The prevalence of fimA genotypes of Porphyromonas gingivalis in patients with chronic periodontitis: A meta-analysis

Haini Wang; Wenyi Zhang; Wanchun Wang; Longmu Zhang

doi:10.1371/journal.pone.0240251

. 2020 Oct 28;15(10):e0240251. doi: 10.1371/journal.pone.0240251

The prevalence of fimA genotypes of Porphyromonas gingivalis in patients with chronic periodontitis: A meta-analysis

Haini Wang ^1,^*, Wenyi Zhang ², Wanchun Wang ², Longmu Zhang ³

Editor: Andrej M Kielbassa⁴

PMCID: PMC7592798 PMID: 33112857

Abstract

FimA is an important virulence factor of Porphyromonas gingivalis (P. gingivalis). According to its DNA sequence, the fimA genotype of P. gingivalis can be divided into six categories (I, Ib, Ⅱ, III, IV, V). The fimA gene may be a key factor in the diversity of virulence found in P. gingivalis. Moreover, the role fimA plays in the pathogenesis of P. gingivalis is closely associated with periodontitis, making it an important factor of study for disease prevention and treatment. In this study, the prevalence of fimA genotypes of P. gingivalis in patients with periodontal diseases was evaluated by meta-analysis. The Embase and PubMed databases were searched for articles from 1999 to 2019 using the following search terms: Porphyromonas gingivalis or P. gingivalis; periodontitis or chronic periodontal disease; fimA or fimA genotype. The reference lists of relevant published articles were searched manually. A total of 17 studies were included in this report. A statistical software package (Stata, version 11.0/mp, StataCorp) was utilized to calculate and analyze the P. gingivalis fimA genotypes for each combined incidence estimate. The pooled rates of fimA Ⅰ, fimA Ib, fimA Ⅱ, fimA Ⅲ, fimA Ⅳ and fimA Ⅴ genotypes of P. gingivalis were 8.4% (95% CI: 5.7–11.1), 11.7% (95% CI: 7.4–16), 42.9% (95% CI: 34.2–51.7), 6.5% (95% CI: 5.1–7.9), 17.8% (95% CI: 9.0–26.5), and 3.2% (95% CI: 1.6–4.9), respectively. This study showed that the fimA Ⅱ and fimA Ⅳ genotypes of P. gingivalis are highly present in patients with periodontal disease. Therefore, these two genotypes may be related to the pathogenesis and progress of periodontal disease, one of the main risk factors of periodontitis.

Introduction

Periodontitis is the chronic inflammation of periodontal tissue caused by an imbalance between local bacterial infection and host immune response, which leads to the formation of periodontal pockets. Periodontitis is characterized by the progressive loss of gum and alveolar bone absorption. Without treatment, this chronic inflammation can lead to the loss of affected teeth [1].

The major microorganisms associated with chronic periodontal disease are Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponemadenticola, Prevotella nigrescens, and Fusobacterium nucleatum [2]. The most common bacterium related to periodontitis is Porphyromonas gingivalis (P. gingivalis), a gram-negative anaerobe. P. gingivalis colonizes in the mouth and is closely linked to chronic periodontitis [3–5].

Many virulent factors contribute to P. gingivalis’ ability to affect the gums; proteases (collagenases, gingipains, hemolysin, trypsin), lipopolysaccharides, its capsule, fimbriae, and hemagglutinins all work in parallel to colonize the host tissue [6–8]. However, studies point to fimbriae as the leading virulence factor of P. gingivalis [9, 10]. According to the nucleotide sequence differences of the fimA gene, which encodes the fimA protein subunit, the fimA gene is divided into six genotypes: I, Ib, Ⅱ, III, IV, and V [11]. Many animal experiments and clinical studies have shown that P. gingivalis with different fimA genotypes resulted in different virulent characteristics; genotypes I, III, and V are non-toxic, while fimA Ⅱ, Ib and IV are highly toxic [11–13].

Due to the high prevalence of periodontitis and the myriad of complications that patients face, determining the risk factors that influence the incidences of this disease is crucial to prevention and management strategies. FimA genotypes of P. gingivalis have been extensively researched and reports have indicated that fimA genotypes are closely connected with periodontitis. Therefore, it is of important to investigate the prevalence of fimA genotypes of P. gingivalis as they may provide a novel approach in the prevention and treatment of periodontitis. Accordingly, a meta-analysis is important for identifying the prevalence of fimA genotypes in periodontal patients [3, 5, 7]. Using a meta-analysis vs a systematic review has the advantages of a larger sample size and higher resolution by combining different study statistics, and is also a comprehensive, accurate, and effective way of understanding the subject under investigation [14]. In our study, articles obtained from Embase and PubMed databases from 1999 to 2019 were analyzed using a statistical software package. The aim of this study is to provide a comprehensive summary of the measures to explore the prevalence of fimA genotypes of P. gingivalis in patients with periodontal disease.

