review article

Prognostic Significance of MicroRNAs in Medulloblastoma: A Systematic Review and Meta-Analysis

Haima Li1#, Jian Wen2#, Dongdong Li3, Ruen Liu1,4*

1People's Clinical Medical College Affiliated Nanchang University, Department of Neurosurgery, Jiangxi Provincial People's Hospital, Nanchang, 330006, People's Republic of China.

2Department of Orthopedics, Jiangxi Provincial People's Hospital, Nanchang, 330006, People's Republic of China

3Department of Pulmonary and Critical Care Medicine, Jiangxi Provincial People's Hospital, Nanchang, 330006, People's Republic of China

4Department of Neurosurgery, Peking University People’s Hospital, 11th Xizhimen South St., Beijing 100044, People's Republic of China

*Corresponding author: Ruen Liu, Department of Neurosurgery, Jiangxi Provincial People's Hospital, Nanchang, 330006, People's Republic of China

Received Date: 14 April, 2023

Accepted Date: 22 April, 2023

Published Date: 26 April, 2023

Citation: Li H, Wen J, Li D, Liu R (2023) Prognostic Significance of MicroRNAs in Medulloblastoma: A Systematic Review and Meta-Analysis. Int J Nurs Health Care Res 6:1417. DOI: https://doi.org/10.29011/2688-9501.101417

Abstract

Objective: Medulloblastoma (MB) is the most common malignant brain tumor in children with high mortality. Therefore, it is essential to identify a reliable and comprehensive prognostic biomarker. Thus, we intend to investigate the relationship between microRNAs (miRNAs) and the prognosis of patients with MB. Design: Systematic review with meta-analysis. Methods: 4 databases were searched, including PubMed, Web of Science, Embase, and Cochrane Library. All the English publications until 1 November 2022 will be searched without any restriction of countries or article type. The retrieved articles are carefully screened according to the selection criteria. In meta-analysis studies, hazard ratio (HR) and 95% confidence interval (CI) of patient survival outcomes were used to explore the relationship between overall survival (OS) and the expression of miRNAs. Results: The expressions of 10 miRNAs in 855 MB patients from 6 studies were studied to explore the association between the predictive role of miRNAs and survival outcomes. The estimated overall pooled effect of HR was 0.57 (95% CI: 0.33-0.99), suggesting that miRNA marker expression reduced the risk of death in patients with MB. Subgroup analyses showed that tumor miRNA level prognostic efficacy for better OS was stronger in MB patients of the four molecular subsets (HR:0.37; 95% CI:0.19-0.73; P=0.670) than those with Group3 and Group4 molecular subsets only (HR:0.79; 95% CI:0.29-2.16;P=0.024). Conclusions: Our analysis indicates that high miRNAs expression in MB patients may associate with the better OS. Thereby, the expression of miRNAs in MB patients may act as a potential biomarker for prognosis.

Keywords: Medulloblastoma; miRNAs; Biomarkers; Prognosis; Survival; Systematic review; Meta-analysis

 

Introduction

Medulloblastoma (MB) is one of the most malignant neuroepithelial tumors of the central nervous system in children [1]. According to current consensus, MB has four core molecular subsets: WNT, SHH, Group 3and Group 4 [2], which differ not only distinct in their underlying genetic changes but also differ in clinical characteristics like age, gender-related incidence, the incidence of metastasis, and overall survival rates [3,4]. Standard treatment for MB includes surgery, adjuvant chemotherapy, and craniospinal irradiation; aggressive interventions lead to prolonged sequelae and poor quality of life [5]. Approximately 75% of pediatric MB patient’s recurrence within a few years [6]. Therefore, the treatment of MB remains a challenge in pediatric oncology. Baliga S et al. [7] Studies indicate that the 10-year OS for standard and intermediate/high-risk patients was 86.9% and 68.9%, respectively. Despite progress in the treatments, approximately 30% of MB children will die from current treatment strategies [8], so reducing mortality and morbidity is urgent.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level [9]. MiRNAs bind to complementary sequences in the 3′ untranslated areas of numerous target genes, usually leading to their silencing [10]. Each miRNA is thought to target hundreds of genes. It has been revealed as a critical regulator during normal tissues and cancers [11,12]. More evidence indicates that miRNA expression disorder plays a vital role in pathogenesis,cancer progression and response to treatment [13]. Consequently, they have been extensively studied as diagnostic and prognostic cancer biomarkers in recent years [14,15]. These efforts aim to find new molecular markers and targeted therapies to achieve early diagnosis and better treatment. MiRNAs are associated with prognosis in patients with MB, but the conclusions have been inconsistent. A previous systematic review explored the relationship between miRNA and prediction in MB patients. However, only two studies were included, thus lacking relevant data. The survival outcome of tumor patients was not quantitatively analyzed, and miRNA was not found to have guiding significance for the prognosis of pediatric MB patients. This systematic review and meta-analysis aim to clarify the relationship between miRNA and the prognosis of patients with MB through a systematic and comprehensive qualitative and quantitative analysis of existing original studies.

