PONE-D-23-28374Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosisPLOS ONE

Dear Dr. Song,

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

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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

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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

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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: In this article Song et. al., have assessed the TST positivity predictors in neonates exposed to TB index cases (healthcare workers) and undergone isoniazid prophylaxis regimen. As claimed by the author, this could become the first published study to find the predictors of positive TSTs among neonates exposed to an infectious index. The identification and characterization of the index cases and follow up success rate of this study should be appreciated. However, the study needs further clarity and major revision to justify the conclusion drawn from it.

All the study subjects were exposed to index cases as defined in this paper. However, looking at the features of index cases (as in Table 1) and with the preventive measure taken for Covid-19 (Page 4, line 83), the likelihood of exposure is minimal. This has also been raised by the authors in the discussion (page 19, line 262). The authors should elaborate on the nature and likelihood of exposure.

In the study, the percentage of TST positive cases among exposed indexes are 5.3%. If the objective was to investigate the impact of potential exposure in neonates on TST, then a cohort of neonates with no-exposure to any index cases will be useful for comparision.

The primary outcome of this study is- age (>< 6 days) at the initial exposure a predictor of TST reactivity. The chi-square test shows BCG vaccination as a determinants of TST positivity (univariate Firth coefficient test also showed some trend (0.08)). Also the Haldane-Anscombe correction emphasized on BCG vaccination as a critical factor (Page 15, line 222). Since the number of TST positive subjects among non-vaccinated cases is zero, it may over-fit statistical models used. The authos should elaborate on the BCG vaccination regimen used for the study subjects. When were they vaccinated after birth? Was there any heterogeneity in the time duration between vaccination and TST test?

Page 6, Table 1: Xpert MTB/RIF positive gives an impression of being Rif-resistant.

Page 11, Table-1: Please clarify the missing 3% in prematurity [<37 weeks: 11 (5.4%), >37 weeks: 119 (91.6)] and 14.5% in delivery type.

Page 16, Table-3: Whether all the subjects completed the 3 months IPT regimen. What was the rationale behind setting the 68 days cut-off?

Page 16, Table-3: Percentage distribution <6 days 110 (99%) 1 (1%) and >6 days 34 (83%) 7 (17%) will give better impression on the data.

Reviewer #2: Author has attempted to see the predictors of positive TST in neonates exposed to Pulmonary Tuberculosis. Study is effectively planned and implemented. However, following points need clarifications:

1. Here index cases of health care workers have been detected by chest CT only. Is it routine practice to do TB screening with CT chest in author's setting? If no, author can explain what is routine practice and why CT were done in these cases.

2. In line no. 103, in index case A, how the nodule was detected? Is it on chest x-ray or CT scan?

3. In line no. 105, for the same index case A, for which sample PCR or GeneXpert was done ? Is it sputum or biopsy sample?

4. Line no. 175, numbers are not matching. 152- 6 refusers - 2 refusers= 144. But author has written 142 completed the treatment.

5. Line No. 18, the author has commented that treatment was given to 18 contacts. But there is no mention of those 11 contacts that were detected positive, first time by IGRA. What happened to those on follow-up? Were they also put on preventive treatment?

6. Lines no. 220 and 236; in sensitivity analysis, author used 5 mm cut-off, but in methodology, author explained that 10mm cut off was chosen for those already taken BCG. Please explain why for analysis 5mm cut-off was considered. It may have given few false positive cases.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-28374R1Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosisPLOS ONE

Dear Dr. Song,

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 Mar 16 2024 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,

Rebecca F. Baggaley

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 #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 #3: Partly

**********

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

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 #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 #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 #3: I appreciate the author (s) for coming up with this work on assessing the predictors of positive tuberculin skin tests in neonates exposed to pulmonary tuberculosis. It is an area with limited information and claimed by the author, it could be the first study in such a setting. We could build on this work for future studies. I am in support and acknowledged the work of other reviewers. However, the study needs to clarify minor corrections moving forward.

1.Neonates are at risk of nosocomial tuberculosis (TB) infection from health care workers (HCWs) in neonatal care facilities, which can progress to severe diseases. The statement "which can progress to severe diseases." It sounds confusing as it may mean nosocomial tuberculosis (TB) infection from health care workers (HCWs) could progress to several other severe diseases than severe TB disease or different forms of TB.

2.The statement "BCG vaccination showed marginal statistical significance (Firth coefficient 2.5, 95% CI -0.4–5.4, P = 0.088) only in univariable analysis" in the abstract and result section could be use with caution. It is important to note that marginal significance differs from true statistical significance. Utilizing the term "marginally significant" is an indirect way of admitting that the resulting p-value was not statistically significant while attempting to give it the appearance of statistical significance. Researchers commit this fraudulent act because the more significant their results are (or, in this case, seem), the more likely the study is to be published; in turn, these publishments may reward researchers with grants or financial aid to continue their research or begin new studies (Lybrand et al., 2021).

3.While I appreciate the author's outstanding work describing the study area and settings, the author did not mention the study design in the abstract and methodology section. In addition, the author needs to be clear on sampling (sample size) and procedures.

References

Lybrand, B., Blackhart, G., Parish, A., Lowe, H., 2021. Investigating the Misrepresentation of Statistical Significance in Empirical Articles.

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Reviewer #3: Yes: Dickens Odongo, Department of Environmental Health and Disease Control, Faculty of Public Health, Lira University, Lira, Uganda.

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Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosis

PONE-D-23-28374R2

Dear Dr. Jin Su Song,

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.

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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,

Novel N. Chegou, Ph.D

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 #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 #3: Yes

**********

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

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 #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 #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 #3: (No Response)

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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 #3: No

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