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\begin{document}

\title{Regular arrangement of collecting venules (RAC) as an endoscopic marker
for exclusion of Helicobacter pylori (H. pylori) infection: A systematic
review and meta-analysis}



\author[1]{Fan Yu}%
\author[1]{shaoyou qin}%
\author[2]{Song Wang}%
\author[1]{Jiangbin  Wang}%
\affil[1]{China-Japan Union Hospital of Jilin University}%
\affil[2]{The First Hospital of Jilin University}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Helicobacter pylori (H. pylori) is the most common cause of
gastric cancer. Growing evidence suggests that the regular arrangement
of collecting venules (RAC) can be used as an endoscopic marker to
diagnose H. pylori infection. However, data on the diagnostic accuracy
of RAC for H. pylori infection are conflicting. We performed a
systematic review and meta-analysis of relevant studies to determine the
diagnostic accuracy and clinical utility of RAC for the diagnosis of H.
pylori infection. Methods: We systematically searched PubMed, Embase,
Web of Science, and the Cochrane Library between inception and Oct 29,
2020, for studies that assessed the diagnostic accuracy of RAC for H.
pylori infection. Results: The literature search yielded 2921
nonduplicated screened titles, of which 58 underwent full-text review.
Fifteen studies, representing a total of 6621 patients, met the
inclusion criteria. The area under the summary receiver operating
characteristic curve was 0.98 (95\% CI 0.96 to 0.99). The pooled
estimates for RAC were 0.98 (95\% CI 0.95 to 0.99) for sensitivity and
0.75 (95\% CI 0.54 to 0.88) for specificity. The pooled positive
likelihood ratio (PLR) and negative likelihood ratio (NLR) were 3.8
(95\% CI 1.9 to 7.7) and 0.03 (95\% CI 0.02 to 0.07), respectively.
Conclusions: RAC can be used as an endoscopic marker for exclusion of H.
pylori infection. However, it cannot be recommended as a single
indicator for the confirmation of H. pylori infection. The conclusion of
this study should be treated with caution because significant
heterogeneity exists between the evaluated studies.%
\end{abstract}%



\sloppy


\textbf{Regular arrangement of collecting venules (RAC) as} \textbf{an
endoscopic marker for exclusion of Helicobacter pylori (H. pylori)
infection: A systematic review and meta-analysis}

\textbf{Running title: RAC as an endoscopic marker for Hp infection}

Fan Yu\textsuperscript{1}, Shaoyou Qin\textsuperscript{1}, Song
Wang\textsuperscript{2,}*, Jiangbin Wang\textsuperscript{1,}*

\textsuperscript{1} Department of Gastroenterology and Hepatology,
China-Japan Union Hospital of Jilin University, Changchun, China.

\textsuperscript{2} Department of Urology, The First Hospital of Jilin
University, Changchun, China.

* Correspondence: Jiangbin Wang, Department of Gastroenterology and
Hepatology, China-Japan Union Hospital of Jilin University, No. 126
Xiantai Street, Changchun 130033, China.
E-mail:\emph{jiangbin@jlu.edu.cn} . Song Wang, Department of Urology,
The First Hospital of Jilin University, No. 71 Xinmin Street, Changchun
130021, China. E-mail: w\_s@jlu.edu.cn.

\textbf{Abstract}

\textbf{Background:} Helicobacter pylori (H. pylori) is the most common
cause of gastric cancer. Growing evidence suggests that the regular
arrangement of collecting venules (RAC) can be used as an endoscopic
marker to diagnose H. pylori infection. However, data on the diagnostic
accuracy of RAC for H. pylori infection are conflicting. We performed a
systematic review and meta-analysis of relevant studies to determine the
diagnostic accuracy and clinical utility of RAC for the diagnosis of H.
pylori infection.

\textbf{Methods:} We systematically searched PubMed, Embase, Web of
Science, and the Cochrane Library between inception and Oct 29, 2020,
for studies that assessed the diagnostic accuracy of RAC for H. pylori
infection.

