Dear Dr. Min,

Several aspects require clarification and refinement before the manuscript can be considered further. These include ensuring consistency in reported sample sizes and denominators, clarifying methodological choices such as exclusion criteria and outcome definitions, and providing more explicit justification for the handling of prior depression and treatment-resistant TB cases. Additional explanatory detail is also needed where results appear counterintuitive, such as the lower frequency of depressive episodes among those with a history of depression.

From an analytical standpoint, the study would benefit from either incorporating additional relevant variables (e.g., body size, regional context, treatment type, regimen, resistance patterns, and management of comorbidities) or, if this is not feasible, acknowledging the limitations clearly. Explicit reporting of sex-based comparisons is also encouraged to improve interpretability.

Finally, we ask that you enhance clarity of presentation by resolving inconsistencies across the text, figures, and tables, marking statistically significant results more clearly, declaring GenAI use, and making minor improvements to the language and style.

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 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,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-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. In the online submission form, you indicated that [The ownership of the primary datasets lies with the Korea National Institute of Health (KNIH). The de-identified datasets generated and/or analysed during the current study can be made available for replication purposes upon reasonable request. Interested researchers should first contact the corresponding author, who will provide detailed instructions for submitting a request to the KNIH, including required documents such as a brief study proposal, institutional review board (IRB) approval, and a data use agreement. Access will be granted only with permission from the KNIH and will be limited to the scope of the approved research.].

All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information.

This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

4. Please include a separate caption for each figure in your manuscript.

5. 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. 

Additional Editor Comments:

Please clarify whether the reported 19.7% prevalence was observed in the total population or restricted to the subgroup with depressive episodes.

Ensure that the cited references directly support the statement on poor adherence; replace or revise as needed.

Please explain why WHO’s culture-based definition of “cure” was not applied. If culture data are available, provide the breakdown of patients meeting “cure” and report on treatment failure.

justify clearly Exclusion of rifampicin-resistant TB patients

Clarify whether subjects with prior depression were receiving antidepressant therapy, and discuss the potential impact on your findings.

Address inconsistencies in patient counts. Please reconcile and correct throughout.

Consider whether body size (BMI/weight), region (urban vs rural), adverse effects, treatment type (initial vs. retreatment), adjunct therapies, TB regimen type, and resistance patterns can be incorporated into the analysis. If not feasible, explain why.

Mark statistically significant p-values in all tables (univariate and multivariate analyses) for ease of reading.

[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?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Overall Summary:

This is a well-designed and scientifically sound cohort study showing that depressive episodes negatively affect treatment outcomes in elderly tuberculosis patients. The study is important for aging populations and should be accepted after minor revision.

Manuscript Number: PONE-D-25-44015

Title: Depressive episode and treatment outcomes in elderly individuals with tuberculosis: a prospective cohort study in Korea

Journal: PLOS ONE

1. Originality and Appropriateness

The manuscript presents results of an original prospective multicenter cohort study conducted in Korea (2020–2022). The findings have not been previously published elsewhere, and the study clearly addresses an important public health problem by examining the relationship between depressive episodes and tuberculosis treatment outcomes in elderly patients. The topic fits the scope of PLOS ONE. This research is particularly timely and needed for aging populations. After World War II, many individuals suffered from poor health due to lack of medical care in their youth. Now, as they reach older age, these long-term health consequences exacerbate disease burden. Addressing mental health in this context is of high importance.

2. Methodological Rigor

Study design: Prospective multicenter cohort across 13 hospitals, representative of different regions in Korea.

Sample: 361 elderly participants (≥65 years) with active TB. Clear inclusion/exclusion process shown in the flowchart.

Assessment: Depression was measured with the validated Korean version of the PHQ-9, with a cutoff ≥10 defining depressive episode.

Analysis: Logistic regression was applied to identify risk factors and associations with treatment success. Adjusted models included important covariates (age, sex, comorbidities, TB severity).

Ethics: IRB approval obtained (C19ONDI0458, XC20ENDI0086). Written informed consent documented.

