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Artificial Intelligence–Assisted Endoscopic Diagnosis of Early Upper Gastrointestinal Cancer: A Systematic Review and Meta-Analysis

Objective The aim of this study was to assess the diagnostic ability of artificial intelligence (AI) in the detection of early upper gastrointestinal cancer (EUGIC) using endoscopic images. Methods Databases were searched for studies on AI-assisted diagnosis of EUGIC using endoscopic images. The pooled area under the curve (AUC), sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with 95% confidence interval (CI) were calculated. Results Overall, 34 studies were included in our final analysis. Among the 17 image-based studies investigating early esophageal cancer (EEC) detection, the pooled AUC, sensitivity, specificity, PLR, NLR, and DOR were 0.98, 0.95 (95% CI, 0.95–0.96), 0.95 (95% CI, 0.94–0.95), 10.76 (95% CI, 7.33–15.79), 0.07 (95% CI, 0.04–0.11), and 173.93 (95% CI, 81.79–369.83), respectively. Among the seven patient-based studies investigating EEC detection, the pooled AUC, sensitivity, specificity, PLR, NLR, and DOR were 0.98, 0.94 (95% CI, 0.91–0.96), 0.90 (95% CI, 0.88–0.92), 6.14 (95% CI, 2.06–18.30), 0.07 (95% CI, 0.04–0.11), and 69.13 (95% CI, 14.73–324.45), respectively. Among the 15 image-based studies investigating early gastric cancer (EGC) detection, the pooled AUC, sensitivity, specificity, PLR, NLR, and DOR were 0.94, 0.87 (95% CI, 0.87–0.88), 0.88 (95% CI, 0.87–0.88), 7.20 (95% CI, 4.32–12.00), 0.14 (95% CI, 0.09–0.23), and 48.77 (95% CI, 24.98–95.19), respectively. Conclusions On the basis of our meta-analysis, AI exhibited high accuracy in diagnosis of EUGIC. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, identifier PROSPERO (CRD42021270443).


INTRODUCTION
Upper gastrointestinal cancer (UGIC) is among the most common malignancies and causes of cancerrelated deaths worldwide, which presents a major challenge for health-care system (1). A majority of UGIC patients are detected at a late stage and have a poor prognosis. In contrast, with early detection, the 5-year overall survival can be more than 90% (2,3). Thus, the early detection of UGIC is essential to improve patient prognosis.
Endoscopy remains the most optimal approach of UGIC detection (4,5). However, endoscopic features of early upper gastrointestinal cancer (EUGIC) lesions are subtle and easily missed. Moreover, diagnostic accuracy depends on the expertise of endoscopists (2). One report revealed that EUGIC misdiagnosis can be high regardless of the number of patients, developed or underdeveloped locations, or in countries performing a remarkably high volume of endoscopies (6).
Artificial intelligence (AI) is gaining much popularity in the field of medicine, including gastrointestinal endoscopy (7)(8)(9)(10)(11). Owing to its good pattern recognition ability, AI is a promising candidate for detection of upper gastrointestinal lesions (12,13). However, the data on AI-assisted EUGIC diagnosis are still lacking. Hence, we conducted this study to assess the diagnostic accuracy of AI in the detection of EUGIC using endoscopic images.

METHODS
This systematic review and meta-analysis was reported in line with PRISMA guidelines and was registered with the international prospective register of systematic reviews PROSPERO (CRD42021270443).

Search Strategy and Study Selection
Two authors (FK and JD) separately searched electronic databases (PubMed, Medline, Embase, Web of Science, Cochrane library, and Google scholar) from the date of establishment until November 2021 using the following prespecified search terms: "endoscopy", "endoscopic", "early gastric cancer", "early esophageal cancer", "early esophageal squamous cell carcinoma", "early Barrett's neoplasia", "early esophageal adenocarcinoma", "artificial intelligence", "AI", "machine learning", "deep learning", "artificial neural network", "support vector machine", "naive bayes", and "classification tree". Potentially relevant studies (based on title and abstract) were then read completely to ensure eligibility in the meta-analysis. In addition, we also reviewed the reference lists of relevant studies to search for eligible studies.

Study Eligibility Criteria
Studies meeting the following criteria were included in the meta-analysis: (1) studies that evaluated AI diagnostic performance for EUGIC using endoscopic images; (2) true positive (TP), false positive (FP), false negative (FN), and true negative (TN) values could be extracted directly or calculated from the original studies. The following studies were excluded from our meta-analysis: (1) reviews, (2) meta-analyses, and (3) comments or protocols. We followed a strict exclusion policy that any study meeting one of the abovementioned exclusion criteria was excluded.

Data Extraction
Two authors (MZJ and XDL) separately extracted data from the included studies, namely, author, publication year, study design, imaging type, AI model, sample size, TP, FP, FN, and TN. TP, FP, FN, and TN were extracted with the histology as the reference standard. Intramucosal carcinoma, T1 cancer, and Barrett's esophagus (BE) with high-grade dysplasia were considered as positive. Normal tissue, BE without high-grade dysplasia, and non-cancerous lesions were considered as negative. The authors of the studies were contacted for missing information, if necessary. Discrepancies were decided through discussion.

Methodological Quality Assessment
Two authors (XDL and XCL) evaluated the quality and potential bias risk of eligible studies based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) (14). Disagreements were resolved through discussion. The QUADAS-2 tool was composed of four domains: "patient selection", "index test", "reference standard", and "flow and timing". In addition, the "patient selection", "index test", and "reference standard" were further tested for "applicability". Each domain was then stratified into high, low, or unclear bias risk.

