clinical and semantic characteristic features, no significant differences were found in the percentage of sex ratio, smoking habit, lesion location, nodular type, presence of cystic change, presence of air bronchogram, shape (smooth, lobulated, or spiculated), and roundness (oval or irregular) between the two groups. Compared to the validation cohort group, no differences in age, nodular size, the solid component in the lung window setting, and CTR were observed in the training cohort (Table 1).

Table 1

Clinical characteristics and semantic nodular profiles of the training and validation cohorts in 260 subjects

Characteristics Training cohort (n=195) Validation cohort (n=65) P value
Gender, n (%) 0.187
   Male 56 (28.7) 14 (21.5)
   Female 139 (71.3) 51 (78.5)
Age, years (mean ± SD) 60.23±9.489 58.09±9.655 0.119
Smoking history, n (%) 0.288
   No 172 (88.2) 54 (83.1)
   Yes 23 (11.8) 11 (16.9)
Lesion location, n (%) 0.939
   Right upper lobe 62 (31.8) 24 (36.9)
   Right middle lobe 13 (6.7) 3 (4.6)
   Right lower lobe 43 (22.1) 12 (18.5)
   Left upper lobe 52 (26.7) 17 (26.2)
   Left lower lobe 25 (12.8) 9 (13.8)
Nodular type, Fleischer classification, n (%) 0.701
   GGN 61 (31.3) 22 (33.8)
   PSN 134 (68.7) 43 (66.2)
Nodular size, range 0.25 to 2.99 cm (mean ± SD) 1.667±1.026 1.529±1.053 0.350
Solid part, lung window (mean ± SD) 0.764±0.843 0.761±0.793 0.980
Cystic change, n (%) 0.130
   Cystic change (−) 178 (91.3) 63 (96.9)
   Cystic change (+) 17 (8.7) 2 (3.1)
Air bronchogram, n (%) 0.112
   Air bronchogram (−) 104 (53.3) 42 (64.6)
   Air bronchogram (+) 91 (46.7) 23 (35.4)
Shape, n (%) 0.813
   Smooth 58 (29.7) 21 (32.3)
   Lobulated 94 (48.2) 32 (49.2)
   Spiculated 43 (22.1) 12 (18.5)
Roundness, n (%) 0.828
   Oval 84 (43.1) 29 (44.6)
   Irregular 111 (56.9) 36 (55.4)
CTR (mean ± SD) 0.347±0.286 0.349±0.295 0.960

SD, standard deviation; GGN, ground-glass nodule; PSN, part-solid nodule; CTR, consolidation/tumor ratio.

LASSO-derived predictive models for invasiveness prediction

Logistic regression with LASSO penalization was conducted to help reduce the dimensions of feature selection through ten-fold cross-validation for IPA lesion prediction. Two LASSO-derived models were developed based on combined semantic-radiomic (Model 1) or clinical-semantic features (Model 2). The combined semantic-radiomic model (Model 1) with optimal value of lambda included the following six non-zero variables: “nodular size”, CTR, “roundness”, GLCM_Entropy_log10, “HISTO_Entropy_log10”, and “CONVENTIONAL_HUmean”. Summary of cross tubulation of model 1 for diagnosis of invasive pulmonary adenocarcinomas in training and validation cohorts are shown in Figure S1.

The clinical-semantic model (Model 2) with optimal value of lambda included the following five non-zero variables: “nodular size”, “CTR”, “roundness”, “shape”, and “air bronchogram”. Univariate and multivariate logistic analyses were performed in the training cohort to establish a combined semantic-radiomics predictive model for IPA lesions. The results of the univariate and multivariate logistic regression analyses for this combined semantic-radiomics predictive model are summarized in Table 2.

