Predictive Clinical and Biological Criteria for Gene Panel Positivity in Suspected Inherited Autoinflammatory Diseases: Insights from a Case–Control Study

Response to Reviewer 1 Comments

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

Point-by-point response to Comments and Suggestions for Authors

Comments 1: The title is not correctly written and contains the punctuation mark "period" or “.” at the end, which is NOT required or allowed in a title! Please, correct it!

Response 1: This mistake was corrected.

Comments 2: The Abstract is too short and does not provide enough information about the study design, results, and conclusions: please, revise and improve the text.

Response 2: Agree. We have accordingly improved the Abstract.

Comments 3: There are abbreviations (CRP, NGS) in the Abstract that are not explained.

Response 3: You are right, The abbreviations for CRP and NGS were explained in the Abstract.

Comments 4: Some keywords are already in the title and should not have been included as keywords once again. Please, adopt the MeSH system for choosing the keywords and revise them accordingly.

Response 4: All the keywords were reworked adopting the MeSH system.

Comments 5: At line 36, please correct as [2,3] instead of [2-3].

Response 5: Done

Comments 6: The academic style of the Introduction should be revised, and more references added to support the study.

Response 6: We improved the Introduction part and also with 2 new references.

Comments 7: All tables should be better explained and discussed.

Response 7: Clarification has been done notably about subgroup analyses. You could read theses modifications in track changes. Table 5 was added to represent exploratory analyses data.

Comments 8: There are drafting errors in the Tables, for example in Table 4, some characteristics are capitalized, while others are NOT

Response 8: These drafting errors have been corrected. All features are now uncapitalized in Table 4.

Comments 9: The final discussions should be improved; the conclusions also need to be reworded.

Response 9: The conclusion was rephrased as requested. We switched position of paragraph in the Discussion to improve the readability.

Comments 10: Please, at line 219: Similuk MN et al. [9], corrected as Similuk et al. [9],…

Response 10: Done

Comments 11: This article necessarily requires a graphical abstract for the reader to better understand the scientific content.

Response 11: We added a graphical abstract on the first page.

Comments 12: A Table of Abbreviations should be included at the end.

Response 12: At the conclusion of the article, preceding the references section, there is now an abbreviations table.

Comments 13: References must be checked and rewritten in the style required by the Genes journal and MDPI platform.

Response 13: We checked the Genes journal instruction and corrected the references.

4. Response to Comments on the Quality of English Language

Point 14: Academic editing of English, grammar, and style is required.

Response 1: The article has been reviewed by the English edition services at CHU Montpellier

Response to Reviewer 2 Comments

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

Point-by-point response to Comments and Suggestions for Authors

Comments 1: None about the genes used in the different panels are said.

Response 1: We thought it was too much (a maximum of 300 genes). This list can be found in our laboratory website https://umai-montpellier.fr/doc/Panel_MAI.pdf and in our former paper cited in [6].

Comments 2: The gene related in figure 1 that have a lot of variants were included in the different genes panels?

Response 2: The genes depicted in Figure 1, whose variants were detected in positive panels, are genes that exist in at least one panel. Genes with the most variants are typically those that were discovered earliest, which often corresponds to the oldest genes in our genetic panel. It is crucial to note that there is only a single panel, which has evolved over time and has progressed in terms of the number of genes. I added a short explanation in the Introduction: “In our laboratory, we have developed a unique NGS panel that investigates inherited autoinflammatory diseases. The panel has undergone expansion in terms of the number of genes over time (32 to 302 genes).’’

Comments 3: How author matched patients and controls in point 3.4?

Response 3: As described in Section 2.3 of the study design, the matching of cases and controls was based on the size of the panel, reflecting the analysis period. Consequently, there were an equal number of cases and controls for each panel version. To clarify, I have included this information in a new sentence: “Therefore cases and controls are matched on panel size (32, 55, 62, 114, 302 genes).’’

Comments 4: What about the missing values in point 3.5? What mean? Data not answered in the patient questioner

Response 4: You are correct. The missing data correspond to the data that the prescriber did not indicate on the questionnaire. It should be noted that there is a difference in the main and exploratory analyses. In the main analysis, missing data are defined as negative for cases and positive for controls to intentionally underestimate sensitivity and specificity, as explained at the end of section 2.2. In the exploratory analysis, we excluded any missing data from the examination, which explains why group sizes are less than 119.

Comments 5: Results related in Point 3.5 are not present as a table please include the data

Response 5: Done

Response to Comments on the Quality of English Language

Point 1: The English is fine, the paper is easy to read, only some complicated lines are present in the text. Only minor corrections are necessary.

Response 1: Typo were corrected.