\textbf{Results:} The literature search yielded 2921 nonduplicated
screened titles, of which 58 underwent full-text review. Fifteen
studies, representing a total of 6621 patients, met the inclusion
criteria. The area under the summary receiver operating characteristic
curve was 0.98 (95\% CI 0.96 to 0.99). The pooled estimates for RAC were
0.98 (95\% CI 0.95 to 0.99) for sensitivity and 0.75 (95\% CI 0.54 to
0.88) for specificity. The pooled positive likelihood ratio (PLR) and
negative likelihood ratio (NLR) were 3.8 (95\% CI 1.9 to 7.7) and 0.03
(95\% CI 0.02 to 0.07), respectively.

\textbf{Conclusions:} RAC can be used as an endoscopic marker for
exclusion of H. pylori infection. However, it cannot be recommended as a
single indicator for the confirmation of H. pylori infection. The
conclusion of this study should be treated with caution because
significant heterogeneity exists between the evaluated studies.

\textbf{KEYWORDS:} regular arrangement of collecting venules, endoscopic
marker, Helicobacter pylori

\textbf{1 \textbar{} INTRODUCTION}

Helicobacter pylori (H. pylori) is a gram-negative bacterium affecting
up to 50\% of the population worldwide and is the most common cause of
chronic gastritis, peptic ulcer, and gastric cancer(1-3). Eradication of
chronic H. pylori infection significantly reduces gastric cancer
risk(4-6). A systematic review including ten randomized controlled
trials provided evidence that H. pylori eradication therapy reduces
gastric cancer incidence in healthy individuals and patients with
gastric neoplasia(7). The strong association between H. pylori and
gastric cancer risk highlights the importance of adequate detection and
eradication of H. pylori in clinical practice.

Conventional examinations for the diagnosis of H. pylori infection
include noninvasive and gastroscopic biopsy-based tests. These
examinations, however, cannot evaluate endoscopic findings associated
with H. pylori infection (8-13). Recently, many investigators have
attempted to characterize endoscopic features indicative of H. pylori
infection. Several endoscopic features in the Kyoto classification of
gastritis, such as the regular arrangement of collecting venules (RAC),
diffuse redness, or atrophy, have been proposed to evaluate the status
of H. pylori infection and the potential risk of developing gastric
cancer(14).

RAC is an endoscopic feature defined as numerous red dots regularly
distributed over the entire gastric body(15, 16). The presence of RAC at
the level of the distal part of the lesser gastric curvature has been
regarded as a characteristic endoscopic feature of the H.
pylori-negative normal stomach. However, data on the diagnostic accuracy
of RAC as an endoscopic marker for the diagnosis of H. pylori infection
are conflicting, with reported sensitivity ranging from 86\% to 100\%
and specificity ranging from 7\% to 98\%(17-31). Variations in the
sensitivity and specificity of RAC for H. pylori infection in these
studies highlight the need for a comprehensive evaluation of the
diagnostic performance of RAC before broader application. Therefore,
this study was conducted to determine the diagnostic accuracy and
clinical utility of RAC for the diagnosis of H. pylori infection.

\textbf{2 \textbar{} METHODS}

This study followed the Preferred Reporting Items for a Systematic
Review and Meta-Analysis of Diagnostic Test Accuracy Studies
(PRISMA-DTA)(32, 33). The study protocol was registered in PROSPERO
prior to study selection (Registration number: CRD42020216437).

\textbf{2.1 \textbar{} Data sources and search strategy}

We systematically searched PubMed, Embase, Web of Science, and the
Cochrane Library for studies that assessed the diagnostic accuracy of
RAC for H. pylori infection. Our medical subject heading terms (for
PubMed), EMTREE terms (for Embase), and search text (for others) were
''(''Kyoto classification of gastritis'' OR ''endoscopic findings'' OR
(endoscopic features) OR ''regular arrangement of collecting venules''
OR RAC) AND (''Helicobacter pylori'' OR H. pylori).'' The detailed
search strategy is shown in \textbf{Supplementary Table 1} . We searched
the databases between inception and Oct 29, 2020. The reference list of
each primary study identified was also searched.