Materials and methods

Literature search

The Embase and PubMed databases were searched from 1999 to January 2019 using the following search terms: Porphyromonas gingivalis or P. gingivalis; periodontitis or chronic periodontal disease; fimA or fimA genotype. The reference lists of relevant published articles were searched manually.

Study selection

167 articles with the keywords were included in the initial list and 150 unrelated studies were excluded. In addition, all studies reporting a fimA genotype of P. gingivalis in chronic periodontal disease were reviewed. Studies were included only if they met the following criteria: (a) studies were written in English or Chinese; (b) studies were from between 1999 and 2019; (c) studies reported the rate of fimA genotypes of P. gingivalis among chronic periodontal disease. Studies were excluded using the following criteria: (a) studies were reviews, case reports, or comments; (b) studies were non-human studies; (c) studies were duplicates.

Data extraction and methodological assessment

Relevant information was extracted, including the year of publication, first author's name, sample size, total number of cases, and number of positive numbers. Adjusted point estimation with 95% confidence intervals was required for quality assessment (Table 1). Data extraction was completed by two authors. Disagreements were resolved by a third reviewer.

Table 1. Summary of data from selected articles on the fimA genotypes of P. gingivalis found in periodontitis.

First author, published year	Language	Quality assessment score	Sample size	FimA genotype
First author, published year	Language	Quality assessment score	Sample size	I	Ib	II	III	IV	V
Amano A,1999 [7]	English	6	73	4	Nd	43	5	9	0
Amano A,2000 [15]	English	6	121	8	Nd	80	7	35	21
Beikler T,2003 [16]	English	7	102	26	0	39	5	19	4
Guo YH,2005 [17]	Chinese	7	89	3	0	22	6	25	16
Zhao L,2007 [12]	English	7	94	8	9	23	6	20	3
Yang BT,2016 [18]	Chinese	8	24	0	3	10	3	4	3
Enersen M,2008 [19]	English	7	82	3	4	28	8	17	1
Missailidis CG,2004 [20]	English	7	135	6	33	53	9	7	0
Teixeira SR, 2009 [21]	English	5	152	Nd	Nd	47	Nd	117	Nd
Davila-Perez C, 2007 [22]	English	8	25	3	5	4	1	1	0
Pérez-Chaparro PJ,2009 [5]	English	7	30	2	5	16	3	4	0
Sandra Moreno, 2015 [23]	English	7	26	3	2	15	2	0	0
Feng X,2013 [24]	English	7	55	9	11	22	3	3	0
Ji-Hoi Moon,2013 [3]	English	7	277	36	49	191	19	43	14
Miriam Puig-Silla,2012 [25]	English	7	33	4	4	13	3	5	0
Asano H,2003 [26]	English	5	32	3	Nd	15	2	5	2
Feng X,2014 [27]	English	7	39	4	9	20	2	1	0

Open in a new tab

*NT = not tested.

The authors assessed data quality using an appropriate quality assessment tool [28]. We assessed each article’s quality using eight criteria: (1) definition of the target population; (2) representative probability sampling; (3) sample characteristics matching the population; (4) adequate response rates; (5) standardized data collection methods; (6) reliable survey measures; (7) effective survey measures; (8) appropriate statistical methods. The criteria score was either 0 or 1, which stood for "non conformity" or "conformity", respectively. The total score for each study was between 0 and 8.

Statistical analysis

We used a statistical software package (Stata, version 11.0/mp, StataCorp) to analyze fimA genotypes of P. gingivalis for each combined incidence estimate. The comprehensive prevalence estimate and 95% confidence interval (CI) were determined based on the random or fixed effect model. Considering the possibility of heterogeneity between the studies, the Q-test (P<0.10 was considered as significant heterogeneity) and I² test (values 25, 50, 75%) were used to represent low, medium, and high heterogeneity, respectively. Due to high heterogeneity (P<0.10), the random effect model was used for statistical analysis. Furthermore, publication bias was assessed by Egger’s and Begger’s tests (P<0.05 represents significant publication bias).

Results

Study selection and characteristics of eligible studies

A total of 167 studies were originally selected through the search process. These articles were identified based on abstracts, titles, and full texts, and after the exclusion process a total of 17 papers were selected for our study. The total sample size was 1389 individuals, including samples from different countries. The search process is demonstrated in Fig 1.

Results of the meta-analysis

In the 17 included studies, the sample size was 1389 periodontal patients from articles published between 1999 and 2016. Studies were divided into two cohorts (1999–2010 and 2011–2016) for group analysis. To begin there were four main early genotypes: fimA Ⅰ, fimA Ⅱ, fimA Ⅲ, fimA Ⅳ and fimA Ⅴ. Over time, the fimA Ib subtype appeared (Table 1).