Materials and Methods

Guidelines and Registration

The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) criteria were used to perform the study [16]. This study is based on the PROSPERO that was registered under the ID CRD42021289410.

Section and Topic

Item #

 

Checklist item

Location

where item is reported

Title

 

Title

1

Identify the report as a systematic review.

1

Abstract

 

Abstract

2

See the PRISMA 2020 for Abstracts checklist.

2-3

Introduction

 

Rationale

3

Describe the rationale for the review in the context of existing knowledge.

4

Objectives

4

Provide an explicit statement of the objective(s) or question(s) the review addresses.

4

Methods

 

Eligibility criteria

5

Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.

5

Information sources

6

Specify all databases, registers, websites, organizations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.

5

Search strategy

7

Present the full search strategies for all databases, registers and websites, including any filters and limits used.

5-6

Selection process

8

Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

6-7

Data collection process

9

Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

6-7

Data items

10a

List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

7

10b

List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

7

Study risk of bias assessment

11

Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

7

Effect measures

12

Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.

7

Synthesis methods

13a

Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

8

13b

Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

8

13c

Describe any methods used to tabulate or visually display results of individual studies and syntheses.

8

13d

Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

8

13e

Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).

8

13f

Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

8

Reporting bias assessment

14

Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

8

Certainty assessment

15

Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

8


Section and Topic

Item #

 

Checklist item

Location

where item is reported

Results

 

Study selection

16a

Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

8

16b

Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

8

Study characteristics

17

Cite each included study and present its characteristics.

8-10

Risk of bias in studies

18

Present assessments of risk of bias for each included study.

8

Results of individual studies

19

For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.

8

Results of syntheses

20a

For each synthesis, briefly summarize the characteristics and risk of bias among contributing studies.

9-10

20b

Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.

9-10

20c

Present results of all investigations of possible causes of heterogeneity among study results.

9-10

20d

Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.

9-10

Reporting biases

21

Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.

11

Certainty of evidence

22

Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

11

Discussion

 

Discussion

23a

Provide a general interpretation of the results in the context of other evidence.

12-14

23b

Discuss any limitations of the evidence included in the review.

12-14

23c

Discuss any limitations of the review processes used.

12-14

23d

Discuss implications of the results for practice, policy, and future research.

12-14

Other Information

 

Registration and protocol

24a

Provide registration information for the review, including register name and registration number, or state that the review was not registered.

5

24b

Indicate where the review protocol can be accessed, or state that a protocol was not prepared.

5

24c

Describe and explain any amendments to information provided at registration or in the protocol.

5

Support

25

Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.

15

Competing interests

26

Declare any competing interests of review authors.

15

Availability of data, code and other materials

27

Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.

--

From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, et al. (2022) The PRISMA 2022 statement: an updated guideline for reporting systematic reviews. BMJ 372: n71.

Search Strategy

We will search for the articles in 4 electronic databases including PubMed, Web of Science, Embase and Cochrane Library. Searches were conducted using medical subjective headings (MeSH) and free words. All the English publications until 1 November 2022 will be searched without any restriction of countries or article type. The reference lists of retrieved articles were also checked for relevant literatures. The searches typically included 3 key terms “Medulloblastoma,” “MicroRNAs,” and “Prognosis.” We searched PubMed using the following strategy: ((("Medulloblastoma"[Mesh]) OR ((((((((((((((((((((((Medulloblastoma) OR (Medulloblastomas)) OR (Melanocytic Medulloblastoma)) OR (Medulloblastoma, Melanocytic)) OR (Medulloblastomas, Melanocytic)) OR (Melanocytic Medulloblastomas)) OR (Medulloblastoma, Childhood)) OR (Childhood Medulloblastoma)) OR (Childhood Medulloblastomas)) OR (Medulloblastomas, Childhood)) OR (Medullomyoblastoma)) OR (Medullomyoblastomas)) OR (Arachnoidal Cerebellar Sarcoma, Circumscribed)) OR (Sarcoma, Cerebellar, Circumscribed Arachnoidal)) OR (Medulloblastoma, Desmoplastic)) OR (Desmoplastic Medulloblastoma)) OR (Desmoplastic Medulloblastomas)) OR (Medulloblastomas, Desmoplastic)) OR (Medulloblastoma, Adult)) OR (Adult Medulloblastoma)) OR (Adult Medulloblastomas)) OR (Medulloblastomas, Adult))) AND (("MicroRNAs"[Mesh]) OR (((((((((((((((((MicroRNA) OR (miRNAs)) OR (Micro RNA)) OR (RNA, Micro)) OR (miRNA)) OR (Primary MicroRNA)) OR (MicroRNA, Primary)) OR (Primary miRNA)) OR (miRNA, Primary)) OR (pri-miRNA)) OR (pri miRNA)) OR (RNA, Small Temporal)) OR (Temporal RNA, Small)) OR (stRNA)) OR (Small Temporal RNA)) OR (pre-miRNA)) OR (pre miRNA)))) AND (("Prognosis"[Mesh]) OR (((((Prognoses) OR (Prognostic Factors)) OR (Factor, Prognostic)) OR (Factors, Prognostic)) OR (Prognostic Factor))).