Table 2

LASSO-derived multivariate logistic regression for predicting invasive pulmonary adenocarcinoma lesions in subjects with SSNs ≤3 cm

Variable Coefficient OR 95% CI P value
Univariate model
   Nodular size 1.855 6.394 3.514–11.635 <0.001
   Roundness 2.399 11.008 5.626–21.537 <0.001
   CTR 7.042 1,143.598 194.833–6,712.490 <0.001
   CONVENTIONAL_HUmean 0.016 1.016 1.011–1.020 <0.001
   HISTO_Entropy_log10 13.964 1,160,172.509 24,415.044–55,129,953.62 <0.001
   HISTO_Entropy_log2 4.204 66.927 20.932–213.988 <0.001
   GLCM_Entropy_log10 5.296 199.583 45.982–866.291 <0.001
   GLCM_Entropy_log2 (= joint entropy) 1.594 4.925 3.166–7.662 <0.001
LASSO-derived model (including nodular size, roundness, CTR, CONVENTIONAL_Humean, HISTO_Entropy_log10, GLCM_Entropy_log10) 6.832 926.783 179.363–4,788.765 <0.001

LASSO, least absolute shrinkage and selection operator; SSN, subsolid nodule; CTR, consolidation/tumor ratio; OR, odds ratio; CI, confidence interval.

Development and validation of the LASSO-derived model/nomogram based on semantic-radiomics features

A nomogram was established to predict IPA lesions based on LASSO-derived multivariable logistic regression according to the selected semantic-radiomic features shown in Figure 2. By adding the scores identified on the point scale for each parameter, a straight line was easily obtained to establish the estimated individual probability score for IPA lesions in the training cohort. For example, to explain the nomogram model, if a 63-year-old man has the following profile of one PSN in RLL: a nodular size of 1.21 cm, irregular shape, CTR value of 0.521, GLCM_Entrophy_log10 value of 3.31, HISTO_Entrophy_log10 value of 1.85, and CONVENTIONAL_HUmean value of −624.72, the probability of IPA lesion was estimated to be 99.7%. Finally, the pathological report demonstrated invasive pulmonary adenocarcinoma in the RLL, as shown in Figure 3A. In a 57-year-old female with a profile of one GGN in the LUL: a nodular size of 0.49 cm, oval shape, CTR value of 0; GLCM_Entrophy_log10 of 1.96, HISTO_Entrophy_log10 value of 1.32, and CONVENTIONAL_HUmean value of −623.54, the probability of IPA lesions was estimated to be 27%. Finally, the pathological report demonstrated adenocarcinoma in situ in the LUL, as shown in Figure 3B.

Figure 2 Nomogram to predict the possibility of invasive pulmonary adenocarcinoma lesions based on the combined nomogram based on six predictors (nodular size, CTR, roundness, GLCM_Entropy_log10, HISTO_Entropy_log10, and CONVENTIONAL_Humean). To use the nomogram, each participant’s value is located on each variable axis, and a line is drawn upward to determine the number of points received for each variable value. The sum of these numbers is located on the total points axis to determine the possibility score of invasive pulmonary adenocarcinoma lesions. CTR, consolidation to tumor ratio.
Figure 3 Nomogram examples demonstration. (A) Example of IPA in a 63-year-old man in the right lower lobe (yellow arrow). According to the semantic and radiomic data profiles of Model 1, the total score is 19.6 points. The predicted probability of invasive pulmonary adenocarcinoma is more than 95%. (B) Example of AIS in a 57-year-old female in the left upper lobe (yellow arrow). According to the semantic and radiomic data profiles of Model 1, the total score is 11.8 points. The predicted probability of invasive pulmonary adenocarcinoma is 27%. AIS, adenocarcinoma in situ; IPA, invasive pulmonary adenocarcinoma.

Using a tenfold cross-validation method, the Hosmer-Lemeshow test was used to estimate and validate the goodness-of-fit of the predictive model/nomogram. The pooled AUC of the nomogram was 0.956 (95% CI: 0.929–0.983) in the training cohort and 0.960 (95% CI: 0.9168–1.000) in the validation cohort. The ROC curve showed that the resulting model had excellent discrimination between the training and validation cohorts. The Hosmer-Lemeshow goodness-of-fit test yielded P values of 0.394 and 0.787 in the training and validation cohorts, respectively, indicating good calibration power, as displayed by the calibration curves in Figures 4,5.

