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As you can see, both reviewers agree that your paper has significantly improved and suggest acceptance.
[# PeerJ Staff Note - this decision was reviewed and approved by Pedro Silva, a PeerJ Section Editor covering this Section #]
The authors addressed the comments raised by editing the manuscript accordingly.
More details have been provided concerning:
- the rationale to study EGF serum levels,
- the correlation of their findings with what is already known concerning EGF/FGF polymorphisms and the phenotypes reported in this study
The abstract has been improved
Comments have been addressed.
The authors addressed the issues raised.
The manuscript was significantly improved
Authors already revised this manuscript according to my comments. Authors also replied my questions point-by-point. I am satisfied with the revision. However, there is a very minor question for this manuscript.
Line 203: I suggest that authors shall indicate the exact variant (allele G or A) of carriers of EGF rs2237051............
No more question.
No more question.
No more question.
The two reviewers have completed their evaluation. as you can see they believe that the paper it is of interest but they have valid comments and suggestions. Therefore, your paper should be revised accordingly before acceptance.
[# PeerJ Staff Note: Please ensure that all review comments are addressed in a rebuttal letter and any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate. It is a common mistake to address reviewer questions in the rebuttal letter but not in the revised manuscript. If a reviewer raised a question then your readers will probably have the same question so you should ensure that the manuscript can stand alone without the rebuttal letter. Directions on how to prepare a rebuttal letter can be found at: https://peerj.com/benefits/academic-rebuttal-letters/ #]
The background section of the abstract needs to be improved.
The connection between the presence of studies of EGF in saliva and gingival crevicular fluid, and the need to study serum EGF levels and polymorphism in patients with GAgP is not clear.
The authors should describe in more detail their findings in the context of what is already known in the literature concerning EGF, EGF polymorphisms, and phenotypes correlated to what reported by them - e.g. BMI alterations, inflammatory diseases, matrix turnover/pathologies associated to matrix modulation. This would strengthen their results and the relevance of their manuscript.
The authors should clarify why they assess serum levels of EGF, and not EGF in saliva / gingival fluid for their study.
The gaps the study wishes to fill are not clear. Do the authors imagine EGF as a therapeutic target? as a prognostic marker for periodontitis?
The study is purely correlative, and as such the experimental design properly described.
The authors report purely correlative findings, and do not overstate the implications of their results.
Is the higher BMI in GAgP patients something reported in the literature? Is there a real correlation?
Is there a known correlation between EGF levels, or EGF polymorphisms, and BMI?
What is the effect of the EGF polymorphisms described on the function of EGF itself? The authors should discuss what is the possible way via which the polymorphisms could actually influence the parameters described in the work.
Authors used 216 patients with GAgP and 138 healthy controls to investigate the association of the EGF rs2237051 variants, serum EGF levels, and Chinese patients with GAgP. Authors concluded that there is a significant association between the genotypes of EGF rs2237051 and GAgP risks as well as serum EGF levels, and showed that the level of serum EGF was increased in patients with GAgP patients. However, authors couldn’t provide the paragraph of conclusion or describe the conclusion in the final sentence of abstract.
In the conclusion paragraph of main text, authors made a statement that Chinese patients presenting with the variants of EGF rs2237051 are associated with increased risk for GAgP due to increased levels of serum EGF. However, I didn’t agree this statement. The relationship between EGF rs2237051 polymorphisms and serum level of EGF was only found in GAgP group but not in the control group. There were no significant effect of interaction between rs2237051 polymorphisms and serum level of EGF on the development of GAgP by the results of univariate and multivariate logistic regression analysis. I mean that an increase of serum EGF level could be an independent risk factor for the development of GAgP Especially, no evidence was reported that polymorphisms in EGF rs2237051 gene was the only one mechanism causing the elevation of serum EGF level. I thought that this statement was overestimated the relationship between EGF rs2237051 variants, EGF serum level, and GAgP risks.