Correlation of fimA genotypes and periodontitis

It was noticed that P. gingivalis with various fimA genotypes were present from chronic periodontitis patients. The pooled rates of fimAⅠ, fimA Ib, fimA Ⅱ, fimA Ⅲ, fimA Ⅳ, and fimA ⅤP. gingivalis were 8.4% (95% CI:5.7–11.1; Fig 2), 11.7% (95% CI: 7.4–16; Fig 3), 42.9% (95% CI: 34.2–51.7; Fig 4), 6.5% (95% CI: 5.1–7.9; Fig 5), 17.8%(95% CI: 9.0–26.5; Fig 6), and 3.2% (95% CI: 1.6–4.9; Fig 7) respectively. As we can see in Figs 3 and 6, the prevalence of fimA Ⅱ and fimA Ⅳ P. gingivalis were statistically significant compared to others. In general, the fimA Ⅱ and fimA Ⅳ genotypes contributed to a elevated risk of periodontitis.

Publication bias

When the Begg’s funnel plots of the prevalence of the fimA Ⅰ, Ib, Ⅲ, and Ⅴ genotypes of P. gingivalis in chronic periodontal patients were examined, no sign of publication bias was observed. In fact, most studies were located in the funnel plots, and therefore the results of all related studies were included in the analysis (P = 0.005) (Fig 8).

When examining the Begg’s funnel plot of the prevalence of the fimA Ⅱ genotype of P. gingivalis in chronic periodontal patients, signs of publication bias were observed (P = 0.005) (Fig 8).

Discussion

Previous studies indicated that fimA genotypes of P. gingivalis are closely connected with periodontitis. In this meta-analysis, we examined the presence of P. gingivalis with various fimA genotypes in chronic periodontitis patients. We found that the fimA Ⅱ and fimA Ⅳ genotypes of P. gingivalis were the two most predominant genotypes [7, 12, 15–19, 21, 24–27]. There are several plausible reasons that may explain why the fimA Ⅱ and fimA Ⅳ genotypes were more predominant in this study. Periodontitis is a chronic inflammatory disease that leads to persistent, low-level, systemic inflammation with elevated levels of circulating inflammatory markers [29]. Various studies have indicated that the P. gingivalis fimA protein could initiate an immune inflammatory response through a variety of receptors, signal pathways, and cytokines, which enable periodontal tissue cells to express proteolytic enzymes, such as matrix metalloproteinase (MMP). These proteolytic enzymes participate in the destruction of periodontal connective tissue and alveolar bone absorption, leading to bone defects [30–35]. The fimA Ⅱ genotype had a greater ability to adhere and invade epithelial cells in mouse models [36] and in vitro studies showed that fimA Ⅱ could induce higher levels of IL-6 and IL-β than fimA Ⅰ [37]. Compared with fimA Ⅰ, the fimA Ⅳ genotype was highly invasive, and this invasiveness was increased in gingival fibroblasts if there was the substituting of allele fimA Ⅳ for allele fimA Ⅰ [38].In addition, fimA Ⅱ and fimA Ⅳ genotypes of P. gingivalis could induce the expression and secretion of MMP-8 and MMP-9 in neutrophils in vivo and in vitro [39, 40]. On the contrary, some studies have implicated that the incidence of fimA Ⅰ and fimA Ib genotypes of P. gingivalis are also high [3, 16, 22–23]. A previous study indicated that the fimA Ⅰ genotype was significantly associated with healthy periodontal people [15]. Further investigation found that fimA Ib had a high sequence homology with fimA Ⅰ, but their distribution profiles were different [41]. Statistical analysis in the same study showed a significant relationship between the fimA Ib genotype and periodontitis [41]. The variations of fimA play a major definitive factor in the virulence and pathogenicity of P. gingivalis, in relation to the specific proteases, capsulation, and other factors that influence pathogenicity [42–44]. Presently, there is no other meta-analysis similar to this research in terms of ability to compare results. To the best of our knowledge, we identified the fimA genotypes of P. gingivalis, which is one of the main etiological factors of chronic periodontal disease. Exploration of the part these genotypes play in this disease can lead to the development of new treatment and prevention methods in the future. In recent years, the research on reducing the pathogenicity of P. gingivalis and preventing periodontal disease through the inhibition of fimA protein function has attracted much attention. Researchers have cloned an IgG monoclonal antibody from purified fimA protein and produced the monoclonal antibody using rice suspension [45]. These results suggest that the specific antibodies produced can be used for passive immunization to prevent P. gingivalis induced periodontal disease, but further research is needed. Recent studies have shown that photo-activated disinfection mediated by photosensitizer toluidine blue has a significant inhibitory effect on the formation of P. gingivalis biofilm. Because of this, the fimA gene is a suitable target for interactions with photo-activated disinfection [46, 47]. There were several limitations in this study that must be addressed. First, publication bias is an inevitable problem in a meta-analysis process, negative trials are sometimes less likely. Considering that our data were extracted from studies written in English and Chinese, which should reduce publication bias to some extent. Second, we were unable to avoid some influential factors, such as smoking, alcohol, age, and gender on account of inadequate data These factors may influence the prevalence of fimA genotypes of P. gingivalis and incidence of chronic periodontitis by affecting the ability of P. gingivalis to invade the gingival tissue and influence the malignant process. Third, the demographic features of the populations in these studies could have an impact on the results. Finally, some studies that examined the prevalence of fimA genotypes of P. gingivalis in periodontitis were not available.