\textbf{2.2 \textbar{} Study selection criteria}

The inclusion criteria for studies were as follows: (1) Assessed the
accuracy of RAC for determining the status of H. pylori infection; (2)
Used a rapid urease test, serum H. pylori antibody, and histological
examination to define the reference standard for H. pylori infection;
and (3) provided sufficient information (true and false positives and
negatives) to construct the 2\selectlanguage{ngerman}×2 contingency table.

The exclusion criteria were as follows: 1) reviews, letters, and case
reports; 2) studies with insufficient data to construct the 2×2 table;
and (3) studies not written in English.

\textbf{2.3 \textbar{} Data extraction and quality assessment}

Two researchers independently examined all potentially relevant papers,
extracted the data, and assessed the quality of retrieved studies. Any
disagreement was resolved by consensus. The extracted data were
characteristics of the study population (adults or children), region,
sample size, types~of~endoscopy devices, gold standard test for H.
pylori infection, prevalence of H. pylori infection, and true and false
positives and negatives. We used the Quality Assessment of Diagnostic
Accuracy Studies 2 (QUADAS-2) checklist to evaluate the quality of the
included studies(34).

\textbf{2.4 \textbar{} Statistical analysis}

We used the extracted True positives (TP), True negatives (TN), False
positives (FP), and False negatives (FN) data to calculate the pooled
sensitivity, specificity, positive likelihood ratio (PLR), negative
likelihood ratio (NLR), and diagnostic odds ratio (DOR) based on
bivariate generalized linear mixed modeling(35). We constructed a
summary receiver operating characteristic (SROC) curve. The overall
diagnostic accuracy of RAC for H. pylori was determined by calculating
the area under the SROC curve (AUROC). We calculated the Q-value and
I\textsuperscript{2} to assess heterogeneity between studies, which can
be quantified as low, moderate, and high, with upper limits of 25\%,
50\%, and 75\% for the I\textsuperscript{2} statistics,
respectively(36). Meta-regression and subgroup analysis were performed
to identify potential factors that could contribute to heterogeneity
between studies.

We used the Fagan nomogram to estimate a patient's posttest probability
of being infected with H. pylori based on a pretest probability.
Furthermore, a likelihood ratio scattergram was used to evaluate the
clinical utility of RAC for the diagnosis of H. pylori infection. In
detail, a PLR\textgreater{}10 suggests that the index test can be used
for confirmation of H. pylori infection, and an NLR\textless{}0.1
suggests it can be used for the exclusion of H. pylori infection.
Publication bias was assessed using the Deeks funnel plot asymmetry
test. We used the MIDAs module for STATA (version 12, StataCorp LP in
College Station, TX) for the bivariate summary receiver operating curve
analysis. Revman software (version 5.3, Cochrane Collaboration) was used
for quality assessment.

\textbf{3 \textbar{} RESULTS}

\textbf{3.1 \textbar{} Literature search and characteristics of the
included studies}

This meta-analysis was organized according to the PRISMA
statement.\textbf{Figure 1} summarizes the results of the literature
search and study selection. Our database search retrieved 4232 articles.
After removing duplicated records, we excluded 1311. After reviewing the
titles and abstracts, we excluded 2863. After a full-text review, we
initially identified 19 potentially eligible studies. Subsequently, we
excluded four studies for reasons reported in the PRISMA
diagram.\textbf{Supplementary Table 2} summarizes the main
characteristics of these four studies excluded at the eligibility stage
along with the exact reasons for exclusion. The search of the reference
lists of the identified articles did not identify any additional
relevant articles.

