PONE-D-24-53513Association between age at first birth and risk of rheumatoid arthritis in women: evidence from NHANES 2011–2020PLOS ONE

Dear Dr. Liu,

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.

Please submit your revised manuscript by Jan 20 2025 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Ahmed Qasim Mohammed Alhatemi

Academic Editor

PLOS ONE

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2. Thank you for stating the following financial disclosure: Funding

1.National Natural Science Foundation of China General Program (82474538);2.Tianjin Municipal Health Commission Jinmen Medical Talents Program (TJSJMYXYC-D2-028);3.Tianjin Science and Technology Plan Project (23KPXMRC00170).

Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" 

If this statement is not correct you must amend it as needed. 

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

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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: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

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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

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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: Yes

Reviewer #2: Yes

Reviewer #3: No

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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: The results of the study do not go in line with what we already know about the subject. Discussion is poorly written and needs major revisions. I am also highlighting some other queries

Major comment 1

Why wasn’t a case-control approach taken for statistical analysis in this cross-sectional study? Taking a particular age group as reference and comparing others with it seems like an unorthodox approach.

Major comment 2

The whole discussion needs to be revised. Overall, it feels that most of the content written in discussion is meant to fill pages and has little relevance with the results of the study at hand.

There is a lot of repetition related to background of RA in discussion in 2nd paragraph. Please remove that.

The pathogenesis related to interaction of RA with hormonal and fertility factors has been described well but it is very extensive. It covers more than half of discussion and should be shortened. Discussion is meant to discuss the results and not the etiopathogenesis. Ideally the pathogenesis or concept behind the study premise is discussed in introduction.

The author has used the line in discussion “Firstly, this study is among those several articles examining the relationship of AFB with RA”. There are several studies in the literature which show that earlier AFB is associated with a lower risk for RA, contrary to the results of this study. Please describe these studies and compare your results with them.

Minor comment 1

In discussion, the line “Among women with an AFB of 18-32 years, the RA prevalence showed a gradual downward trend, while women with an AFB > 35 years exhibited an upward trend in terms of the RA prevalence” is contradictory to the authors results. Please correct it.

Minor Comment 2

In the abstract and conclusion, instead of mentioning all the different age categories separately (AFB < 18, 18–20, 21–23, 24–26,), it would be better to write as 18-26 years of age group.

Minor comment 3

In the second paragraph of introduction “Women's health is influenced by various reproductive factors, which may be important for OA occurrence”, correct OA to RA

Minor comment 4

In the abstract, in methods section, the author can’t write that data has been taken from women >20 years of age since the study population contains women less than 18 years of age also. Please correct it.

Reviewer #2: In the article, the age at first birth for women aged 27-35 did not show a significant difference in terms of rheumatoid arthritis (RA) risk compared to other age groups. In other words, the first birth in this age range did not significantly increase the risk of RA. However, these results are based on analyses conducted on the NHANES database, and caution should be exercised when making generalizations. Because RA risk can vary depending on many factors, and such epidemiological studies only show associations, not cause-and-effect relationships.

The study was conducted using the NHANES database, which provides a large and diverse sample. Analyses were conducted using logistic regression models, which is an appropriate method because it allows for the evaluation of relationships and probabilities among various variables. However, since the study had a cross-sectional design, it may be difficult to establish cause-and-effect relationships. The study also made detailed adjustments by controlling for age, race, education level, and many other potential variables. The NHANES database includes individuals from various ethnic and socioeconomic groups across the United States, which makes the findings highly generalizable to the U.S. population.

However, the effects may not be the same across populations in different countries. The scope of the study focused on a specific factor, namely childbearing history, which may affect the risk of RA in women. There are limited studies in the literature on childbearing history and RA risk. The results of this study may be consistent with the findings of previous studies, but more studies are needed in this area. In particular, there is evidence that giving birth at an earlier age may increase the risk of RA, and giving birth at a later age may also pose a potential risk. The article stated that it has no financial conflict of interest.

Critiques:

Data Source and Methodology: The use of the NHANES database provides a diverse and extensive sample; however, the cross-sectional study design limits the ability to establish cause-and-effect relationships. Self-reported data may introduce recall bias affecting the study's reliability.

Analysis Methods: While logistic regression is suitable for examining relationships among variables, details on model adequacy and validation should be further addressed.

Generalizability: Findings are highly generalizable within the U.S. population but may not directly apply to other populations due to cultural and genetic differences.

Consistency with Literature: The findings align with previous studies; however, this area of research has limited literature, highlighting the need for further studies to confirm these observations.

Suggestions:

Multi-Center and Longitudinal Studies: To better understand the etiology of RA, conducting multi-center and longitudinal studies across different populations would be beneficial.

