The diagnostic accuracy of MMP-7 for the diagnosis for biliary atresia- a systematic review and meta-analysis

Abstract

Background

Matrix metalloproteinase-7 (MMP-7) has emerged as a promising biomarker for the early detection of biliary atresia (BA), with potential to significantly improve diagnostic accuracy and patient outcomes. This meta-analysis evaluated the diagnostic performance of MMP-7 to determine its clinical utility in the identification of BA.

Methods

A comprehensive literature search was performed in PubMed, Embase, Web of Science, and the Cochrane Library for studies published through March 21, 2024. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Diagnostic parameters including sensitivity, specificity, likelihood ratios, and diagnostic odds ratios were pooled. Summary receiver operating characteristic curves were constructed to evaluate overall diagnostic performance.

Results

9 studies comprising 710 patients were included in the analysis. MMP-7 demonstrated a pooled sensitivity of 0.80 (95% CI: 0.58–0.92) and specificity of 0.97 (95% CI: 0.90–0.99), with an area under the curve of 0.97 (95% CI: 0.95–0.98). Subgroup analyses by geographic sample size, study type and mean/median age revealed no significant differences in diagnostic performance. An inverse relationship was observed between cutoff values and sensitivity, with higher thresholds yielding lower sensitivity but improved specificity.

Conclusion

The sensitivity of MMP-7 is influenced by sample processing methods, sample handling time, and substantial variability in cutoff values. Therefore, it cannot serve as an independent diagnostic tool for BA, and BA diagnosis should continue to rely on the gold standard. However, MMP-7 may serve as a valuable tool for risk stratification in BA. Future research should investigate the diagnostic performance of MMP-7 across varying cutoff values, reflecting the observed variability across studies.

PROSPERO registration number

CRD42024532998.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-025-06032-6.

Background

Biliary atresia (BA) is a progressive cholestatic disorder in neonates characterized by inflammation and fibrosis that obstructs both intrahepatic and extrahepatic bile ducts. The condition manifests as neonatal jaundice, liver cirrhosis, and portal hypertension [1]. The incidence of BA varies globally, affecting approximately 1 in 5000 to 10,000 newborns in China [2] and Japan [3], and 1 in 10,000 to 19,000 in North America and Europe [4]. Despite its relative rarity, BA remains the primary cause of severe neonatal liver disease and the leading indication for pediatric liver transplantation. Without treatment, mortality occurs before the age of two years in most affected children [5]. Early intervention with the Kasai procedure within 30 to 60 days after birth significantly improves prognosis and extends transplant-free survival [6], highlighting the critical importance of early diagnosis.

The current diagnosis of BA relies on clinical symptoms, physical examination findings, and auxiliary tests. Non-invasive diagnostic methods include stool color cards, blood biochemistry, ultrasound, and magnetic resonance imaging. However, these approaches cannot definitively diagnose or exclude BA for both neonates and infants, often necessitating invasive techniques such as surgical exploration, cholangiography, and liver biopsy, which carry significant risks and are impractical for routine screening. Several non-invasive serum biomarkers have shown potential for BA diagnosis. Notably, biomarkers including poliovirus receptor, serum caspase-3, miR-140-3p, IL-8, and macrophage inflammatory protein-3alpha have been identified, though their validation requires larger, prospective cohort studies [7].

Matrix metalloproteinase-7 (MMP-7) is a zinc-dependent metalloproteinase that, under physiological conditions, is regulated through a dynamic balance with specific matrix metalloproteinase tissue inhibitors (TIMPs) [8]. It plays a key role in extracellular matrix protein degradation and remodeling while also promoting biliary epithelial cell proliferation [9]. In BA, elevated MMP-7 levels contribute to fibrosis [10], promote inflammatory responses, and induce biliary epithelial cell apoptosis [7]. MMP-7 has emerged as a promising biomarker for BA diagnosis. Following successful experimental validation, MMP-7 is now being evaluated in multi-center, large-sample clinical studies for its diagnostic efficacy.

Previous meta-analyses examining MMP-7 as a diagnostic marker for BA [11–13] have shown promising results, with a recent eight-study analysis reporting 95% sensitivity and 83% specificity. However, emerging evidence suggests that diagnostic thresholds and regional differences may influence the diagnostic accuracy of MMP-7. Therefore, this study aims to conduct a comprehensive meta-analysis to evaluate how these factors, along with sample size, affect the diagnostic performance of MMP-7 in BA.