In conclusion, the fimA gene is P. gingivalis' main virulence factor, it is important to identify the different fimA genotypes and their prevalence in chronic periodontitis. This study showed that the fimA Ⅱ and fimA Ⅳ genotypes were present at increased levels in patients with periodontal disease. Therefore, these two genotypes may be related to the pathogenesis and progression of periodontal disease and can be considered as the main potential risk factors of periodontal disease. These results indicate that the pathogenicity of fimA genotypes of P. gingivalis needs to be further studied.

Supporting information

S1 Checklist. PRISMA checklist.

(DOC)

Click here for additional data file.^{(63.5KB, doc)}

Acknowledgments

The authors wish to thank Professor Dongmeng Qian and Dr. Qin Zheng for their help in revising the manuscript.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors acknowledge the funding support of Qingdao Key Health Discipline Development Fund 2020-2022 to HW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0240251.r001

Decision Letter 0

Andrej M Kielbassa

28 May 2020

PONE-D-20-06291

The prevalence of fimA genotype of Porphyromonas gingivalis in patients with chronic periodontitis :a meta-analysis

PLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLoS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands.

After having intensively reviewed your draft, our external referees have indicated major drawbacks. Moreover, our reviewers strongly differed with their final recommendations, and, thus, I have invited a further external referee, to come to a more balanced decision. All in all, the indicated shortcomings are considered reasonable with regard to both PLoS ONE's quality standards and our readership's expectations. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 12 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Andrej M Kielbassa, Prof. Dr. med. dent. Dr. h. c.

Academic Editor

PLOS ONE

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General remark

- English remains a concern, and authors are strongly encouraged to thoroughly revise their draft. Please check grammar and spelling. Please seek some help from a native speaker, to revise, and to facilitate reading.

Abstract

- "Therefore, the two genotypes of Porphyromonas gingivalis appear to contribute to the pathogenesis and progress of periodontal disease, one of the main risk factors of periodontitis." How can you say this? Please provide a sound conclusion, only based on your outcome.

Intro

- "Plaque is the initiating factor of periodontal disease." Please note that "plaque" is a dental term. Use "biofilm" instead, and add a definition.

- Please revise writing, see: "aggregatibacte,Actinomycetemcomitans,Treponemadenticola, Prevotella nigrescens,and Pusobacterium nucleatum". Incorrect spelling is not acceptable with a scientific paper.

- Please elaborate your aims, and give your objectives.

- Deduce a sound and indisputable null hypothesis from your foregoing elaboration.

Meths

- Please expand this section by given more details.

Results

- Again, please expand this section, to facilitate reading.

- Please note that it is your task to guide the readers. Do not leave the latter alone with your graphs. Provide a neutral explanation.

Disc

- The same with this section. Please note that your Discussion has not been convincingly elaborated.

Concl

- "Therefore, the two genotypes of Porphyromonas gingivalis are related to the pathogenesis and progress of periodontal disease." Please see comments given above.

Refs

- Following the Authors' Guidelines is strongly recommended.

In total, although covering an interesting topic, this draft would not seem worth following without a stringent and thorough revision.

Reviewer #2: Review Comments to the Author

"Nice paper"

Reviewer #3: Please check word spacing, organism names and syntax errors in the manuscript. No other major corrections is noted. All the relevant data has been mentioned and the manuscript written in intelligible fashion.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Oct 28;15(10):e0240251. doi: 10.1371/journal.pone.0240251.r002

Author response to Decision Letter 0

12 Jun 2020

Please let me know if you have any information about the manuscript. thank you.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(18.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0240251.r003

Decision Letter 1

Andrej M Kielbassa

29 Jun 2020

PONE-D-20-06291R1

The prevalence of fimA genotype of Porphyromonas gingivalis in patients with chronic periodontitis :a meta-analysis

PLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but again does not meet PLOS ONE’s publication criteria as it currently stands.

Having intensively reviewed your draft, our external referees still have indicated major shortcomings. Moreover, our reviewers strongly differed with their final recommendations, and, thus, I have invited a further external referee, to come to a more balanced decision. All in all, the indicated shortcomings are considered reasonable with regard to both PLOS ONE's quality standards and our readership's expectations.

Therefore, we invite you to submit a revised version of the manuscript that addresses each and every point raised during the review process. Please note that a further non-convincing revision (not considered acceptable with regard to language, content, and/or Authors' Guidelines) will lead to outright reject.