\textbf{Table 1} summarizes the baseline characteristics of the eligible
studies. All eligible studies were published between 2002 and 2020. A
total of 15 studies with 6621 participants were included in the
meta-analysis. Of these, one was conducted in America, 2 in Europe, and
the remaining 12 in Asia. Sample sizes ranged from 52 to 1875. H. pylori
infection was assessed using a rapid urease test in 8 studies, serum H.
pylori antibody in 6 studies, and histological examination in 13
studies, suggesting that each individual study might have used more than
one test for H. pylori infection at the same time. The RAC pattern was
evaluated by standard endoscopy in 10 studies and by high-resolution
magnified endoscopy in 7 studies, suggesting that each individual study
might have used both standard endoscopy and high-resolution endoscopy at
the same time. The prevalence of H. pylori among the included studies
ranged between 15.3\% and 76\% (mean 46.1\%).

\textbf{3.2 \textbar{} Quality of the included studies}

We used QUADAS-2 criteria to evaluate each of the included studies in 4
domains: patient selection, index test, reference standard, and test
timing. For the included studies, ``Patient Selection'' and ``Flow and
Timing'' revealed slight shortcomings (13.3\% and 33.3\%, respectively),
which may indicate bias regarding inclusion. Overall, the study quality
was satisfactory (\textbf{Supplementary Figure 1} ).

\textbf{3.3 \textbar{} Pooled results}

The pooled sensitivity and specificity of RAC for the endoscopic
diagnosis of H. pylori infection were 0.98 (95\% CI 0.95 to 0.99) and
0.75 (95\% CI 0.54 to 0.88), respectively (\textbf{Figure 2} ). The
pooled PLR and NLR were 3.8 (95\% CI 1.9 to 7.7) and 0.03 (95\% CI 0.02
to 0.07), respectively (\textbf{Supplementary Figure 2} ). The DOR was
115 (95\% CI 36 to 365) (\textbf{Supplementary Figure 3} ). The area
under the summary receiver operating characteristic curve was 0.98 (95\%
CI 0.96 to 0.99), suggesting a high overall diagnostic accuracy for H.
pylori infection (\textbf{Figure 3} ).

\textbf{3.4 \textbar{} Evaluation of clinical utility}

The clinical utility of RAC was assessed by utilizing like-hood ratios
to simulate a Fagan nomogram. With a 46\% pretest probability of H.
pylori infection, the posttest probabilities of H. pylori infection were
77\% (with a positive test result) and 3\% (with a negative test
result). The Fagan nomogram revealed that the posttest probability
increased by 31\% in patients with a positive test but decreased by 43\%
in patients with a negative test, suggesting that RAC was useful in
clinical practice (\textbf{Figure 4} ). Furthermore, the likelihood
ratio scattergram showed a PLR of \textless{}10 and an NLR of
\textless{}0.1, suggesting that RAC can be used as an endoscopic marker
for exclusion rather than confirmation of H. pylori infection
(\textbf{Figure 5} ).

\textbf{3.5 \textbar{} Publication bias and heterogeneity}

We used the Deeks plot asymmetry test to examine publication bias. The
funnel plot did not reveal significant publication bias (p=0.37)
(\textbf{Supplementary Figure 4} ). Heterogeneity among the included
studies was measured using the Cochran-Q method and
I\textsuperscript{2}. Substantial heterogeneity existed among the
studies (overall I\textsuperscript{2} for bivariate model 99.95\%, 95\%
CI 94 to 100). The proportion of heterogeneity likely due to the
threshold effect was small (p\textless{}0.05).

\textbf{3.6 \textbar{} Univariable meta-regression and subgroup
analysis}

To identify the source of heterogeneity, we performed meta-regression
analyses. Three study characteristics were used as covariates for
univariable meta-regression analysis, including whether patients with a
history of H. pylori infection were excluded, whether enrollment was
consecutive, and whether a single reference standard for H. pylori
infection was used (\textbf{Supplementary Figure 5} ). The results
showed that whether patients with a history of H. pylori infection were
excluded significantly affected the sensitivity of RAC for the diagnosis
of H. pylori infection (p\textless{}0.01). Likewise, whether enrollment
was consecutive significantly affected the sensitivity of RAC
(p\textless{}0.05). Thus, the heterogeneity could partly be explained by
meta-regression analysis.