Detailed Hormonal Profile Studies: Exploring the effects of other hormones such as FSH and prolactin on RA could provide deeper insights into the hormonal influences on autoimmune diseases.

Socioeconomic Factors Analysis: Investigating the impact of socioeconomic factors on RA risk could elucidate additional determinants that affect health outcomes.

Public Health and Education Programs: Based on the findings, targeting women in high-risk age groups for RA screening and prevention should be considered to mitigate disease impact.

Conclusion: The manuscript provides valuable insights into the epidemiological factors associated with RA in women. Enhancements in data analysis robustness and a broader consideration of socioeconomic and hormonal variables could further strengthen the conclusions drawn.

Reviewer #3: The manuscript provides valuable insights into the relationship between reproductive history and rheumatoid arthritis. However, several aspects of the methodology, organization, and presentation could be improved to enhance the study’s clarity, rigor, and contribution to the field. Below are specific comments and suggestions for improvement:

1. Addressing Multicollinearity

Motivational Context:

In multivariable regression models, multicollinearity between independent variables can significantly affect the stability and interpretability of the estimated coefficients. Given the comprehensive set of covariates included in the fully adjusted model (e.g., age, BMI, hypertension, diabetes, and others), addressing potential multicollinearity is crucial to ensure reliable results and valid conclusions.

Question to the Authors:

Could the authors clarify how multicollinearity was assessed and managed during the development of the regression models? Specifically, were any diagnostic measures (e.g., Variance Inflation Factor, correlation matrices) employed, and were any corrective actions, such as variable selection or regularization techniques, undertaken to mitigate its effects?

2. Use of STATA for Statistical Analysis

The use of STATA version 18.0 for statistical analyses is a valid and robust choice, particularly given the complexities of the NHANES design and the application of Mobile Examination Center (MEC) sampling weights. However, the current description in the manuscript ("due to the complicated NHANES design") is somewhat generalized and could benefit from additional specificity.

For instance, it would be helpful to explicitly state which aspects of the NHANES design (e.g., stratification, multistage sampling, clustering) and the need to apply sampling weights influenced the decision to use STATA. This would not only clarify the rationale behind the methodological choice but also enhance the scientific rigor and transparency of the article.

3. Formatting and Organization of the "Methods Statements" Section

a) Section Title:

The title of the section "Methods Statements" is written in lowercase and bold font, which deviates from the formatting style used in the other subsections of the "Methods" section, where titles are capitalized and not bolded. To ensure consistency and professionalism, we recommend aligning this title with the formatting of other subsections.

b) Additionally, the term "Methods Statements" might not be the most appropriate for this context. Considering the content and structure of the article, the "Methods" section could be more aptly titled "Materials and Methods," as it includes a description of "Study Subjects," which represents the material of the research.

c) Duplication of Content:

The statements included in the "Methods Statements" subsection are repeated in the subsequent "Study Subjects" subsection. This redundancy does not add value and could be streamlined by removing the duplication or integrating the information into the appropriate subsection.

d) Highlighted Text:

A fragment of the text in the "Methods Statements" subsection is highlighted in red. While such formatting might have been used during the drafting or editing process, it appears inappropriate in a finalized manuscript. We recommend removing the red highlight to ensure consistency with standard scientific formatting and improve the professional presentation of the article.

4. Contextualization with Prior Research

While the current study provides valuable insights into the relationship between reproductive history and rheumatoid arthritis, it appears that the article does not reference prior research addressing similar topics using the same dataset.

For example, the study "Reproductive history and postmenopausal rheumatoid arthritis among women 60 years or older: Third National Health and Nutrition Examination Survey" (DOI: 10.1097/gme.0b013e3182a14372), published in 2013, explores the association between reproductive factors and RA, including age at first pregnancy, using data from NHANES, the same dataset employed in the present study.

Inclusion of such prior research in the discussion section would provide a more comprehensive contextualization of the current findings. Specifically, comparing the methodologies, population characteristics, and key results of the present study with those of earlier works could clarify how the current research builds upon, diverges from, or complements existing knowledge derived from the same dataset.

5. Conclusion Section

In the conclusion, the statement reads:

“Women with an AFB < 18, 18–20, 21–23, 24–26, or > 35 years have a higher risk of developing RA later in life. Policymakers must focus more on women in these AFB age ranges in screening RA and making preventive measures.”

This conclusion would be clearer and more impactful if it summarized the risk for broader age categories instead of listing specific intervals. For example, grouping women as "younger than 26 years" rather than specifying "<18, 18–20, 21–23, 24–26" would make the statement more concise and generalizable.

