PONE-D-24-51574A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for methimazole and propylthiouracilPLOS ONE

Dear Dr. Sun,

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 Apr 25 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,

Vijayalakshmi Kakulapati, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.

3. We note that there is identifying data in the Supporting Information file < original data.zip>. Due to the inclusion of these potentially identifying data, we have removed this file from your file inventory. Prior to sharing human research participant data, authors should consult with an ethics committee to ensure data are shared in accordance with participant consent and all applicable local laws.

Data sharing should never compromise participant privacy. It is therefore not appropriate to publicly share personally identifiable data on human research participants. The following are examples of data that should not be shared:

-Name, initials, physical address

-Ages more specific than whole numbers

-Internet protocol (IP) address

-Specific dates (birth dates, death dates, examination dates, etc.)

-Contact information such as phone number or email address

-Location data

-ID numbers that seem specific (long numbers, include initials, titled “Hospital ID”) rather than random (small numbers in numerical order)

Data that are not directly identifying may also be inappropriate to share, as in combination they can become identifying. For example, data collected from a small group of participants, vulnerable populations, or private groups should not be shared if they involve indirect identifiers (such as sex, ethnicity, location, etc.) that may risk the identification of study participants.

Additional guidance on preparing raw data for publication can be found in our Data Policy (https://journals.plos.org/plosone/s/data-availability#loc-human-research-participant-data-and-other-sensitive-data) and in the following article: http://www.bmj.com/content/340/bmj.c181.long.

Please remove or anonymize all personal information, ensure that the data shared are in accordance with participant consent, and re-upload a fully anonymized data set. Please note that spreadsheet columns with personal information must be removed and not hidden as all hidden columns will appear in the published file.

4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

[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: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

**********

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

**********

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: Li et al entitle “A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for methimazole and propylthiouracil” clearly reported that MMI/PTU could be adverse drug for thyrotoxicosis.

Why are you using the FAERS database to study these drug, it should be that someone else has done this with this similar database similar methodology, so you can write cite in the INTRODUCTION section about some specific other similar studies, such as recommending a few (It is equivalent to saying that someone else has done this type of research using the FAERS database, and you can use this database to do research related to methimazole and propylthiouracil as well):【1】Zhao B, Fu Y, Cui S, Chen X, Liu S, Luo L. A real-world disproportionality analysis of Everolimus: data mining of the public version of FDA adverse event reporting system. Front Pharmacol. 2024 Mar 12;15:1333662. doi: 10.3389/fphar.2024.1333662. PMID: 38533254; PMCID: PMC10964017.【2】Zhong, C., Zheng, Q., Zhao, B., & Ren, T. (2024). A real-world pharmacovigilance study using disproportionality analysis of United States Food and Drug Administration Adverse Event Reporting System events for vinca alkaloids: comparing vinorelbine and Vincristine. Expert Opinion on Drug Safety, 23(11), 1427–1437. https://doi.org/10.1080/14740338.2024.2410436【3】Wang Y, Zhao B, Yang H, Wan Z. A real-world pharmacovigilance study of FDA adverse event reporting system events for sildenafil. Andrology. 2024 May;12(4):785-792. doi: 10.1111/andr.13533. Epub 2023 Sep 19. PMID: 37724699.【4】Zhao B, Zhang X, Chen M, Wang Y. A real-world data analysis of acetylsalicylic acid in FDA Adverse Event Reporting System (FAERS) database. Expert Opin Drug Metab Toxicol. 2023 Jan-Jun;19(6):381-387. doi: 10.1080/17425255.2023.2235267. Epub 2023 Jul 12. PMID: 37421631.【5】Yang H, Wan Z, Chen M, Zhang X, Cui W, Zhao B. A real-world data analysis of topotecan in the FDA Adverse Event Reporting System (FAERS) database. Expert Opin Drug Metab Toxicol. 2023 Apr;19(4):217-223. doi: 10.1080/17425255.2023.2219390. Epub 2023 May 30. PMID: 37243615.【6】Li, Jie, Zhao, Bin, Zhu, YongQing, Wu, Jibiao, Vitreoretinal Traction Syndrome, Nitrituria and Human Epidermal Growth Factor Receptor Negative Might Occur in the Aromatase-Inhibitor Anastrozole Treatment, International Journal of Clinical Practice, 2024, 5132916, 9 pages, 2024. https://doi.org/10.1155/2024/5132916

Besides,

I have general suggestion is:

1) Can Author put a bar chart for the percentage of MMI/PTU uses in five country and hospitalization, death, life threating events, and disability.

2) I also encourage to author please put the bar chart for table 3 where author indicated that digestive system cancers related adverse event for use of MMI/PTU.

3) I also encourage the author please use 1 graphical representation of MMI/PTU and their adverse event (MMI/PTU affecting which organ in human body)

Reviewer #2: Although numerous studies on drug adverse reactions based on the FAERS database have been published, the authors focus on commonly used endocrine drugs and analyze the adverse events associated with MMI and PTU—a topic that has not yet been explored. This work is of significant interest; while only major revisions are recommended, I do have some concerns that should be addressed�

Regarding the reporting standards for disproportionality analysis based on Individual Case Safety Reports (ICSR) in pharmacovigilance, the READUS-PV guidelines were established in 2024 under the leadership of the University of Bologna (doi:10.1007/s40264-024-01423-7). Based on FAERS adverse event reports, we call for standardized reporting in accordance with these guidelines.

The manuscript mentions that the downloaded raw data were deduplicated and that primary suspect drug reports were selected using the primary report ID, but it lacks detailed explanation. It is recommended to include specific details on the deduplication process, the criteria for excluding duplicate reports, and how cases of polypharmacy are handled, in order to enhance the transparency and reproducibility of the study.

Table 1 can be moved to the supplementary files.

In Table 2, for comparisons between different groups, you might consider including the p-values and specifying the statistical methods used.

Some studies have reported that hepatotoxicity is relatively more common in children taking PTU. Could you perform an age-stratified cross-sectional analysis comparing the effect sizes of PTU and MMI for different adverse events?

The manuscript indicates that only 11.8% (MMI) and 8.9% (PTU) of patients have time data, which may affect the representativeness of the time-to-event analysis. Also, for PTU, the reported median time of 84 days is inconsistent with the IQR (10.3–30.8 days). Please recheck and clarify these issues.

The manuscript mainly employs the Reporting Odds Ratio (ROR) method to detect signals. We suggest that the authors discuss why ROR was chosen over other methods (such as PRR, IC, or EBGM), outlining the strengths and weaknesses of each. Additionally, if possible, a sensitivity analysis on the main signals should be conducted to verify the consistency of the results across different methods.

**********

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

**********

[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.

A disproportionality analysis of FDA adverse event reporting system (FAERS) events for methimazole and propylthiouracil

PONE-D-24-51574R1

Dear Dr. Long,

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,

Vijayalakshmi Kakulapati, Ph.D

Academic Editor

PLOS ONE

author addressed all review comments 

Comments to the Author

Reviewer #4: All comments have been addressed

**********

Reviewer #3: Authors carefully answered the reviewers questions and therefore the quality of the manuscript improved

Reviewer #4: The author has satisfactorily addressed the questions I raised in the revised manuscript. I have no additional comments.

**********