Dear Dr. Theerakulpisut,

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Afagh Hassanzadeh Rad

Academic Editor

PLOS One

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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?

Reviewer #1: Partly

Reviewer #2: No

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

Reviewer #1: I Don't Know

Reviewer #2: No

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: It would be helpful to provide more information about the radioactive iodine treatment protocol at your center. Is there a standardized treatment at your center? This information is important for the reader to know if changes in treatment regimen may have affected the results.

The use of a significance level of p < 0.2 in univariate regression may be confusing to some readers. Typically, a p-value < 0.05 is used in both steps. If there is a specific reason for choosing a p-value level of < 0.2 in this step, it is suggested that a brief explanation be provided. This will help clarify your reasoning for this choice.

The section on dividing the data into subgroups is well explained, but needs further clarification. Why were these specific combinations chosen for the subgroup division?

These can explain to readers why this particular approach was chosen and how it might affect the results.

In cases where Tg values < 0.04 or >500 ng/mL or TSH > 100 µIU/mL are reported, a clear explanation of how these values were handled in the analyses appears to be provided. However, further clarification of how these missing or incorrect data are handled (such as omitting these data or using alternative methods for analysis) would be useful.

Especially in subgroups where these specific values exist, mention whether incomplete data were removed from the analyses or how you dealt with these values.

Further explanation on how lymph node metastasis was assessed in the study (was advanced imaging used?) and how metastasis was detected at an early stage. However, it is suggested that more explanation be provided in the ROC analysis about the sensitivity and specificity at these thresholds.

In the analysis section, age is discussed in detail, but it seems that further explanation of why age ≤45 years is not effective as an independent factor in some studies would be valuable.Is this due to a lack of evidence in small samples, or are different analysis methods in different studies causing different results?

Ultimately, your article is very valid and useful, and by making these corrections, its scientific credibility will increase

Reviewer #2: Dear Editor

Thank you for the opportunity to review this manuscript.

My comments are as follows:

This manuscript addresses an important and clinically relevant topic, namely the prediction of response to radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer (DTC). The finding regarding sTg ≥ 9.4 ng/mL is noteworthy, and the use of internationally recognized sources such as GLOBOCAN and ATA guidelines reflects an appropriate scientific foundation. However, the study has several important limitations that require substantial revision prior to consideration for publication.

First, the manuscript relies on the ATA 2015 guidelines, suggesting that risk stratification and treatment response assessment were based on an outdated framework. Since then, significant updates have been introduced, including the 2022 update and the more comprehensive 2025 ATA guidelines. Continued reliance on ATA 2015 may limit alignment with current standards of care, particularly regarding recurrence risk stratification, RAI dosing strategies, and management of patients with N1b disease. The authors should either update their framework in accordance with ATA 2025 or explicitly acknowledge these updates in the Discussion and justify the use of the earlier version.

Second, the study’s retrospective, single-center design inherently limits control of confounding variables and reduces external validity. As the research was conducted in a single institution in Thailand, the generalizability of the findings to other populations and healthcare systems may be restricted.

Third, the change in laboratory assay methodology (from RIA to ECLIA) and the exclusion of earlier data potentially introduced selection bias and reduced the effective sample size. While the timeline, laboratory methods, and exclusion criteria are clearly described, inclusion of certain operational details (e.g., exact dates of data access approval) appears unnecessary and may detract from the methodological clarity of the manuscript.

Fourth, the limited sample size within certain subgroups and the presence of multicollinearity among sTg, the sTg/TSH ratio, and other covariates likely contributed to the loss of statistical significance of key variables (notably the sTg/TSH ratio and N1b status) in multivariable regression analysis. Despite this, the Discussion emphasizes the potential usefulness of the sTg/TSH ratio, which is not supported by the adjusted model. This creates inconsistency between statistical findings and interpretation.

Fifth, the follow-up period of 6–18 months primarily reflects short-term treatment response rather than long-term prognosis. Given the typically indolent course of DTC, longer follow-up would be necessary to assess recurrence and durable outcomes.

Sixth, important lymph node characteristics (such as size and number of metastatic nodes), which may influence prognosis, were not fully analyzed.