Figure 4 Calibration plot of the nomogram for predicting invasive pulmonary adenocarcinoma lesions from the training cohort. The Hosmer-Lemeshow test had a P value of 0.394 in the training cohort.
Figure 5 Calibration plot of the nomogram for predicting invasive pulmonary adenocarcinoma lesions from the validation cohort. The Hosmer-Lemeshow test had a P value of 0.787 in the validation cohort.

Comparison of the seven predictive models

Table 3 presents a summary of the discriminating ability and diagnostic performance of the seven predictive models, including the semantic-radiomic (Model 1), clinical-semantic (Model 2), radiologist 1 (Model 3), radiology 2 (Model 4), CTR (Model 5), nodular size (Model 6), and roundness models (Model 7). In this study, we hypothesized that the combined semantic-radiomic model would have superior diagnostic performance in differentiating IPAs from preinvasive lesions. The comparisons and differences between these predictive models are summarized in Table 4. Our study results demonstrated that the LASSO-based semantic-radiomic model has a significantly superior discrimination ability, higher c-statistics, and lower AIC and BIC values than the other four predictive models. Compared with other predictive models, the LASSO-derived semantic-radiomic nomogram model showed better diagnostic performance with an AUC of 0.957 (95% CI: 0.918–0.981) for the detection of IPA lesions in Asian populations with persistent SSNs, with balanced sensitivity (92.45%) and specificity (88.64%). In addition, the LASSO classifier provided optimal predictive models with AUC values of 0.957 and 0.924 for Models 1 and 2, respectively. The ROC curves for the combined semantic-radiomic model, clinical-semantic model, two-radiologist performance, and other semantic models are shown in Figure 1.

Table 3

Diagnostic performance of seven predictive models for predicting invasive pulmonary adenocarcinoma lesions in subjects with SSNs ≤3 cm

Model AIC BIC AUC (95% CI) Cut-point Sensitivity, %
(95% CI)
Specificity, %
(95% CI)
+LR (95% CI) −LR (95% CI) +PV (95% CI) −PV (95% CI) Accuracy
Model 1 117.1143 139.9893 0.957 (0.918–0.981) >0.4979 92.45 (85.7–96.7) 88.64 (80.1–94.4) 8.14 (7.4–8.9) 0.085 (0.04–0.2) 90.7 (83.6–95.5) 90.7 (82.4–95.9) 0.903
Model 2 150.417 170.055 0.924 (0.878–0.957) >0.4796 90.57 (83.3–95.4) 83.15 (73.7–90.2) 5.37 (4.8–6.0) 0.11 (0.05–0.2) 86.5 (78.7–92.2) 88.1 (79.2–94.1) 0.872
Model 3 213.9875 220.5335 0.728 (0.660–0.790) >0 49.06 (39.2–59.0) 96.63 (90.5–99.3) 14.55 (11.9–17.7) 0.53 (0.2–1.6) 94.5 (84.9–98.9) 61.4 (52.8–69.5) 0.708
Model 4 163.4837 170.0297 0.851 (0.793–0.898) >0 91.51 (84.5–96.0) 78.65 (68.7–86.6) 4.29 (3.8–4.8) 0.11 (0.05–0.2) 83.6 (75.6–89.8) 88.6 (79.5–94.7) 0.856
Model 5 165.0951 171.6411 0.886 (0.833–0.927) >0.2977 85.85 (77.7–91.9) 79.78 (69.9–87.6) 4.24 (3.7–4.8) 0.18 (0.09–0.3) 83.5 (75.2–89.9) 82.6 (72.9–89.9) 0.826
Model 6 202.6057 209.1517 0.856 (0.799–0.902) >1.08 91.51 (84.5–96.0) 66.29 (55.5–76.0) 2.71 (2.3–3.2) 0.13 (0.06–0.3) 76.4 (68.0–83.5) 86.8 (76.4–93.8) 0.795
Model 7 214.6351 221.1811 0.765 (0.699–0.823) >1 81.13 (72.4–88.1 71.91 (61.4–80.9) 2.89 (2.5–3.4) 0.26 (0.2–0.4) 77.5 (68.6–84.9) 76.2 (65.7–84.8) 0.769

Model 1: Semantic-radiomic model; Model 2: Clinical-semantic model; Model 3: Reader 1; Model 4: Reader 2; Model 5: CTR model; Model 6: Nodular size; Model 7: Roundness. AIC, Akaike information criterion; BIC, Bayesian information criterion; AUC, area under the ROC curve; CI, confidence interval; LR, likelihood ratio; PV, predictive value; CTR, consolidation to tumor ratio.