Please submit your revised manuscript by Aug 13 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Andrej M Kielbassa

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: General remarks

- This revised draft has been improved to some extent, no doubt. However, there are still minor and major drawbacks, and this re-submitted version is not considered ready to proceed.

- Again, the authors are strongly encouraged to seek help from a native speaker experienced with scientific writing.

Title

- "The prevalence of fimA genotype of Porphyromonas gingivalis in patients with chronic periodontitis :a meta-analysis". Please revise for correct punctuation. Remember that it is not considered the reviewers' task to co-author and/or re-edit your submitted draft.

- Go for italics with your species names.

- The term "prevalence of fimA genotype of Porphyromonas gingivitis" would seem misleading. Remember that you did not study other genotypes than "fimA". (Indeed, you have focussed on the fimA Ⅱ and fimA Ⅳ genotypes). Please revise thoroughly.

Abstract

- Not acceptable in the present form. This reviewer indeed is somewhat astonished about the low quality of this revised draft. Please see, for example:

* ( P.gingivalis) must read (P. gingivialis) (must be italicized). Remember to define abbreviations upon first appearance in the text, then use the abbreviated forms.

* Please stick to PLOS ONE's Guidelines for Authors: "The Abstract — which must be no more than 300 words long and contain no references — should serve both as a general introduction to the topic and as a brief, non-technical summary of the main results and their implications." Ignoring these recommendations must lead to outright reject, in particular with a re-submitted draft. Please note that this part must be a stand-alone section, enabling future readers to switch to your full text. Provide as much information as possible here, but do not repeat again and again multiple aspects. For example, "P. gingivitis" has been mentioned 11 (!) times.

- Double check for grammar and style.

- What is "Martials"?

- Stick to the established sections and their respective names given with the Authors' Guidelines.

- Delete blank spaces and hard paragraphs marks considered dispensable.

- In contrast, "periodontaldisease" must read "periodontal disease". Same with "fimA Ⅳand", "fica ⅤPorphyromonas", "respectively.Conclusion", fimAⅡand". Please revise thoroughly, and remember that authors are responsible for procuring copy editing or language editing services for their manuscripts. Obtaining this service is the responsibility of the author, and should be done before initial submission (but NOT after the re-submission).

Intro

- Same aspects as given above would be evident with the full text sections. This revised and re-submitted draft would not seem ready to proceed. Major revisions would seem mandatory.

- Please remember that each and every statement needs a reference. See, for example, "Periodontitis is a chronic inflammation (...) characterized by the progressive loss of attachment and alveolar bone absorption." Reference missing.

- Again, authors are strongly encouraged to visit a recent paper published by PLOS ONE. There you will see that referencing does follow a format like this: "(...) interdental hygiene [6, 9], even with high-risk (...) [10, 11]. In fact, this approach (...) [12]." This also is clearly stated with the Guidelines for Authors, so please revise thoroughly throughout your text.

- See last recommendation: "Again, please elaborate your aims, and give your objectives." Obviously, the authors did not want to follow here.

- See last recommendation: "Deduce a sound and indisputable null hypothesis from your foregoing elaboration." Obviously, the authors did not want to follow here.

Meths

- From this revised draft it would seem clear that only two of the included studies were rated "high quality". This is considered poor.

- What about possible bias of the included studies?

- While some scientists occasionally have considered the systematic review (SR) as the top level of evidence for clinical science research in the past, please note that SR per se cannot be endorsed solely due to their format ("because they are a systematic review"), but must be critically evaluated for the problem reviewed in the respective article. Consequently, different qualities of RCTs, explicit statements of protocols, careful estimates of risk bias, large numbers of studies, and sophisticated statistical meta-analyses are not considered true substitutes for a thorough understanding of the literature, for critical analysis, and for scientifically sound and clinically relevant conclusions.

Results

- Providing several forest plots without guiding the reader would not seem acceptable.

Disc

- This section still has not been convincingly elaborated.

- Please do not simply repeat your results here. Instead, provide an intellectual discourse.

- Remember that section heading is NOT "Repetition". Provide a critical analysis of your findings. Provide interpretations. Discuss limitations.

- Please see above, and stick to the weaknesses of the included papers, give explanations and arguments.

- What about your null hypothesis?

Concl

- "This study showed that the fimA Ⅱand fimA Ⅳgenotypes of Porphyromonas gingivalis are

highly present in patients with periodontal disease." First, this already has been known before. Second (and again), do not simply repeat your results here. Instead, provide a reasonable extension of your outcome, and try to find some generalizing statements.

Refs

- Again, the authors obviously have failed to revise this section for a constant formatting, and this would seem surprising with a revised draft. Thorough revision still is mandatory, but, again, this would not seem the reviewer's task.

In total, this revised and re-submited paper draft is considered neither convincing nor satisfying. Please note that all authors are expected to have reviewed, discussed, and agreed to their individual contributions ahead of (re-)submission. Authors' „approval“ means that the (co-)author confirms the (co-)author has made a significant scientific contribution to the study and that he is thoroughly familiar with the primary data outlined in the manuscript, and that he has read and revised the complete manuscript, takes responsibility for the content and completeness of the final submitted manuscript.