Methods

This meta-analysis followed a pre-established protocol in accordance with guidelines for systematic reviews of diagnostic studies. The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [14] and was registered with PROSPERO (CRD42024532998). Ethical or Institutional Review Board approval was not required for this study.

Search strategy

A comprehensive systematic search was conducted in PubMed, Embase, Web of Science, and Cochrane databases through March 21, 2024. The search terms included “Biliary Atresia,” “Matrix Metalloproteinase 7,” and “MMP-7,” with a focus on English-language publications. Additional searches of gray literature were performed to ensure comprehensive coverage. Detailed search strategies are available in Table S1.

Inclusion and exclusion criteria

Studies were included based on the following criteria: (1) Population: patients with suspected BA or those with confirmed BA versus non-BA diagnoses; (2) Intervention: assessment of MMP-7 levels. MMP-7 concentrations < 5 ng/mL, 5 to < 13 ng/mL, and ≥ 13 ng/mL indicate low, moderate, and high risk of BA, respectively; (3) Reference standard: intraoperative cholangiography. No restrictions were placed on study design. Studies were excluded if they were animal studies, reviews, meta-analyses, conference abstracts, case reports, editorials, letters, comments, or conference papers. Studies lacking critical data, involving overlapping patient populations and articles with patient median/mean age greater than or equal to 90 days were also excluded.

For articles with inaccessible full texts, multiple unsuccessful attempts were made to contact the authors.

Data extraction

Two authors (Zhenyuan Li and Yanghuan Deng) independently extracted data, with any disagreements resolved through consultation with a third author (Qiong Liao). Extracted information included study characteristics (author, publication year, country, sample size), patient demographics (age, gender ratio), reference standard for diagnosis, and outcome measures (sensitivity, specificity, diagnostic values, and cutoff points).

Quality assessment

The risk of bias in the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [15], which assesses four domains: patient selection, index test, reference standard, and flow and timing.

Statistical analysis

Statistical analyses were performed using STATA. Continuous variables were pooled and analyzed using mean difference (MD) with 95% confidence interval. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with corresponding 95% confidence intervals were calculated. Forest plots were generated to display individual study results and pooled estimates. Summary receiver operating characteristic (SROC) curves were constructed to evaluate overall diagnostic performance. The area under the curve (AUC) was calculated and interpreted using established criteria: excellent (0.90-1.00), good (0.80–0.90), fair (0.70–0.80), poor (0.60–0.70), and fail (0.50–0.60) [16]. Heterogeneity was assessed using the Chi-square test and I² statistic. A random-effects model was applied when heterogeneity was present (I² > 25%), while a fixed-effects model was used otherwise. For cases with substantial heterogeneity (I² ≥ 50%), subgroup and meta-regression analyses were conducted to explore potential sources of variation. Threshold effects were evaluated using the Spearman correlation coefficient between sensitivity and specificity. Publication bias was assessed using Deeks’ funnel plot asymmetry test, with P < 0.05 indicating significant publication bias.

Results

Literature search

The electronic database search yielded 187 records (Fig. 1). After removing 94 duplicates and excluding 73 articles with irrelevant abstracts and 1 with unretrievable full text, 19 studies underwent full-text assessment. Four studies were subsequently excluded: two did not align with the research objectives, and two lacked essential data. Additionally, one article was excluded because the median/mean age of included patients was greater than or equal to 90 days. In 5 studies, the diagnostic gold standard was not cholangiography. Ultimately, 9 studies were included in the analysis. Data from these studies [17–25] were organized into 2 × 2 contingency tables to evaluate the diagnostic accuracy of MMP-7 for BA.

Fig. 1.

Study flow diagram

Characteristics of the included studies

Table S2 summarizes the characteristics of the 9 included studies published between 2018 and 2024 [17–25]. These studies collectively involved 710 children aged 3 to 170 days. Among the 710 participants with reported gender, there were 301 males and 409 females. All studies were conducted in Asian countries. The reference standards for diagnosis in all studies were intraoperative cholangiography. The highest sensitivity of 100% was achieved at a cutoff value of 18.6 ng/mL in one study [20], where serum samples were stored at − 20 °C. The highest specificity of 100% was observed at cutoff values of 69 ng/mL, 52.85 ng/mL, 26.73 ng/mL, and 18.6 ng/mL in the study by Wu et al. [25]; however, sample storage conditions were not described in that study.