The methodology is adequate, technically sound, and well described. Analyses are appropriate and reproducible. However, one suggestion for improvement: sex should be analyzed and presented more fully, not only by using “female” as a reference category. Explicit comparisons between males and females would make interpretation clearer for readers.

3. Results

Prevalence: 19.1% of participants had a depressive episode.

Risk factors: Unemployment (aOR 5.07), higher Charlson comorbidity score, cough, and constitutional symptoms.

Functional impairment: Increased with depression severity.

Suicidal ideation: Reported by 19.7%; associated with alarming TB symptoms.

Treatment outcomes: Depressive episode significantly reduced treatment success (64.7% vs. 79.1%, p=0.012). Independent association confirmed (aOR 0.478, 95% CI 0.261–0.878).

The results are clearly presented with supportive tables and figures. The statistical evidence supports the conclusions.

4. Discussion and Conclusions

The discussion appropriately interprets findings:

- Depression is common among elderly TB patients and linked with poor adherence, functional decline, and suicidality.

- Highlights the importance of routine depression screening at TB diagnosis.

- Discusses public health relevance and implications for integrated care.

- Limitations are acknowledged: self-reported PHQ-9, limited generalizability beyond elderly cohort.

Conclusions are supported by data, not overstated, and aligned with the study’s scope. The authors should consider revising the reporting of sex differences to make male–female comparisons explicit rather than leaving readers to infer.

5. Writing and Presentation

The article is written in standard English, intelligible and well structured.

Abstract accurately reflects the study.

Tables and figures are appropriate and clear.

References are up to date and relevant.

Minor language polishing could further enhance readability, but the manuscript already meets PLOS ONE standards.

6. Ethics and Data Availability

Ethics approval and informed consent are properly documented.

Data availability is described: de-identified datasets are accessible upon request via KNIH with IRB approval and data use agreement. This is compliant with PLOS ONE data policy.

No competing interests declared.

Funding disclosure complete.

7. Recommendation

The manuscript is scientifically sound, ethically compliant, and meets PLOS ONE criteria.

I recommend acceptance after minor revision, specifically encouraging the authors to (1) polish English slightly, and (2) report sex differences explicitly (male vs. female) for clearer interpretation.

Reviewer #2: Kim and colleagues have performed a logistic regression analysis to identify significant factors associated with depressive episodes and TB treatment outcome. Notably, the authors assessed functional impairment and suicidal ideation using different scales, which strengthens the analysis by highlighting factors that distinctly impact each. The findings that unemployment, higher comorbidity burden, and constitutional symptoms were associated with depressive episodes, and that alarming symptoms were linked to suicidal ideation, are important observations. Furthermore, the association of depressive episodes with poor treatment success adds clinical relevance.

The work is valuable; however, I have identified several areas for improvement that would enhance the clarity, robustness, and interpretability of the study:

Major Comments

1. Line 54–55: Please clarify whether suicidal ideation (19.7%) was observed in the total population or specifically in the subgroup with depressive episodes.

2. Line 77: References 7 and 8 do not appear to contain data directly related to poor treatment adherence. Please verify and provide appropriate references.

3. Line 127–128: According to WHO, a negative sputum culture defines cure or treatment success. Why was this not applied? If available, please provide the breakdown of patients who met the “cure” definition. Including data on treatment failure would also be highly informative.

4. Line 148: Please provide the rationale for excluding rifampicin-resistant TB patients.

5. Line 173: Including subjects with prior depression may bias the analysis. Were any of these subjects receiving antidepressant therapy? Please clarify.

6. Results: Consider incorporating additional variables into the analysis to strengthen robustness, such as:

Body size (weight, BMI)

Region (urban vs. rural)

Adverse effects or pre-treatment adverse effects

Treatment type (initial vs. retreatment)

Additional therapies (e.g., immunotherapy, management of depression)

TB regimen type

Resistance pattern (XDR, MDR, etc.)

7. Table 1: It is counterintuitive that patients with prior depression have fewer depressive episodes. Could this be due to antidepressant therapy or other management strategies? Please comment.

8. Table 1: The methods indicate rifampicin-resistant TB patients were excluded, yet this variable appears in the table. Please explain.