Seventh, the analysis of RAI dosage may be affected by confounding by indication. Higher RAI doses (150–200 mCi) were likely administered to patients with more advanced disease or higher ATA risk categories. Therefore, the observed association between higher RAI dose and poorer treatment response may reflect baseline disease severity rather than an independent causal effect of the administered dose. The manuscript does not clearly demonstrate adequate statistical adjustment for this potential bias. Stratified analyses within risk categories or the use of propensity score methods would strengthen internal validity.

Finally, there appears to be a discrepancy between the primary objective and the final conclusions. The study aimed to evaluate the impact of the sTg/TSH ratio and N1b status on treatment response; however, neither variable remained significant in multivariable analysis. Ultimately, only sTg was identified as an independent predictor — a finding already well established in prior literature. Consequently, the degree of novelty is limited.

In light of these considerations, the manuscript requires major revision, including updating the guideline framework, refining the statistical modeling, simplifying subgroup analyses, and providing a clearer and more balanced discussion of limitations and clinical implications, before it can be considered for publication in a reputable journal.

Sincerely

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Reviewer #1: Yes: Sara Nikpour

Reviewer #2: No

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Dear Dr. Theerakulpisut,

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.

The manuscript has been evaluated by two reviewers, and their comments are available below.

Could you please revise the manuscript to carefully address the concerns raised?

Please submit your revised manuscript by Jul 26 2026 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.

• A 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Alejandro Torrado Pacheco, PhD

Associate Editor

PLOS One

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If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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??>

Reviewer #2: Yes

Reviewer #3: Partly

**********

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

Reviewer #2: I Don't Know

Reviewer #3: No

**********

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

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: (No Response)

Reviewer #3: This retrospective study of 227 patients with differentiated thyroid cancer assessed predictors of response to first radioactive iodine treatment. The sTg/TSH ratio and N1b lymph node status were not independent predictors, while poorer outcomes were associated with male sex, higher recurrence risk, stage II disease, and elevated stimulated thyroglobulin (≥9.4 ng/mL). The sTg/TSH ratio performed similarly to sTg alone, offering no added benefit, indicating that sTg remains the more useful predictor.

Minor Suggested Revisions (New Concerns):

1- Add a formal sample size/power justification: The manuscript does not describe how the sample size was determined or whether the study was adequately powered to detect meaningful effects, which limits confidence in negative findings.

2- Cite the statistical software: Specify the statistical software (e.g., SAS, R, SPSS) used for the analysis to improve reproducibility and transparency.

3- Include model diagnostics: Additional details on model evaluation, such as assessment of multicollinearity (e.g., variance inflation factors) and goodness-of-fit, should be provided to support the validity of the regression results.

4- Clarify handling of missing data: The manuscript should explicitly state how missing data were handled (e.g., exclusion vs imputation), as this can influence both estimates and generalizability.

5- Provide events-per-variable justification: Report the number of outcome events and comment on the events-per-variable ratio to ensure the multivariable model is not overfit and results are stable.

6- Table 1: For the cervical node metastasis location and sTg/TSH ratio subgroups, first report an overall p-value testing for differences across all groups, followed by appropriate stepdown (post hoc) comparisons to identify which specific group pairs differ.

Prior Reviewer Comments Not Fully Addressed:

1- Subgroup analysis rationale remains weak: The explanation for subgroup construction is still ad hoc and lacks a clear statistical or prespecified justification.

2- Handling of extreme/censored values is unclear: Although some exclusions are described, the analytical approach for values below/above assay limits is not fully specified and may introduce bias.

3- ROC analysis lacks formal comparison: The added discussion is descriptive; no statistical comparison of AUCs or model performance is provided.

4- Confounding by indication not addressed analytically: The issue is acknowledged, but no statistical adjustment (e.g., stratification or propensity methods) was performed.

5- Limited novelty only reframed: The conclusions were revised for alignment, but the underlying concern about limited incremental contribution remains.

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what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #2: Yes: Matin mojaveri samak

Reviewer #3: No

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

The effects of stimulated thyroglobulin/ thyroid-stimulating hormone ratio and N1b status on the efficacy of the first I-131 treatment in patients with differentiated thyroid cancer

PONE-D-25-59175R2

Dear Dr. Theerakulpisut,

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.

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Kind regards,

Antimo Migliaccio, M.D.

Academic Editor

PLOS One

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