The goodness-of-fit test for testing the Hardy-Weinberg equilibrium was very important in the analysis of genetic susceptibility. Please provide it. If the results could not fit the Hardy-Weinberg equilibrium, please discuss their effects on the study findings.
The description in some sentences of results were not confirmed by the data in tables. Please see the following:
Line 144: Individuals with a BMI≥18.5 and <24.9 kg/m2 did not present with GAgP, whereas those with a BMI<18.5 kg/m2 (P=0.9964) did. However, participants with BMI<18.5 kg/m2 could be defined as a reference group. Therefore, the content in this sentence was not confirmed by the table 2.
Line 165: The serum EGF concentration in total subjects with the AA genotype of EGF rs2237051 was 2.86 pg/ml higher than that in the subjects with AG and GG genotypes (adjusted β=2.86; 95% 167 CI: 0.88, 4.84). Line 168: The serum EGF concentration in patients with GAgP with the AA genotype was 4.70 pg/ml higher than that in patients with the AG and GG genotypes after adjustment of age, gender and BMI (adjusted β=4.70; 95% CI: 2.09, 7.31). I thought that authors might misunderstand the meanings of beta value in the regression equation. Please ask an expert of statistics for help to revise the description.
I suggested that authors can discuss the differences between salivary EGF, gingival EGF, and serum EGF in the roles of GAgP development.
Line 228: Please change the term of “Reference” as “References”.
Line 268: I suggested that “: official journal of the American Association of Oral and Maxillofacial Surgeons” can be deleted.
Line 288: It was needed to add a space between “Communicatoins” and “317:887-892.”.
The data presentation of statistics on table 2 were not a typical style. Please ask an expert of statistics for help to revise them.
On table 1, the mean value of attachment loss in control group was 0.00. In my knowledge, it was little impossible that the general control group could get the data like this. Please verify this data. If it was true, the control group had a very good oral health and some bias could be happened. It might need another control group recruited from the general population to validate the findings in this study.
On the notes of table 3 and 4, I suggested that “Adjust I model adjust for:” and “Adjust II model adjust for: can be revised as “Model I was adjusted for“ and “Model II was adjusted for”, respectively.
Authors reported that periodontal parameters (plaque index, PD, AL, BI) were clinically evaluated by two skilled examiners. However, no evaluated results in the consistence between these two examiners were reported in this study. In addition, I suggested that authors can determine the association between EGF rs2237051 variants and periodontal parameters and the correlation between serum EGF levels and periodontal parameters. The distributions of different allele frequencies and the results of genetic recessive model should be added in table 1.
Authors reported that the controls were volunteers from the staff and student population of the hospital. It was not clear what knid of plans did authors make for the invitation of volunteers. It was possible that an information bias could be caused by the hospital staff and students which were attracted by a free oral health examination. In the section of discussion, authors also gave a statement that selection bias could be identified in this study. According to the study design of epidemiology, information bias and selection bias could not be adjusted by the statistical analysis and after the participants’ recruitment into this study. I strongly suggested that authors shall discuss the effects of these two types of bias on the findings of the present study.
In multivariate regression analysis, an increase in serum EGF levels by one and five units should be recognized as the same variable using the different expression pattern. Therefore, it was not suitable that these two data were included in the same statistical analysis.
Please give an explanation why authors would like to use model I and model II in the statistical analysis of table 3 and 4. No special discussion for the roles of BMI in the development of GAgP was found in this study.
Some statistical analysis were not completed in the present study. I suggested that the results and conclusion shall be revised according to the updated statistical analysis and discussion.
The sample size is not so big. Some statistical analysis were not completed in the present study. The information bias and selection bias could be possible identified from the present study. The mean age of healthy controls was less than 36 years in the present study. These participants might potentially have been subjects with periodontitis but have not manifested signs and symptoms yet. I suggested that authors can modify the title according to the final data analysis and add a description of “a preliminary study” before the end of title.
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