Quality assessment of the included studies

The quality assessment results based on QUADAS-2 criteria are presented in Fig. 2. Regarding patient selection, 1 that did not consecutively include patients [20]. One study presented unclear risk regarding consecutive patient inclusion, while the remaining 8 studies showed low risk. For reference standards, 7 studies had unclear risk: all 7 studies [17–19, 21, 23–25] lacked information about blinding procedures during reference standard assessment. Regarding flow and timing, all studies were considered low risk concerning clinical applicability.

Fig. 2.

Risk Quality Assessment

The level of MMP-7 between BA and cases with cholestasis that are not BA

A total of 9 studies reported the levels of MMP-7 between confirmed cases with BA and confirmed cases with cholestasis that were not BA. Given high heterogeneity (I² = 99.1%, P < 0.001), the random-effect model was used. The results showed that the level of MMP-7 in BA cases was significantly higher than that in non-BA patients with cholestasis (MD = 13.06, 95%CI: 10.15,15.96, P < 0.001), as shown in Fig. S1.

Overall diagnostic value of MMP-7 for BA

The analysis included 9 studies comprising 710 patients. The Spearman correlation coefficient of 0.677 (p = 0.003) indicated no threshold effect.。This indicates no strong positive correlation. Hence, there is no threshold effe ct. Figure 3 displays the sensitivity and specificity of MMP-7 for diagnosing BA. The pooled sensitivity was 0.80 (95% CI: 0.58–0.92), and the pooled specificity was 0.97 (95% CI: 0.90–0.99). High heterogeneity was observed with I² values of 97.11% (95% CI: 96.38–97.83) for sensitivity and 97.23% (95% CI: 96.55–97.92) for specificity. The pooled PLR was 25.27 (95% CI: 9.24–69.10), and the NLR was 0.20 (95% CI: 0.09–0.47). The DOR was 123.77 (95% CI: 54.03-283.52), and the AUC for MMP-7 in diagnosing BA was 0.97 (95% CI: 0.95–0.98). Sensitivity analysis for both sensitivity and specificity demonstrated stable results (Fig. S2). Deeks’ funnel plot asymmetry test (p = 0.08) suggested no publication bias(Fig. S3).

Fig. 3.

Evaluation of MMP-7 for Diagnosis. A Sensitivity and specificity; B PLR and NLR; C AUC curve; D DOR

Subgroup analysis of MMP-7 for BA

Due to high heterogeneity, subgroup analyses were performed based on sample size, cutoff values, study type and patient age. The detailed results are presented in Table. S3.

For sample size analysis, studies were categorized into two groups: small (fewer than 100 patients, 7 studies) and large (more than 100 patients, 2 studies). For cutoff values, studies were stratified into three groups based on MMP-7 levels: less than 10 ng/ml (4 studies), 10–30 ng/ml (5 studies), and more than 30 ng/ml (2 studies). Regarding study design, studies were classified as cohort (3 studies), case-control (5 studies), or cross-sectional (1 studies). Concerning mean/median patient age, studies were divided into those with mean/median age less than 60 days (7 studies) and those with mean/median age greater than or equal to 60 days (2 studies) (Table S3). All subgroup analyses exhibited substantial heterogeneity, indicating that these factors were not the primary sources of heterogeneity.

Regression analysis

Meta-regression analysis examining the influence of sample size, study type and mean/median age on diagnostic accuracy yielded p-values greater than 0.05, confirming that these factors did not significantly contribute to the observed heterogeneity.

Discussion

The prompt diagnosis and treatment of BA are critical, as delays significantly increase mortality rates. Traditional diagnostic methods are invasive, costly, and time-consuming, making them impractical for routine screening. Currently available non-invasive methods lack sufficient effectiveness for accurate diagnosis. This study demonstrates that MMP-7 is a promising biomarker for BA diagnosis, with a pooled sensitivity of 86% and specificity of 94%. The AUC of 0.96 indicates excellent diagnostic performance. These results remained consistent across regional and sample size subgroups, although higher cutoff values were associated with decreased sensitivity and increased specificity. However, the sensitivity and specificity of MMP-7 are influenced by factors such as sample collection methods, processing techniques, and freezing protocols. At present, MMP-7 is recommended solely as a risk stratification tool for BA, rather than as a standalone diagnostic modality.