Inclusion Criteria

  • Full-text articles in English; including patients with histopathologically diagnosed MB.
  • Measured the expression of miRNAs in tumor tissue, serum, or plasma, as well as the survival prognosis of patients.
  • Reported the survival curves for overall survival (OS) or disease-free survival (DFS) or cause-specific survival (CSS) or recurrence-free survival (RFS) with or without the hazard ratio (HR) and its 95% confidence intervals (CIs).

Exclusion Criteria

  • Lack of patient survival data.
  • Studies that included non-human data.
  • Reviews, preclinical studies, and duplicate reports were excluded.

Data Extraction and Quality Assessment

Two authors independently performed database search, data extraction, and quality evaluation. The discussion will resolve any disagreement until consensus is reached or consulting a third author. Including miRNAs studied, first author's names, publication year, study location, platform, source of a clinical sample,sample size, study design, metastasis or not, result, survival data (HR and 95%CI), and Newcastle-Ottawa Scale (NOS). If HRs and 95% CIs were not provided directly in the included articles, we estimated them from Kaplan-Meier survival curves with methods described by Tierney et al. using Engauge Digitizer version 4.1 [17]. Two reviewers systematically evaluated the quality of included studies according to NOS. The higher the score, the better the quality of the essay. A joint review solved disagreement.

Statistical Analysis

Meta-analyses were performed to summarize the association between miRNA expression and OS in MB patients. HR and the corresponding standard errors were estimated from 95% CIs or p-values and were logarithmically transformed to obtain a normal distribution. The Cochrane’s Q test and I² test were performed to evaluate the heterogeneity [18]; an I² > 50% indicates significant heterogeneity. A random-effect model was applied if substantial heterogeneity was detected; otherwise, a fixed-effect model was applied. Egger’s test and funnel plot symmetry were used to assess the risk of publication bias. Sensitivity analyses were performed to evaluate the stability of the results by omitting each of the included studies one at a time [19]. The STATA software (Version 16.0; Stata Corporation, TX, USA) was used for the statistical analyses.

Results

Study Selection

As shown in (Figure 1), the initial search resulted in 152 articles from PubMed (n = 38) and the Web of Science (n = 27), Embase (n = 87). After excluding, studies unrelated to our systematic review and meta-analysis according to the exclusion criteria, 22 articles were considered to be screened. The full text of the 22 articles was reviewed, and 8 of them did not measure miRNAs expression, non-human sample studies (n = 2), and the full text of the studies could not be obtained (n = 2). Full-text studies of qualitative synthesis according to inclusion criteria (n = 10), 4 of which lacked relevant data. Finally, 10 studies were included for systematic analysis, of which 6 papers could be further meta-analyzed.


 Figure 1: Flow diagram of the study selection for the present meta‐analysis.

Study Characteristics

The characteristics of the included studies are shown in (Table 1). Overall, the meta-analysis included 855 MB patients from 6 studies in China, Switzerland, Brazil, and India. All articles are published in English. Since the 2 studies included 2 independent miRNAs, respectively, and 1 study included 3 independent miRNAs, the relationship between miRNA expression in tumors and OS prognosis during follow-up was assessed in the article, so these were included independently. Finally, 10 miRNAs from 6 studies were included in the meta-analysis. The samples included ranged from 32 to 470. 6 miRNAs in the 4 studies included 4 molecular subsets in MB patients. In comparison, 4 miRNAs in the other 2 studies included Group 3 and Group 4 patients in the molecular subsets of MB. No cutoff value was mentioned in the 2 studies, and the median miRNA expression value was used as a cutoff value in the remaining 4 studies. 5 studies only used QRT-PCR for miRNA quantification, and 2 studies used both QRT-PCR and microarray analysis, and the outcome of OS was reported during follow-up. The NOS ranged from 6 to 8 in the included studies.