Table 4

Comparison of diagnostic performance of combined semantic-radiomic model with other six models

Group Difference between areas SE 95% CI P value
Model 1 vs. Model 2 0.0328 0.0137 0.0059–0.0597 0.017
Model 1 vs. Model 3 0.229 0.0244 0.181–0.276 <0.001
Model 1 vs. Model 4 0.107 0.0219 0.0642–0.150 <0.001
Model 1 vs. Model 5 0.0718 0.0194 0.0337–0.110 <0.001
Model 1 vs. Model 6 0.0963 0.0244 0.0485–0.144 <0.001
Model 1 vs. Model 7 0.187 0.0290 0.131–0.244 <0.001

Model 1: Semantic-radiomic model; Model 2: Clinical-semantic model; Model 3: Reader 1; Model 4: Reader 2; Model 5: CTR model; Model 6: Nodular size; Model 7: Roundness. SE, standard error; CI, confidence interval; CTR, consolidation to tumor ratio.


Discussion

This single-hospital study analyzed the clinical-semantic-radiomic predictive model individually and in combination to develop and validate this combined predictive model to help identify IPA lesions manifesting as SSNs to guide clinical decision-making for surgical planning. This combined semantic-radiomic model had the highest AUC (0.957) and achieved the best diagnostic accuracy when compared with the other models (Model 2, AUC =0.924, P=0.017; Model 3, AUC =0.728, P<0.001; Model 4, AUC =0.851, P<0.001; Model 5, AUC =0.886, P<0.001; Model 6, AUC =0.856, P<0.001; Model 7, AUC =0.765, P<0.001).

This study had three major findings. First, a LASSO-derived combined nomogram predictive model was developed based on six predictors (nodular size, CTR, roundness, GLCM_Entropy_log10, HISTO_Entropy_log10, and CONVENTIONAL_HUmean) to predict IPA lesions in SSNs, providing an excellent level of diagnostic performance for identifying these lesions in SSNs. Second, the LASSO-derived semantic-radiomic model exhibited a significantly better discrimination ability and lower AIC and BIC values compared with those of the other models, including the clinical-semantic, radiologist 1, radiologist 2, CTR, roundness, and nodular size definition models (sensitivity, 92.45%; specificity, 88.64%; cutoff point of probability score, ≥0.4979). Third, the LASSO-derived risk-predictive model (Model 1) exhibited good calibration ability in the both training and validation cohorts.

However, previous studies have demonstrated controversial results regarding clinical, semantic, and radiomic features or combinations in predicting IPAs in patients with GGNs, PSNs, or SSNs (17,19-24). Wu et al. demonstrated that separating ground-glass and solid CT radiomic features yielded a significantly better predictive performance than clinical-semantic models in patients with PSNs (22). Similarly, a recent study by Weng demonstrated that the combined model outperformed only CT-based semantic models in PSNs (21). For GGN analysis, two studies demonstrated that combined models have superior performance compared to clinical models (20,23). However, a recent study by Xu et al. found that the selected radiomic features did not provide useful information for improving the performance of the combined predictive model (24). In addition, for diagnostic performance analyses based on different study designs in patients with GGNs or PSNs, the diagnostic performance in studies focusing on PSNs showed good-to-excellent diagnostic accuracy (21,22). However, the diagnostic performance in studies focusing on GGNs showed only good diagnostic accuracy (0.750–0.889) with a wide range of variability (20,23,24,34,35). The differences in the study results may be due to the misclassification of PSNs or GGNs.