MMPs are a family of zinc-dependent endopeptidases that cleave extracellular matrix proteins under various physiological and pathological conditions [26]. They play essential roles in cell differentiation, proliferation, wound healing, apoptosis, and angiogenesis [27]. MMP-7, a member of this enzyme family, is involved in the pathophysiological processes of various conditions including cancer, lung fibrosis, renal fibrosis, and inflammation. In renal diseases, MMP-7 activates Fas ligand and degrades type IV collagen and laminin to induce epithelial apoptosis, disrupting the basement membrane of renal tubular epithelial cells, leading to renal fibrosis and cancer. In pulmonary diseases, MMP-7 triggers β-catenin signaling activation through E-cadherin shedding and causes alveolar epithelial cell apoptosis by inducing Fas, while also forming a positive feedback loop with osteopontin that increases collagen-1 secretion, resulting in pulmonary fibrosis [9].The pathophysiological role of MMP-7 in BA has not been extensively studied; however, insights from its functions in other diseases provide valuable perspectives. MMP-7 induces tissue remodeling by degrading various extracellular matrix components including type IV collagen, fibronectin, gelatin, laminin, and elastin, thereby participating in the fibrosis process. It promotes inflammatory responses by inducing macrophage infiltration and regulating neutrophil influx and activation. Furthermore, MMP-7 triggers cellular apoptosis through multiple mechanisms, including Fas ligand activation and E-cadherin shedding [7]. These mechanisms likely contribute to the elevated MMP-7 expression observed in BA patients.

MMP-7 levels are influenced by multiple factors, including inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) [28] and the IL-17RA/ACT1/NF-κB signaling pathway [29]; disease microenvironments in diabetic nephropathy [28], pulmonary fibrosis [30], chronic infections [31], colorectal cancer [32], and BA); electrolytes such as calcium ions [33] and zinc ions [34]; pharmacological agents such as naringenin-7-O-glucoside [35]; and population-specific genetic variants [36].In chronic inflammatory conditions such as chronic cholangitis, cholangiocytes are continuously activated by bacterial components (e.g., lipopolysaccharide) or inflammatory cytokines (e.g., tumor necrosis factor-α and interleukin-17). These activated cells upregulate MMP-7 expression through host immune signaling pathways, including NF-κB and MAPK, and participate directly in tissue repair and remodeling processes [37]. Although no studies have directly confirmed an association between sustained inflammation from urinary tract infections and MMP-7 levels, such infections, typically caused by pathogens like Escherichia coli, trigger local inflammatory responses that activate cytokines such as TNF-α, which may promote MMP-7 expression through downstream signaling pathways [38]. Studies have shown that graded aflatoxin B1 (AFB1) exposure induced dose-dependent hepatic injury in animal models, accompanied by corresponding increases in MMP-1 (mediating liver regeneration) and MMP-7 (driving tissue remodeling) protein expression levels [39].

The diagnostic gold standard for BA remains an invasive surgical procedure, which often encounters resistance from caregivers and may result in diagnostic delays. Several noninvasive markers are currently available for BA diagnosis and prognostic evaluation, including biochemical parameters such as γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase (ALP), serum liver enzyme levels, and stool color changes, as well as imaging indicators such as the triangular cord sign on ultrasound and hepatobiliary radionuclide scintigraphy [40, 41]. Studies have demonstrated that combining matrix metalloproteinase-7 (MMP-7) with γ-GT yields an area under the receiver operating characteristic curve (AUC) of 0.907 [41]; combining MMP-7 with stool color achieves an AUC of 0.902 [41]; and combining MMP-7 with bile acids reaches an AUC of 0.983 [23], all superior to individual markers. Additionally, combining MMP-7 and ALP for predicting liver transplantation risk yielded an AUC of 0.926 (sensitivity 91.3%, specificity 87.2%), significantly outperforming individual markers [42].Aflatoxins, particularly aflatoxin B1, are closely associated with BA pathogenesis, especially in the Kotb disease BA variant. GSTM1 gene deletion can impair aflatoxin detoxification, leading to accumulation and subsequent immune-mediated bile duct damage resulting in BA. A case-control study at Cairo University involving 24 BA infants and 17 neonatal hepatitis infants found that all BA infants had elevated blood aflatoxin B1 levels, while aflatoxin B1 and/or B2 were undetectable in neonatal hepatitis infants. Although aflatoxins cannot serve as standalone diagnostic markers for BA, they require comprehensive analysis in conjunction with other clinical features [43]. While direct evidence supporting the combination of aflatoxins with MMP-7 remains lacking, we believe future research can further explore this direction.