Statistical Analysis
Statistical analysis was performed using the Meta-Disc software (version 14). To assess AI performance in EUGIC diagnosis, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with 95% confidence interval (CI) were computed. In addition, we plotted a summary receiver operating characteristic (SROC) curve. The area under the curve (AUC) was computed to predict precision in diagnosis. We evaluated AI diagnostic performance based on images (image-based analysis) and patients (patient-based analysis). The forest plot was constructed. The inconsistency index (I 2 ) test determined presence or absence of heterogeneity among studies using sensitivity (15). A fixed-effects model was used if the I 2 value < 50%; otherwise, a random-effects model was selected. The Spearman correlation coefficient (SCC) between sensitivity and false positive rate was calculated, and a value > 0.6 indicated a threshold effect.
In the 17 image-based studies investigating AI-assisted EEC diagnosis, the pooled AUC, sensitivity, specificity, PLR, NLR, and DOR were 0. respectively, suggesting no significant threshold effect among these studies.
Only two patient-based studies evaluated AI in the diagnosis of EGC, so meta-analysis was not performed. In Namikawa's study, the sensitivity and specificity were 0.99 and 0.93, respectively. In Wu's study, the sensitivity and specificity were 1.00 and 0.8429, respectively.

Subgroup Analysis Based on Imaging Type
To compare the AI diagnostic performance of EEC and EGC detection using WLI and NBI endoscopic images, we performed a subgroup analysis based on imaging type. On the basis of the results of subgroup analysis, the NBI mode showed a better diagnostic performance than the WLI mode. The results are summarized in Table 2.

Meta-Analysis of AI-Assisted EGC Diagnosis Using NBI Endoscopic Images
Four studies (35,37,38,42) reported the AI diagnosis performance for EGC using endoscopic NBI images based on per image. In

Subgroup Analysis Based on Pathologic Type in Esophagus
We also performed a subgroup analysis between early esophageal squamous cell carcinoma (EESCC) and early esophageal adenocarcinoma (EEAC). On the basis of the results of subgroup analysis, AI showed a better diagnostic performance in EESCC than EEAC. The results are summarized in Table 3.

DISCUSSION
In this study, we conducted a comprehensive literature search and included all studies that assessed diagnostic performance of AI in EUGIC using endoscopic images. Next, we conducted a metaanalysis to explore the diagnostic performance of AI in EUGIC detection. On the basis of our results, AI demonstrated an excellent diagnostic ability, with high accuracy, sensitivity, specificity, PLR, and DOR, and with low NLR in detecting EUGIC, suggesting the feasibility of AI-assisted EUGIC diagnosis in clinical practice. To the best of our knowledge, this is the first systematic review and metaanalysis that explored the AI-assisted detection of EUGIC based on upper gastrointestinal endoscopic images.
Endoscopy is the primary tool used in the diagnosis of UGIC (50,51). However, EUGIC lesions manifest as indistinct mucosal alterations under the classic WLI images. Therefore, EUGIC detection is often highly dependent on endoscopist's experience and expertise (52). Previous studies also revealed that WLI-based EGC diagnosis is possible, but with poor sensitivity or specificity (36,47,48). More recently, AI-assisted image recognition makes remarkable breakthroughs in the field of medical imaging diagnosis and is gaining popularity in clinical practice (7-11, 53, 54). Traditional AI algorithms like SVM and decision trees require experts to manually design the image features, before the algorithm extracts the feature from images (53,55). This results in the detection of only specific lesions, and in case the features are insufficient, satisfactory identification results cannot be obtained. Simultaneously, manual design is highly dependent on the previous knowledge of designers. Thus, it is not feasible to work with large amounts of data. At present, many studies on medical image recognition adopt deep learning algorithm based on CNN. The deep learning can automatically learn the most predictive characteristics from a large image data file with no requirement of previous knowledge and classify these images. In our study, most included studies used the CNN algorithm, so we did not compare the AI diagnostic ability between the different algorithms. Many studies demonstrated excellent AI performance in detecting early esophageal and stomach cancers with the CNN algorithm. Consistent with these studies, in our study, AI exhibited an excellent diagnosis performance for EUGIC with high accuracy, sensitivity, and specificity.
Although several advanced technologies like NBI, confocal laser endomicroscopy, and blue laser imaging have shown great promise in the endoscopic detection of EUGIC, endoscopists still need extensive specialized training and substantial experience to identify early cancer lesions accurately. NBI endoscopy is an optical image-enhanced technology that better visualizes surface structures and blood vessels than does WLI (56). Multiple studies have demonstrated NBI has a high sensitivity in detecting EUGIC (37,57,58). To compare the AI diagnostic performance for EUGIC detection using WLI and NBI endoscopic images, we performed a subgroup analysis based on imaging type. On the basis of our results, the NBI imaging mode has a superior diagnostic performance for both EEC and EGC detection, with higher AUC, sensitivity, specificity, PLR and DOR, and lower NLR.
There are limitations to this study. First, most studies were based on the retrospective review of selected images. At the same time, the number of positive images and negative images included in some included studies was significantly different. All retrospective studies were considered at high risk for selection bias, so those studies might overestimate the diagnostic accuracy of AI. Second, few studies compared the diagnostic efficacy between AI and endoscopists, so we could not perform meta-analysis to compared the diagnostic efficacy between AI and endoscopists.
In conclusion, on the basis of our meta-analysis, AI achieved high accuracy in diagnosis of EUGIC. Further prospective studies comparing the diagnostic performance between AI and endoscopists are warranted.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTION
DL designed the study. FK and JD screened electronic databases. MZ and XDL extracted data from the selected articles. XDL and XCL evaluated eligible study quality and potential bias risk. Statistical analyses were performed by YT and BL. DL wrote the manuscript. SS supervised the study. All authors contributed to the article and approved the submitted version.