Reviewer #2: Why didn't you adjust for factors such as smoking, alcohol , age and gender? Also tsome spaces between the words were ignored. Please make the correction.

Reviewer #3: Introduction:

1. Spacing is needed after the comma : Porphyromonas

gingivalis,Aggregatibacte actinomycetemcomitans,

2. Aggregatibacte actinomycetemcomitans: Spelling mistake: Correct would be Aggregatibacter actinomycetemcomitans

3. Term P.gingivalis has been used only in few places in the introduction but the term Porphyromonas

gingivalis has been used is the most part of the manuscript. Keeping it uniform would better help the readers.

Letter A in Acknowledgements and Letter R in References needs to bold to make it uniform.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

PLoS One. 2020 Oct 28;15(10):e0240251. doi: 10.1371/journal.pone.0240251.r004

Author response to Decision Letter 1

5 Aug 2020

Dear Editors and Reviewers:

Thank you for your letter and for the reviewers'comments concerning our manuscript entitled“The prevalence of fimA genotypes of Porphyromonas gingivalis in patients with chronic periodontitis: a meta-analysis” (ID: PONE-D-20-06291R1). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. We have polished the language of the full text, see supporting information for the certificate. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

Responds to the reviewer’s comments:

Response to comment:1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Response: The author has dealt with the comments raised in the last round of review. Of course, there may be insufficient answers. The author will make supplementary amendments according to the opinions of this round.

Response to comment:2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Response: This study describe a technically sound piece of scientific research with data that supports the conclusions. A total of 167 studies were identified through the search process. The articles processed were based on abstracts, titles and full texts, with a total of 17 papers were included. The total sample size was 1389 individuals with samples collected from different countries. The conclusions of this study are drawn from the data extracted from the literature.

Response to comment:3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Response: The statistical methods used in this study have been explained in detail in the statistical analysis part of the article. We used a statistical software package (Stata, version 11.0/mp, statacorp) to calculate the data analysis for each combined incidence estimate.

Response to comment:5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Response: The article has been revised in standard English.

Reviewer #1:

Response to comment:- This revised draft has been improved to some extent, no doubt. However, there are still minor and major drawbacks, and this re-submitted version is not considered ready to proceed.

- Again, the authors are strongly encouraged to seek help from a native speaker experienced with scientific writing.

Response: We are very sorry for our negligence of the minor and major drawbacks in this draft ,according that we revised the draft thoroughly. In addition, we seek the help from the native speaker to revise our draft.

Response to comment:- Title - "The prevalence of fimA genotype of Porphyromonas gingivalis in patients with chronic periodontitis :a meta-analysis". Please revise for correct punctuation. Remember that it is not considered the reviewers' task to co-author and/or re-edit your submitted draft.

- Go for italics with your species names.

Response: We are very sorry for our incorrect writing of the title. We have revised the title's punctuation and italics with species names.

Response to comment:- The term "prevalence of fimA genotype of Porphyromonas gingivitis" would seem misleading. Remember that you did not study other genotypes than "fimA". (Indeed, you have focussed on the fimA Ⅱ and fimA Ⅳ genotypes). Please revise thoroughly.

Response: Thank you for your kind reminder. We have performed the genotyping analyses for fimA I, II, III, IV and V. The results were shown in Fig. 2 through Fig. 7.

Response to comment: Abstract -- Not acceptable in the present form. This reviewer indeed is somewhat astonished about the low quality of this revised draft. Please see, for example:

* ( P.gingivalis) must read (P. gingivialis) (must be italicized). Remember to define abbreviations upon first appearance in the text, then use the abbreviated forms.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:* Please stick to PLOS ONE's Guidelines for Authors: "The Abstract — which must be no more than 300 words long and contain no references — should serve both as a general introduction to the topic and as a brief, non-technical summary of the main results and their implications." Ignoring these recommendations must lead to outright reject, in particular with a re-submitted draft. Please note that this part must be a stand-alone section, enabling future readers to switch to your full text. Provide as much information as possible here, but do not repeat again and again multiple aspects. For example, "P. gingivitis" has been mentioned 11 (!) times.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- Double check for grammar and style.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- What is "Martials"?

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- Stick to the established sections and their respective names given with the Authors' Guidelines.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- Delete blank spaces and hard paragraphs marks considered dispensable.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- In contrast, "periodontaldisease" must read "periodontal disease". Same with "fimA Ⅳand", "fica ⅤPorphyromonas", "respectively.Conclusion", fimAⅡand". Please revise thoroughly, and remember that authors are responsible for procuring copy editing or language editing services for their manuscripts. Obtaining this service is the responsibility of the author, and should be done before initial submission (but NOT after the re-submission).