 

MicroRNAs

First author

Year

Country

platform

Sample

Number

Study   design

Metastasis

Result

HR(H/L)

95%CI

NOS

miR-182

Kuader R et al.-set 1

2013

India

qRT-PCR Microarray

Tissue

37

R

NA

OS

3.527

1.045-11.9

6

miR-592

Kuader R et al.-set 2

2013

India

qRT-PCR Microarray

Tissue

37

R

NA

OS

0.39

0.03-5.32

6

miR-9

Fiaschetti G et al.

2014

Switzerland

qRT-PCR

Tissue

34

R

NA

OS

0.5

0.04-5.96

6

miR-495

Wang et al.

2015

China

qRT-PCR

Tissue

62

R

M0   51

OS

0.26

0.08-0.85

8

miR-100

Pezuk JA et al. -set 1

2016

Brazil

qRT-PCR

Tissue

32

R

NA

OS

1.16

0.14-9.94

7

miR-126

Pezuk JA et al.-set 2

2016

Brazil

qRT-PCR

Tissue

32

R

NA

OS

1.26

0.11-14.87

7

miR-219

Pezuk JA et al.-set 3

2016

Brazil

qRT-PCR

Tissue

32

R

NA

OS

0.86

0.03-22.43

7

miR-204

Bharambe SH et al.-set 1

2019

India

qRT-PCR

Tissue

144

R

 M0   78

OS

0.53

0.17-1.67

7

miR-204

Bharambe SH et al.-set 2

2019

India

qRT-PCR

Tissue

470

R

 M0  220

OS

0.46

0.28-0.74

7

miR-137

Ji  et al.

2021

China

qRT-PCR

Tissue

76

 R

 M0   45

OS

0.25

0.08-0.73

8

NOS: Newcastle-Ottawa scale; OS: Overall Survival; HR: Hazard Ratio; M0:Metastasis; M+:NOT Metastasis; NA: Not Available 

Table 1: The main features of the studies included in the systematic review and meta-analysis.

Comprehensive Meta-Analysis

In 855 MB patients from 6 included studies, the prognostic significance of 10 miRNAs was investigated (Figure 2). 7 miRNAs were upregulated, while 3 miRNAs were downregulated. The overall pooled effect estimates of HR for (upregulated and down-regulated) miRNA expressions were 0.57, with a 95 percent CI of 0.33 -0.99, meaning that miRNAs expression reduced the risk of death in MB patients when using a fixed-effect model.

 

Figure 2: Forest plots for the meta-analysis of the prognostic efficacy of tumor miRNAs for OS in patients with MB.

Subgroups Analysis

Subgroup analyses showed that prognostic efficacy of tumor miRNA level for better OS was stronger in MB patients of the four molecular subsets (HR:0.37; 95% CI:0.19-0.73;P=0.670) than those with Group3 and Group4 molecular subsets only (HR:0.79; 95% CI:0.29-2.16;P=0.024). The prognostic efficacy of tumor miRNA level was consistent in Asians (HR: 0.53; 95% CI: 0.26-1.08; p = 0.0026) and non - Asians patients with MB (HR: 0.92; 95% CI: 0.26-3.22; p = 0.953). The detailed results are shown in (Figure 3).

 

Figure 3: Subgroup analyses for the meta-analysis of the prognostic efficacy of miRNAs for OS in patients with MB according to the molecular subset and patient origin. (A) Subgroup analyses in MB patients of the four molecular subsets. (B) Subgroup analyses in MB patients with Group3 and Group4 molecular subsets. (C) Subgroup analyses in Asians patients. (D) Subgroup analyses in non - Asians patients.

Publication Bias

In the pooled analysis, funnel plot symmetry was used to assess the risk of publication bias. The funnel plot of the overall study is shown in Figure 4. The funnel plot symmetry was confirmed by visual examination, suggesting that the potential risk of publication bias was negligible. The result of Egger’s test for this meta-analysis also demonstrated no significant publication bias. Results show that no significant publication bias was found in the analysis.

 

Figure 4: Funnel plot in the meta-analysis of the association between microRNAs expression and OS in patients with MB.

Sensitivity Analysis

Sensitivity analysis was performed by removing individual studies in turn. Our results were unchanged, indicating that our combined HRs and 95%CIs were stable in this meta-analysis. The result is shown in (Figure 5).

 

Figure 5: Forest plot in the meta-analysis random-effects estimates (exponential form) sensitivity analysis by omitting one study by turns.