\textbf{4 \textbar{} DISCUSSION}

Several endoscopic features of the gastric mucosa have been proposed for
the diagnosis of H. pylori infection, such as RAC, diffuse or spotty
redness, mucosal swelling, and nodular changes(1). Our study included 15
relevant studies(17-31) assessing the diagnostic accuracy of RAC for H.
pylori, and the results suggest that RAC has a high diagnostic accuracy
for H. pylori infection, with a pooled estimate of 0.98 (95\% CI 0.95 to
0.99) for sensitivity and 0.75 (95\% CI 0.54 to 0.88) for specificity.

Many studies have evaluated the diagnostic accuracy of RAC as a single
endoscopic feature for H. pylori, with inconclusive results. A
prospective study in a European population enrolling 140 adults found
that the presence of RAC in the lesser curvature evaluated with
high-definition endoscopy can help identify patients without H. pylori,
with a sensitivity of 100\% and a specificity of 48.96\%(20). A
prospective study in Korea involving 617 individuals concluded that the
RAC pattern observed using standard endoscopy could predict H. pylori
infection status, with a sensitivity of 93.3\% and a specificity of
89.1\%(19). Again, in a Brazilian cohort of 99 individuals, Machado et
al. investigated the diagnostic accuracy of RAC for H. pylori,
suggesting that RAC can provide a sensitivity of 96.9\% and a
specificity of 88.1\% for diagnosing H. pylori infection(26).

In a meta-analysis from 2020 including studies published between 2002
and 2019, Li and colleagues concluded that RAC is a valuable endoscopic
finding for predicting patients without H. pylori infection(37).
However, this meta-analysis has substantial shortcomings in its
quantitative data analysis for heterogeneity, with a reported
I\textsuperscript{2} of 0 (95\% CI: 0-100\%). In contrast, our study
found significant heterogeneity between studies, with an
I\textsuperscript{2} of 99.95\% (95\% CI: 99-100\%). Furthermore, we
performed a univariable meta-regression and subgroup analysis to
identify the potential source of heterogeneity between the studies. The
results showed that whether patients with a history of H. pylori
infection were excluded and whether consecutive enrollment was used in
each study significantly affected the sensitivity of RAC, indicating
that these two factors might partly contribute to the heterogeneity
between studies.

Likelihood ratios and posttest probabilities are also of importance
because they provide information regarding the likelihood that a patient
with a positive or negative test has H. pylori infection or not. In our
study, a positive likelihood ratio of 3.8 implies that a person with H.
pylori infection is 3.8 times more likely to have a positive test result
than is a healthy person. Likewise, a negative likelihood ratio of 0.03
indicates that a person without H. pylori infection is 33 times more
likely to have a negative test result than is a person with H. pylori
infection. Therefore, RAC can serve as a reliable marker for exclusion
rather than confirmation of H. pylori infection.

As our results show, RAC is not a perfect endoscopic marker for the
diagnosis of H. pylori. Although RAC has a high overall diagnostic
accuracy for H. pylori infection, it is not a good predictor for
confirming H. pylori infection because of its low positive likelihood
ratio. The pathophysiological process of H. pylori infection is complex
and can be affected by many factors, which probably contributes to the
variations in endoscopic findings(38-41). Therefore, a single endoscopic
feature of RAC might be insufficient for confirmation of H. pylori
infection because of the relatively low positive likelihood ratio, thus
highlighting the need for a combination of multiple endoscopic features
to confirm H. pylori infection.