This is the first study to combine semantic and radiomic features to establish an individual predictive model of SSNs. Previous studies have assessed conventional CT features or signs for IPA lesion prediction (29,36-41). A previous literature review investigated, for the first time, pure GGNs or PSNs to build and validate a predictive model based on combined clinical-semantic-radiomic features for IPA lesion identification in SSNs, and comprehensively compared the diagnostic performances of other predictive models, semantic features, or radiologists’ performance. However, these diagnoses based on semantic features would need to be examined by experienced radiologists, and interobserver differences have been found in previous studies (42,43). Previous studies have demonstrated conventional CT features for predicting the pathological invasiveness of SSNs with fair to good diagnostic accuracy (29,36-41). Our study results also support that conventional CT features such as nodular size, CTR, or roundness (shape) have fair to good diagnostic performance for IPAs.

In this study, Model 2 used clinical and semantic parameters with similar diagnostic performance compared with Model 1. For the current real-world clinical practice, Model 2 would be more convenient than Model 1. However, previous studies have demonstrated that inter-observer variability in CT-based semantic features is higher than that in CT-based radiomic features (25,42,43). In addition, we identified three radiomic-based features with high reproducibility for radiomic-based model development in differentiating IPA from preinvasive lesions, which could enhance radiomics application to facilitate its acceptance in clinical practice (44,45). Therefore, the reproducibility of Model 1 may be superior than that of Model 2 owing to the high interobserver agreement in radiomic feature analysis. Furthermore, a LASSO-derived predictive model incorporating semantic-radiomic features in pulmonary invasive adenocarcinoma lesions was built, which yielded substantially higher AUC values with balanced sensitivity and specificity than the semantic models. The combined semantic-radiomic models outperformed the performance of the two radiologists.

Therefore, this nomogram/predictive model could improve radiologists’ performance in diagnosing IPAs in SSNs. Our rationale was to develop a radiomic-based model to differentiate IPA from preinvasive lesions (AAH, AIS, and MIA) before surgery to guide clinical management strategies. Specifically, recent evidence supports the notion that lobectomy is generally preferred for patients with IPAs. Sublobar resection, especially wedge resection, has been generally accepted as a safe and effective surgical option for patients with preinvasive lesions, such as MIA/AIS lesions (46,47). The selected radiomic features reflected environmental habitat heterogeneity. It also exhibited good calibration ability in both the training and validation cohorts. In this study, we used a simplified, standardized non-contrast chest CT protocol and an open-source software platform designed to improve the feasibility of general clinical practice implementation. However, multicenter studies are needed to conduct external validation of the findings and model stability.

Study limitation

This study has some limitations and flaws. First, this was a retrospective study, and only patients with surgically resected persistent SSNs were enrolled. Therefore, selection bias is inherent in the study design. However, a wide spectrum of patients with SSNs was enrolled in this study rather than only those with GGNs or PSNs like in previous studies. Second, the ROI was segmented manually over time. In the future, automatic ROI segmentation through artificial intelligence should be addressed in a real-world setting, thereby improving patient care and helping physicians become more efficient and effective using a clinical decision nomogram through artificial intelligence segmentation. Third, different vendor settings will result in more bias with batch effects in radiomic feature analysis (45,48,49). The batch effect can be reduced using the ComBat approach, as demonstrated in recent studies. Further studies are warranted to reduce the batch effect using the ComBat approach (50).


Conclusions

A LASSO-derived predictive model was successfully developed and validated based on six parameters, including “nodular size”, “CTR”, “roundness”, “GLCM_Entropy_log10”, “HISTO_Entropy_log10”, and “CONVENTIONAL_HUmean”, providing good diagnostic performance in predicting IPA from preinvasive lesions. This nomogram could help clinicians identify IPA lesions to guide personalized medicine and make informed decisions in SSN management with good calibration.


Acknowledgments

Funding: This study was supported by grants from Kaohsiung Veterans General Hospital (Nos. KSVGH111-108, KSVGH111-D02-3, MOST 110-2314-B-075B-008).


Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-22-308/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-308/coif). The authors have no 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 study was reviewed and approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (No. VGHKS19-CT2–09). Considering the retrospective design of the study, the requirement for informed consent was waived by the institutional review board.

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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Cite this article as: Wu FZ, Wu YJ, Tang E. An integrated nomogram combined semantic-radiomic features to predict invasive pulmonary adenocarcinomas in subjects with persistent subsolid nodules. Quant Imaging Med Surg 2023;13(2):654-668. doi: 10.21037/qims-22-308

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