9. Line 203–205: In Table 2, 292 patients are listed under “no depressive episodes,” but here the number is 205. Please clarify this discrepancy.

10. Line 225: The total sample size is 361, but treatment success is reported for 350. Was treatment outcome assessed only in this subset? Please clarify why 11 subjects were excluded.

Minor Comments

* Please mark statistically significant p-values in both univariate and multivariate analyses with an asterisk for improved readability.

**********

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: Yes:  Dr. Jing Liang

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.

Attachments

Attachment

Submitted filename: Reviewer_Report_PONE-D-25-44015_Updated.docx

Depressive episode and treatment outcomes in elderly individuals with tuberculosis: a prospective cohort study in Korea

PONE-D-25-44015R1

Dear Dr. Min,

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. For questions related to billing, please contact billing support .

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,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: I have carefully reviewed the revised manuscript and the authors’ detailed responses. The revision has fully addressed all prior reviewer and editor comments. The manuscript now meets the scientific, ethical, and editorial standards required by PLOS ONE. The study is methodologically sound, the presentation is clear, and the revisions improve transparency and rigor. I recommend acceptance of the manuscript.

Editor’s Comments

1.Clarification of suicidal ideation prevalence (19.7%)

→ Revised and clarified that this percentage refers to all 361 participants. Clear statements added to Abstract and Results sections.

2.Reference accuracy on treatment adherence

→ Reference #8 updated to Panati et al., Clin Epidemiol Glob Health (2023), directly supporting poor adherence in TB patients with depression.

3.WHO definition of “cure” and reporting treatment failure

→ The revised manuscript now explicitly follows WHO guidance, clarifies the rationale for using a 9-month cutoff for treatment success, and provides a detailed outcome table (Supplemental Table 6).

4.Exclusion of rifampicin-resistant TB patients

→ Justified based on clinical heterogeneity and small sample size (3.0%, n=11). Explanation added to both Methods and Results sections.

5.Prior depression and antidepressant therapy

→ Defined as clinician-diagnosed and under active treatment; discussion of bias and sensitivity analysis excluding 7 such participants were added. Results unchanged.

6.Consistency of patient counts

→ Clarified that PHQ-9 <10 group (n=292) includes both 0–4 and 5–9 subgroups; explicit breakdown provided.

7.Additional variables suggested (BMI, regimen, region, etc.)

→ BMI and regimen type were added to models; other variables (region, AE data, adjunct therapy) were unavailable and acknowledged as a limitation.

8.Marking significant p-values

→ All tables now include asterisks (*) for significant results for improved readability.

All editorial concerns have been fully resolved.

Reviewer #1 Comments

1.Male–female comparison clarity

→ Added explicit sex-based comparisons in text and tables, including male/female counts and adjusted odds ratio (female a OR = 1.168, 95% CI 0.685–2.076).

2.Language quality

→ English refined for clarity, formatting standardized, and terminology harmonized (e.g., rifampicin).

Reviewer #1’s suggestions have been thoroughly addressed.

Reviewer #2 Comments

All ten major comments and one minor comment have been carefully addressed:

1. Clarified suicidal ideation base (19.7%) → Corrected and clarified.

2. Updated references for poor adherence → Completed.

3. WHO cure definition and treatment outcome table → Fully revised and justified.

4.Exclusion of RR-TB → Clear rationale added.

5.Prior depression and antidepressant therapy → Defined, analyzed, and discussed with sensitivity analysis.

6.Added BMI and other covariates → Included and explained, unchanged conclusions.

7.Prior depression fewer episodes issue → Explained due to active treatment and small sample size.

8.RR-TB in Table 1 explanation → Clarified as descriptive baselines for all 361 participants.

9.Count discrepancy (292 vs 205) → Corrected with explicit PHQ-9 breakdown.

10.Treatment success denominator (350) → Explained exclusion of 11 RR-TB participants.

11.Mark significant p-values → All tables revised accordingly.

Each issue raised by Reviewer #2 is now completely resolved.

Reviewer #2: (No Response)

**********

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: Yes:  Dr. Jing Liang

Reviewer #2: No

**********

Attachments

Attachment

Submitted filename: PLOS ONE Re-review 10152025.docx