This study has limitations. First, we detected substantial heterogeneity
between the studies and found that two of the study characteristics
contributed to the observed heterogeneity. However, there are probably
additional study characteristics that have impacted study heterogeneity
but have not been addressed, such as sample size, geographic area,
variation in the methods used for the diagnosis of H. pylori between
studies, and variation in the anatomic location where endoscopic
physicians observed the RAC, because these factors were challenging to
quantitatively analyze. Second, we only included studies written in
English, which might have led to selection bias, although the funnel
plot did not reveal significant publication bias (p=0.37). Third, this
systematic review did not include studies that assessed endoscopic
features other than RAC that are possibly associated with H. pylori
infection. Despite these limitations, this meta-analysis investigating
the diagnostic accuracy of RAC for H. pylori infection is the largest
and most comprehensive assessment to date.

\textbf{5 \textbar{} CONCLUSION}

In conclusion, RAC can be used as an endoscopic marker for the exclusion
of H. pylori infection. However, it cannot be recommended as a single
indicator for the confirmation of H. pylori infection. The conclusion of
this study should be treated with caution because significant
heterogeneity exists between the included studies.

\textbf{Conflict of interest}

The authors have declared no conflict of interest.

\textbf{Author contributions}

Fan Yu, Shaoyou Qin, and Jiangbin Wang designed the study. Fan Yu wrote
the manuscript. Fan Yu, Shaoyou Qin, and Song Wang searched the
databases, selected the studies, assessed the quality of the included
studies, and performed the statistical analysis. Jiangbin Wang and Song
Wang approved the last version and should be regarded as
co-corresponding authors. Fan Yu and Shaoyou Qin contributed equally to
the manuscript and should be regarded as co-first authors.

\textbf{Data availability statement}

Research data could be shared upon reasonable request to the
corresponding author.