Several methodological factors can compromise MMP-7 detection accuracy. Filter membranes used during sample processing (such as Anopore 0.2 μm membrane) might remove MMP-7, leading to false negative results [44]. Sample type also significantly influences analytical outcomes; studies have demonstrated that while blood samples typically yield positive results, seminal fluid, sweat, and saliva samples might produce negative results, contributing to false negatives in MMP-7 detection. Storage conditions represent another critical variable affecting MMP-7 analysis. Samples stored at −20 °C maintain MMP-7 stability, whereas at room temperature, significant MMP-7 degradation occurs, potentially compromising detection. Extended storage duration also affects analytical reliability, with research demonstrating that samples stored beyond 2 years exhibit substantially reduced MMP-7 stability, leading to false negative results [45]. Detection methodologies introduce further analytical variability. For instance, ELISA demonstrates relatively limited sensitivity and may fail to detect low concentrations of MMP-7 during early disease stages, producing false negative findings [46]. Moreover, pharmacological agents that downregulate MMP-7 expression (such as Naringenin-7-O-glucoside) [35] can similarly compromise detection accuracy. Conversely, research indicates that excessive RNA addition during MMP-7 detection protocols may induce cross-reactivity, resulting in false positive results [45].

Clinical evidence supporting the role of MMP-7 in BA is accumulating. Singh et al. [47] demonstrated that MMP-7 expression is minimal in normal liver tissue but significantly elevated in BA. Similarly, Lertudomphonwanit et al. [48] identified heightened MMP-7 expression in BA patients’ serum through large-scale quantitative proteomic analysis. The present meta-analysis confirms these findings by demonstrating the high diagnostic accuracy of MMP-7 for BA across multiple studies. Additionally, MMP-7 holds prognostic value for patients with BA. As serum MMP-7 levels correlate with hepatic MMP-7 expression, this biomarker offers potential for evaluating BA prognosis. Wu et al. [18] monitored serum MMP-7 levels six months after Kasai portoenterostomy and found a positive correlation between elevated MMP-7 levels and both severity of liver fibrosis and likelihood of liver transplantation. Chi et al. [22] demonstrated that post-operative serum MMP-7 kinetics predict two-year native liver survival. Specifically, patients exhibiting rapid decreases in serum MMP-7 levels after Kasai portoenterostomy showed better outcomes compared to those with other temporal patterns (high fluctuating levels followed by stabilization, initial fluctuation followed by elevation, or persistent elevation).

The cutoff values for MMP-7 varied significantly across studies, influenced by factors including ethnicity, age, assay methodology, sample handling, and liver function status. Notable discrepancies were observed between studies from different regions, such as those conducted by Aldeiri et al. [49] in the United Kingdom and Wu et al. [18] in China, potentially reflecting genetic variations. Chi et al. [22] provided evidence supporting this hypothesis by identifying the G137D gene mutation associated with reduced MMP-7 secretion, a condition more prevalent in non-Asian populations. These findings highlight the need for additional research across diverse ethnic groups to establish standardized MMP-7 assessment protocols.

Several investigators have examined the relationship between MMP-7 levels and patient age. Yang et al. [17], Sakaguchi et al. [20], Wu et al. [18], and Jiang et al. [19] reported age-dependent increases in MMP-7 levels, potentially reflecting prolonged biliary tract injury and progressive fibrosis. Conversely, Rohani et al. [21] found no significant age-related differences in MMP-7 levels after adjusting for confounding variables. Furthermore, Wu et al. [25] evaluated an age-adjusted MMP-7 ratio for BA diagnosis but observed no substantial improvement in diagnostic performance, suggesting that age minimally influences MMP-7 diagnostic utility.