6. Inconsistencies in References

The formatting of the references in the manuscript is inconsistent:

a) Author names are written in a mix of uppercase and lowercase letters.

Spacing is inconsistent after punctuation marks.

b) Page ranges are inconsistently formatted, alternating between short dashes (e.g., 73–7) and long dashes with spaces (e.g., 3218 － 3228).

It is recommended to thoroughly review the reference list and ensuring uniform formatting that adheres to the chosen citation style. Consistency in formatting is essential for maintaining the professionalism and credibility of the manuscript.

By addressing these points, the authors can enhance the clarity, rigor, and overall impact of their study.

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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.

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Reviewer #1: No

Reviewer #2: Yes: Selçuk Yüksel

Reviewer #3: Yes: Artyom Borbat

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PONE-D-24-53513R1Association between age at first birth and risk of rheumatoid arthritis in women: evidence from NHANES 2011–2020PLOS ONE

Dear Dr. Liu,

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. 

Please submit your revised manuscript by Feb 05 2025 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.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ahmed Qasim Mohammed Alhatemi

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

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2. 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: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

********** 

4. 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

********** 

5. 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

********** 

6. 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: Thank you for making the suggested corrections. All the best for your manuscript

Minor comment 1

Please correct the abstract on the title page of the manuscript also.

Reviewer #2: 24 / 5.000

I found the revision sufficient.The authors have positively evaluated my suggested contributions in their articles. The changes made are satisfactory to me.

Reviewer #3: The revised manuscript demonstrates significant improvements in clarity, particularly in the description of statistical methods. The question raised in the initial review regarding the selection of factors for multivariable analysis is now resolved, as the authors have provided a clearer explanation of their analytical approach. This enhances the transparency and robustness of the study.

However, some aspects of the manuscript still warrant further attention:

1. Inconsistency in Claims about Previous Research

The introduction claims that no studies have specifically examined the relationship between Age at First Birth (AFB) and rheumatoid arthritis (RA) risk. However, the discussion section references several studies that indirectly or directly address this topic. This discrepancy undermines the novelty of the study and should be clarified.

2. Stylistic Deviations and Non-Academic Tone

The manuscript contains several instances of stylistic deviations from an academic tone, such as:

a) The phrase, "Policymakers must focus more on women in these AFB age ranges in screening RA and making preventive measures," employs emotionally charged language ("must") and shifts the tone from scientific to political. A more neutral phrasing is recommended.

b) A subjective critique of Zhu et al.'s study, emphasizing insufficient sample size without detailed justification.

c) Statements regarding the increased risk due to late childbirth ("longer period to accumulate exposures to environmental and lifestyle factors") presented as factual without sufficient evidence.

d) These examples are not exhaustive; the authors are encouraged to thoroughly review the manuscript for similar stylistic deviations to enhance its academic rigor.

3. Lack of Control for Multiple Comparisons and Type I Errors

The manuscript reports multiple statistically significant findings (P < 0.05) across various subgroups and categories but does not address whether adjustments for multiple comparisons were applied. This raises concerns about inflated Type I error rates (false positives). The absence of correction methods like Bonferroni or Holm adjustments undermines the validity of some conclusions, particularly given the extensive number of statistical tests performed. The authors should clarify whether such adjustments were applied or acknowledge this as a limitation in the discussion.

In conclusion, the manuscript provides valuable insights into the relationship between AFB and RA risk, and the improvements made after the initial review are commendable. Addressing the points mentioned above will further enhance the academic rigor and overall quality of the study.

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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: Yes: Selçuk Yüksel

Reviewer #3: Yes: Artyom Borbat

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[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.

Association between age at first birth and risk of rheumatoid arthritis in women: evidence from NHANES 2011–2020

PONE-D-24-53513R2

Dear Dr. Liu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ahmed Qasim Mohammed Alhatemi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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4. 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

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5. 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. 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: All my concerns have been addressed by the authors. I have no more queries

All the best for your article.

Reviewer #2: From my perspective, the necessary changes that I suggested have been made. I have no further reccomendation.

Reviewer #3: After a thorough second review of the manuscript, I am pleased to confirm that the article meets the necessary standards for publication in a scientific journal. The authors have addressed the previous concerns effectively, improving the clarity, structure, and scientific rigor of the paper.

The study presents a well-conceived methodology, sound statistical analysis, and a clear discussion of the findings, which contribute significantly to the field. Furthermore, the adjustments made to ensure consistency in tone and academic style enhance its readability and impact.

I recommend the manuscript for publication, as it represents a valuable contribution to the scientific community.

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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: Yes: Artyom Borbat

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