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\textbf{Table 1} . Characteristics of the studies included in the
meta-analysis\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllllll@{}}
\toprule
\textbf{Author} & \textbf{Year} & \textbf{Region} & \textbf{Population}
& \textbf{Simple size(n)} & \textbf{Endoscopy Devices for index test
(RAC)} & \textbf{Reference standard for H.pylori infection} &
\textbf{Prevalence of H.pylori infection(\%)} & \textbf{TP} &
\textbf{TN} & \textbf{FP} & \textbf{FN} & \textbf{Sensitivity{[}95\%
CI{]}} & \textbf{Specificity{[}95\% CI{]}}\tabularnewline
\midrule
\endhead
Alaboudy A\textsuperscript{{[}17{]}} & 2011 & Egypt & Adults & 390 &
Standard Endoscopy & \selectlanguage{ngerman}·IHC testing of gastric tissues in 184 patients
·Serum H.pylori IgG antibody in 206 patients & 58.7 & 185 & 22 & 95 & 2
& \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.99{[}0.96-1.00{]} & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.19{[}0.12-0.27{]}\tabularnewline
Anagnostopoulos GK\textsuperscript{{[}18{]}} & 2007 & United Kingdom &
Adults & 95 & HD Magnifying Endoscopy & \selectlanguage{ngerman}·Histological tissues testing
with HE and toluidine blue stain ·Histological tissues for a CLO or CLO
test & 27.4 & 26 & 64 & 5 & 0 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}1.00{[}0.87-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.93{[}0.84-0.98{]}\tabularnewline
Cho J H\textsuperscript{{[}19{]}} & 2013 & Korea & Adults & 617 &
Standard Endoscopy & \selectlanguage{ngerman}·RUT of gastric tissues ·Histological tissues
testing with Giemsa stain & 42 & 335 & 230 & 28 & 24 &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.93{[}0.90-0.96{]} & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.89{[}0.85-0.93{]}\tabularnewline
Garc\selectlanguage{ngerman}és-Durán R\textsuperscript{{[}20{]}} & 2019 & Spain & Adults & 140 &
HD Endoscopy & \selectlanguage{ngerman}·Histological tissues testing with Giemsa stain ·IHC in
negative histologic study for H.pylori ·RUT of gastric tissues & 31.4 &
44 & 47 & 49 & 0 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}1.00{[}0.92-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.49{[}0.39-0.59{]}\tabularnewline
Gonen C\textsuperscript{{[}21{]}} & 2009 & Turkey & Adults & 129 & HD
Magnifying Endoscopy & \selectlanguage{ngerman}·Histological tissues testing with Giemsa stain
·RUT of gastric tissues ·\textsuperscript{14}C-UBT & 76 & 84 & 24 & 5 &
14 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.86{[}0.77-0.92{]} & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.83{[}0.64-0.94{]}\tabularnewline
Hidaka N\textsuperscript{{[}22{]}} & 2010 & Japan & Children & 87 &
\selectlanguage{ngerman}·Standard Endoscopy (small caliber) ·Magnifying Endoscopy in 8 patients
& \selectlanguage{ngerman}·UBT ·RUT ·SAT & 29 & 25 & 57 & 5 & 0 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}1.00{[}0.86-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.92{[}0.82-0.97{]}\tabularnewline
Inui M\textsuperscript{{[}23{]}} & 2020 & Japan & Adults & 576 &
Standard Endoscopy & \selectlanguage{ngerman}·\textsuperscript{13}C-UBT ·Serum H.pylori IgG
antibody ·Histological tissues testing with Giemsa stain & 15.3 & 88 &
144 & 344 & 0 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}1.00{[}0.96-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.30{[}0.25-0.34{]}\tabularnewline
Katake Y\textsuperscript{{[}24{]}} & 2013 & Japan & Adults & 723 & HD
Endoscopy & \selectlanguage{ngerman}·Serum H.pylori antibody test ·Histological tissues testing
with HE and any special stains (Giemsa, Warthin\selectlanguage{english}-Starry) and IHC & 70.5 &
506 & 189 & 24 & 4 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.99{[}0.98-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.89{[}0.84-0.93{]}\tabularnewline
Kato T\textsuperscript{{[}25{]}} & 2013 & Japan & Adults & 275 & HD
Endoscopy & \selectlanguage{ngerman}·Histological tissues testing with HE staining
·Immunostaining in negative histologic study for H.pylori & 52.7 & 131 &
60 & 65 & 9 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.94{[}0.88-0.97{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.48{[}0.39-0.57{]}\tabularnewline
Machado R S\textsuperscript{{[}26{]}} & 2008 & Brazil & Children and
adolescents & 99 & Standard Endoscopy(paediatric) & \selectlanguage{ngerman}·Histological
tissues testing with HE and Giemsa stain ·RUT of gastric tissues & 32.3
& 31 & 59 & 8 & 1 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.97{[}0.84-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.88{[}0.78-0.95{]}\tabularnewline
Na S\textsuperscript{{[}27{]}} & 2011 & Korea & adults & 263 & Standard
Endoscopy & \selectlanguage{ngerman}·RUT of gastric tissues & 51.3 & 131 & 53 & 75 & 4 &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.97{[}0.93-0.99{]} & 0.41{[}0.33-0.50{]}\tabularnewline
Nakayama Y\textsuperscript{{[}28{]}} & 2004 & Japan & Children and young
adult(8-29) & 52 & Standard Endoscopy & \selectlanguage{ngerman}·\textsuperscript{13}C-UBT
·Serum H.pylori IgG antibody ·Histological tissues testing with Giemsa
stain & 38.5 & 20 & 29 & 3 & 0 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}1.00{[}0.83-1.00{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.91{[}0.75-0.98{]}\tabularnewline
Tatewaki M\textsuperscript{{[}29{]}} & 2010 & Japan & 15-71 yrs & 1875 &
Transnasal Endoscopy & \selectlanguage{ngerman}·Serum H.pylori antibody test ·Histological
tissues testing with IHC stain & 36.8 & 665 & 1166 & 19 & 25 &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.96{[}0.95-0.98{]} & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.98{[}0.98-0.99{]}\tabularnewline
Terao S\textsuperscript{{[}30{]}} & 2015 & Japan & Adults & 743 &
Standard Endoscopy & \selectlanguage{ngerman}·Serum H.pylori antibody test ·RUT of gastric
tissues ·Histological tissues testing ·\textsuperscript{13}C-UBT & 60 &
412 & 21 & 276 & 34 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.92{[}0.90-0.95{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.07{[}0.04-0.11{]}\tabularnewline
Yagi K\textsuperscript{{[}31{]}} & 2002 & Japan & 14-86 yrs & 557 &
\selectlanguage{ngerman}·Standard Endoscopy in 162 patients ·Magnifying Endoscopy in 301
patinets & \selectlanguage{ngerman}·Histological tissues testing with HE and Giemsa stain ·The
culture of histological tissues ·RUT of gastric tissues & 69.8 & 381 &
153 & 15 & 8 & \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.98{[}0.96-0.99{]} &
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}0.91{[}0.86-0.95{]}\tabularnewline
\bottomrule
\end{longtable}