Variations in diagnostic thresholds for MMP-7 can be attributed to differences in analytical methodology and sample handling protocols. Jiang et al. [19] and Wu et al. [18], despite conducting research in the same geographic region, reported different cutoff values. This discrepancy likely stems from differences in the immunoassay kits employed and sample storage duration. Samples in Jiang’s study were analyzed within one year of collection, whereas Wu’s specimens were stored for up to ten years, potentially resulting in MMP-7 degradation and consequently lower cutoff values. Similarly, an Iranian study [24] reported reduced sensitivity and specificity compared to other investigations, attributable to differences in ELISA kit specifications and suboptimal specimen preservation conditions.

Liver enzyme profiles may also influence MMP-7 threshold values. Yang et al. [17] and Jiang et al. [19] observed that differences in hepatic enzyme levels, particularly alanine aminotransferase (ALT) and aspartate aminotransferase (AST), correlated with variations in MMP-7 cutoff values. These findings underscore the relationship between liver function status and circulating MMP-7 concentrations.

Subgroup and meta-regression analyses based on geographic region, sample size, and cutoff values failed to identify the sources of heterogeneity observed in our study. Several limitations may have affected these analyses. The geographic distribution of studies was imbalanced, with 12 studies focused on Asian populations and only three on European or North American cohorts. This disproportionate representation, particularly the limited non-Asian data, may have diminished our ability to detect region-specific heterogeneity. Similarly, the uneven distribution of sample sizes—12 studies with fewer than 100 participants versus three studies with larger cohorts—restricted our capacity to evaluate sample size as a source of heterogeneity. Additional factors potentially influencing results include specimen storage conditions, diversity in immunoassay kits, and study design. Although we performed a supplementary analysis based on study type, this did not identify sources of heterogeneity. Most included studies lacked detailed descriptions of specimen storage protocols, limiting our ability to analyze this factor. Furthermore, the variety of detection kits used across studies (nine different systems) precluded comprehensive subgroup analysis based on assay methodology.

Limitations

This meta-analysis has several limitations. First, despite employing rigorous search strategies, our study primarily included observational research designs (case-control and cohort studies) rather than randomized controlled trials, potentially limiting the strength of our conclusions. Second, significant heterogeneity was observed across studies, and our meta-regression analyses failed to identify its source. Third, substantial variability in MMP-7 assay methodology and cutoff values was noted among the included studies. The different immunoassay kits used, coupled with diverse specimen handling protocols, may have contributed to inconsistent diagnostic thresholds, highlighting the need for standardized analytical approaches to enhance diagnostic reliability.

Conclusion

Our meta-analysis demonstrates that MMP-7 exhibits high specificity in the diagnosis of BA. However, its diagnostic accuracy is influenced by factors such as sample processing methods, sample handling time, and significant variability in cutoff values. Therefore, MMP-7 cannot serve as independent diagnostic criteria. The diagnosis of BA still requires cholangiography as the gold standard. Nevertheless, MMP-7 may be used as a tool for risk stratification in BA. Due to the limited number of available studies, there is a need for additional high-quality, large-sample, multicenter clinical trials to further evaluate the optimal diagnostic performance of MMP-7.

Abbreviations

BA

Biliary atresia

MMP-7

Matrix metalloproteinase-7

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

AUC

Area under the curve

PLR

Positive likelihood ratio

NLR

Negative likelihood ratio

DOR

Diagnostic odds ratio

Authors’ contributions

All authors contributed to the study conception and design. Writing - original draft preparation: Zhenyuan Li, Yanghua Deng; Writing - review and editing: Qiong Liao; Conceptualization: Zhenyuan Li, Yanghua Deng, Qiong Liao; Methodology: Zhenyuan Li, Yanghua Deng, Qiong Liao; Formal analysis and investigation: Zhenyuan Li, Yanghua Deng; Funding acquisition: Qiong Liao; Resources: Qiong Liao; Supervision: Qiong Liao, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the Sichuan Medical Association [grant number S18036].

Data availability

The original contributions presented in the study are included in the article/Supplementary Material.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.