Response: We are very sorry for our incorrect writing . We have made correction according to the Reviewer’s comments.

Response to comment: Intro - Same aspects as given above would be evident with the full text sections. This revised and re-submitted draft would not seem ready to proceed. Major revisions would seem mandatory.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- Again, authors are strongly encouraged to visit a recent paper published by PLOS ONE. There you will see that referencing does follow a format like this: "(...) interdental hygiene [6, 9], even with high-risk (...) [10, 11]. In fact, this approach (...) [12]." This also is clearly stated with the Guidelines for Authors, so please revise thoroughly throughout your text.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- See last recommendation: "Again, please elaborate your aims, and give your objectives." Obviously, the authors did not want to follow here.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:- See last recommendation: "Deduce a sound and indisputable null hypothesis from your foregoing elaboration." Obviously, the authors did not want to follow here.

Response: We have made correction according to the Reviewer’s comments.

Response to comment: Meths - From this revised draft it would seem clear that only two of the included studies were rated "high quality". This is considered poor.

Response: Thank you for your comments. Yes. There are less high-quality original articles used for the meta-analysis. So we performed the further analysis to compare the high-quality and low-quality articles.

Response to comment:- What about possible bias of the included studies?

Response: There may be publication bias, that is, there may be negative results not published.

Response to comment:- While some scientists occasionally have considered the systematic review (SR) as the top level of evidence for clinical science research in the past, please note that SR per se cannot be endorsed solely due to their format ("because they are a systematic review"), but must be critically evaluated for the problem reviewed in the respective article. Consequently, different qualities of RCTs, explicit statements of protocols, careful estimates of risk bias, large numbers of studies, and sophisticated statistical meta-analyses are not considered true substitutes for a thorough understanding of the literature, for critical analysis, and for scientifically sound and clinically relevant conclusions.

Response: Yes. I very agree with you. The meta-analysis is only the analysis of more data by collecting the related studies when there are less clear results. The aim of meta-analysis is for higher power of statistical analysis. But the results were affected by the quality of the original article. In fact, it should be best for RCT with large participants, just as the RECOVERY Study done by Oxford University for the study of COVID-19.

Response to comment: Results- Providing several forest plots without guiding the reader would not seem acceptable.

Response: We have made correction according to the Reviewer’s comments.

Response to comment: Disc- This section still has not been convincingly elaborated.

- Please do not simply repeat your results here. Instead, provide an intellectual discourse.

- Remember that section heading is NOT "Repetition". Provide a critical analysis of your findings. Provide interpretations. Discuss limitations.

- Please see above, and stick to the weaknesses of the included papers, give explanations and arguments.

- What about your null hypothesis?

Response: Considering the Reviewer’s suggestion, We have re-written this part according to the Reviewer’s suggestion.

Response to comment: Refs- Again, the authors obviously have failed to revise this section for a constant formatting, and this would seem surprising with a revised draft. Thorough revision still is mandatory, but, again, this would not seem the reviewer's task.

Response: We have made correction according to the Reviewer’s comments.

Reviewer #2:

Response to comment: Why didn't you adjust for factors such as smoking, alcohol , age and gender? Also some spaces between the words were ignored. Please make the correction.

Response: Thank you for your comments. Yes. We should adjust the smoking, alcohol , age and gender, but the data were inadequate. We have corrected the spaces between the words.

Reviewer #3:

Response to comment: Introduction:

1. Spacing is needed after the comma : Porphyromonas gingivalis,Aggregatibacte actinomycetemcomitans,

Response: We have made correction according to the Reviewer’s comments.

Response to comment: 2. Aggregatibacte actinomycetemcomitans: Spelling mistake: Correct would be Aggregatibacter actinomycetemcomitans

Response: We have made correction according to the Reviewer’s comments.

Response to comment:3. Term P.gingivalis has been used only in few places in the introduction but the term Porphyromonas gingivalis has been used is the most part of the manuscript. Keeping it uniform would better help the readers.

Response: We have made correction according to the Reviewer’s comments.

Response to comment: Letter A in Acknowledgements and Letter R in References needs to bold to make it uniform.

Response: We have made correction according to the Reviewer’s comments.

Response to comment:7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Response: We have made correction according to the Reviewer’s comments.

Thank you！

Attachment

Submitted filename: Response to Reviewers-8.3.docx

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PLoS One. doi: 10.1371/journal.pone.0240251.r005

Decision Letter 2

Andrej M Kielbassa

17 Aug 2020

PONE-D-20-06291R2

The prevalence of fimA genotypes of Porphyromonas gingivalis in patients with chronic periodontitis: a meta-analysis

PLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Having intensively reviewed your draft, your revised and re-submitted draft still would not seem satisfying. I have double checked your submitted draft, and, in particular, you should follow the R #1 comments, to finalize your paper convincingly, and to meet both PLOS ONE's quality standards and our readership's expectations. Please note that a further non-convincing revision (not considered acceptable with regard to language, reviewers' constructive criticism, content, generalizable outcome, and/or Authors' Guidelines) will lead to outright reject.