RAC: Regular arrangement of collecting venules; H.pylori: Helicobacter
pylori; TP: True positives; TN: True negatives; FP: False positives; FN:
False negatives; HD: High Definition; IHC: Immunohistochemistry; CLO:
Campylobacter-like organism; RUT: rapid urease test; UBT: urea breath
test; SAT: stool antigen test; HE: hematoxylin-eosin.

\textbf{Fig. 1} The PRISMA flow diagram of the systematic review and
meta-analysis.

\textbf{Fig. 2} Sensitivity and specificity of RAC for the diagnosis of
H. pylori infection.

\textbf{Fig. 3} Summary receiver operating characteristic curve of the
accuracy of RAC for the diagnosis of H. pylori infection.

\textbf{Fig. 4} Fagan nomogram of RAC for the diagnosis of H. pylori
infection.

\textbf{Fig. 5} Likelihood ratio scattergram of RAC for the diagnosis of
H. pylori infection.

\textbf{Fig. S1} Quality assessment of the included studies.

\textbf{Fig. S2} Likelihood ratios of RAC for the diagnosis of H. pylori
infection.

\textbf{Fig. S3} Diagnostic odds ratio of RAC for the diagnosis of H.
pylori infection.

\textbf{Fig. S4} Deeks' funnel plot for assessing the publication bias
of RAC for the diagnosis of H. pylori infection.

\textbf{Fig. S5} Univariable meta-regression and subgroup analyses for
RAC in the diagnosis of H. pylori infection. (Variable 1, Exclusion of
past Hp infection; Variable 2, A single reference standard for H.pylori
infection; Variable 3, Consecutive enrollment.)

\textbf{Table S1} Detailed search strategies used in this meta-analysis

\textbf{Table S2} Studies excluded in this meta-analysis according to
the PRISMA flow diagram\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-The-PRISMA-flow-diagram-of-the-systematic-review-and-meta-analysis/Figure-1-The-PRISMA-flow-diagram-of-the-systematic-review-and-meta-analysis}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-Sensitivity-and-specificity-of-RAC-for-the-diagnosis-of-H/Figure-2-Sensitivity-and-specificity-of-RAC-for-the-diagnosis-of-H}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-Summary-receiver-operating-characteristic-curve-of-the-accuracy-of-RAC-for-the-diagnosis-of-H/Figure-3-Summary-receiver-operating-characteristic-curve-of-the-accuracy-of-RAC-for-the-diagnosis-of-H}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-Fagan-nomogram-of-RAC-for-the-diagnosis-of-H/Figure-4-Fagan-nomogram-of-RAC-for-the-diagnosis-of-H}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5-Likelihood-ratio-scattergram-of-RAC-for-the-diagnosis-of-H/Figure-5-Likelihood-ratio-scattergram-of-RAC-for-the-diagnosis-of-H}

\end{center}
\end{figure}

\selectlanguage{english}
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