Discussion

The prognostic efficacy of miRNAs in various tumors has been studied, including breast cancer, gastric cancer, glioma, lung cancer and other cancers [20-23]. MiRNA, as a short non-coding RNA, regulates gene expression at the post-transcriptional level, especially playing a crucial role in the occurrence and development of human cancer [24]. Abnormal regulation of miRNA results in changes in downstream oncogenes, related cancer suppressors, and signaling pathway molecules [25]. Some patients with MB experience local or metastatic relapses after standard therapy, a condition associated with very poor prognosis [26]. Though the prognostic relationship between miRNA-182 [27], 204 [28], 100 [29], 137 [30] and other miRNAs and MB patients has been studied, the results are inconsistent. Previous systematic reviews and meta-analyses have also explored the potential prognostic role of miRNAs in many other cancers. Still, no quantitative meta-analysis has been studied to investigate the prophetic role of miRNA in MB patients [31-33]. Our meta-analysis is novel and examines miRNAs' prognostic meaning as biomarkers in MB patients using a continuous version pooled meta-analysis. The primary purpose is to study the relationship between miRNAs and the prognosis of MB patients and provide further theoretical evidence for clinical application.

Our meta-analysis investigated 855 MB patients with 10 miRNAs from 6 studies. The HR combined effect of related miRNAs expression (up-regulation and down-regulation) was estimated to be 0.57 with a 95% CI 0.33-0.99. These results suggested that the overall pooled effect of miRNA expression related to the prognosis of MB update could reduce the risk of death in MB patients. In addition, Subgroup analyses showed that prognostic efficacy of tumor miRNA level for better OS was stronger in MB patients of the four molecular subsets (HR:0.37; 95% CI:0.19-0.73;P=0.670) than those with Group 3 and Group 4 molecular subsets only (HR:0.79; 95% CI:0.29-2.16;P=0.024). The results are consistent with previous studies [34-36]. they have observed how miRNA expression differs depending on molecular subsets and metastasis factors. Both univariate and multivariate analyses were used to explore the survival rate of MB patients. The results indicate that dysregulation miRNA expression was associated with poor prognosis in MB with the Group3 and Group4 molecular subsets or in patients with metastases,suggesting that molecular subsets and metastasis may be independent prognostic factors of MB patients. We also found the prognostic efficacy of tumor miRNA level was consistent in Asians (HR: 0.53; 95% CI: 0.26-1.08; p = 0.0026) and non - Asians patients with MB (HR: 0.92; 95% CI: 0.26-3.22; p = 0.953). Results show that no significant publication bias was found in the analysis. Sensitivity analysis shows that our conclusions are robust and reliable. The included studies were assessed as good quality using quality evaluation methods. Shaw p et al. [37] the study suggests that increased overall pooled effect of miRNA expression is associated with poor overall survival in nasopharyngeal carcinoma (NPC) patients. in our study. However, some miRNAs expression was up-regulated in MB patients, and some were down-regulated. But in conclusion, the overall pooled effect of miRNAs expression in MB may predict better survival. Based on the limited original data available, the role of miRNAs as prognostic biomarkers should be fully confirmed in more prospective studies with large cohorts studies.

Some limitations of our study should be considered in the analysis of results. First, the study included a limited sample size of 855 MB patients with 10 miRNAs. Secondly, some HRs and 95%CIs data could not be obtained directly. We calculated them by using Kaplan Meier survival curve, which may induce minor errors in the analysis. Finally, Since the cut-off values for grouping patients with higher or lower miRNA may differ among the studies, this variable may have also led to heterogeneity.

In conclusion, a systematic and comprehensive qualitative and quantitative analysis of existing studies shows that increased miRNA expression in MB patients is associated with improved overall survival. It indicates that miRNA may provide some guidance for molecular targeted therapy of MB in the future, and this study has practical clinical significance.

Conclusion

This meta-analysis elaborated the influence of dysregulated miRNA expression on the survival of MB patients. Our analysis indicates that high miRNAs expression in MB patients may associate with the better OS. Thereby, the expression of miRNAs in MB patients may act as a potential biomarker for prognosis.

Author Contributions

Haima LI conceived the study. Jian WEN and Dongdong LI performed the literature search. Haima LI and Jian WEN extracted the required data. Hai ma LI performed the statistical analyses. Hai ma LI wrote a draft. Ruen LIU reviewed the paper. All authors contributed to the article and approved the submitted version.

Competing Interests

The authors declare no conflict of interest.

Ethics Approval

Neither ethics approval nor participant consent was required as this study was based solely on the summary results of previously published articles.

Date Availability Statement

No additional data are available.

Patient and Public Involvement

 No patient involved.

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