Please submit your revised manuscript by Oct 01 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Andrej M Kielbassa

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Abstract

- Please change sequence: "A total of 17 studies were included in this report." should follow after "The reference lists of relevant published articles were searched manually."

Intro

- PMID number never will appear with your text, and this reviewer clearly is wondering about the authors' intention. Again, it should be emphasized that having a closer look into recently published PLOS ONE papers would be advantageous. Please delete "( PMID:23991022 )" and all other PMIDs. These should appear with your Ref section.

- Same with your Ref numbers. This must be separated by using the spacebar. See, for example: "(...) can lead to the loss of affected teeth [1]." Please note that this should not be necessary with a third (re-)submission, and, to be honest, the authors should re-think their attitude towards their willingness to adequately revise their draft. Remember that with your re-submission, you affirm that ALL FOUR CO-AUTHORS have read and approved this revised draft.

- What do you refer to when stating "In this study, (...)"? Do you mean the present study, or do you refer to [14]? Again, please revise thoroughly, to facilitate reading.

- Again, please elaborate both aims and objectives more clearly. Remember that aims are statements of intent. They are usually written in broad terms. They set out what you hope to achieve at the end of the project. Objectives, on the other hand, should be specific statements that define measurable outcomes, e.g. what steps will be taken to achieve the desired outcome (see https://learn.solent.ac.uk/mod/book/view.php?id=116233&chapterid=15294).

- Finally, a clear and indisputable null hypothesis is missing. Please remember that H0 must be deducible from the foregoing thoughts.

Please note that this section still would not seem convincing.

Meths

- "All articles with the keywords were (...)." How many articles are you talking about?

- "Studies were excluded (...)." How many articles are you talking about? Please add numbers.

- "(...) assessment tool.[28] We assessed (...)." Why do you superscript the Ref number here?

- "The total score for each study was between 0 and 8." This would be self-explaining. What about providing a complete analysis, thus revealing the exact quality of the various studies?

Results

- "(...) and therefore the results of most related studies were included in the analysis." Most, but not all, right? Again, please add complete and exact information, and do not stick to vague statements.

Disc

- Please stick to H0 when staring this section.

- "(...) in mouse models[31](PMID: 17081195)[36] and (...)." Please see comments given above. Make use of your spacebar to separate Refs, delete PMID, and do not superscript Refs.

- "Presently, there is no other meta-analysis similar to this research in terms of ability to compare results." One sentence does not constitute one paragraph.

- "First, publication bias is an inevitable problem in a meta-analysis process." This should be discussed more thoroughly. Same with the other aspects.

Concl

- "In conclusion, P. gingivalis is one of main bacteria in chronic periodontitis." This aspect is not considered a conclusion deducible FROM YOUR STUDY.

- Same with "These results indicate that the pathogenicity of other fimA genotypes of P. gingivalis needs to be further studied." This might be widely spread, but, to be honest, would be a simple stereotype only.

Refs

- Please note that your Refs still have not been uniformly formatted. Again, please check Guidelines, and consult some recent papers published in PLOS ONE.

In total, this re-revised and re-re-submitted draft is, unfortunately, not ready to proceed.

Please note that SR per se cannot be endorsed solely due to their format ("because they are a systematic review"), but must be critically evaluated for the problem reviewed in the respective article. Consequently, different qualities of RCTs (as given with your study, please see below), explicit statements of protocols, careful estimates of risk bias, large numbers of studies, and sophisticated statistical meta-analyses are not considered true substitutes for a thorough understanding of the literature, for critical analysis, and for scientifically sound and clinically relevant conclusions considered generalizable.The authors might additionally wish to go to https://pubmed.ncbi.nlm.nih.gov/31088221/, and discuss these problems.

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. 2020 Oct 28;15(10):e0240251. doi: 10.1371/journal.pone.0240251.r006

Author response to Decision Letter 2

11 Sep 2020

Dear Editors and reviewers:

Thank you for your letter and for the reviewers'comments concerning our manuscript entitled "The prevalence of fimA genotypes of Porphyromonas gingivalis in patients with chronic periodontitis: a meta-analysis" (ID: PONE-D-20-06291R1). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

Responds to the reviewer’s comments:

Reviewer #1: (No Response)

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Response: This study describe a technically sound piece of scientific research with data that supports the conclusions. We evaluated the quality of the 17 included literatures and all met the requirements. The conclusions of this study are drawn from the data extracted from the literature.

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Response: Thank you for your comments. We have revised our article in standard English.

- Please change sequence: "A total of 17 studies were included in this report." should follow after "The reference lists of relevant published articles were searched manually."

Response: Thank you for your comments. We have made correction according to the Reviewer’s comments.

Response: Thank you for your comments.We have made correction according to the Reviewer’s comments.