PONE-D-24-35318Active Tuberculosis in Household contacts of Bacteriologically confirmed Pulmonary Tuberculosis patients: A Multicenter Study Finding the ‘Missed One' in Central Ethiopia.PLOS ONE

Dear Dr. Abegaz,

Thank you for submitting your manuscript, PONE-D-24-20230, entitled "Active Tuberculosis in Household contacts of Bacteriologically confirmed Pulmonary Tuberculosis patients: A Multicenter Study Finding the ‘Missed One' in Central Ethiopia" to PLoS One. Your work has been reviewed by experts in the field, who recognize the importance of your research and its potential value to readers. However, the reviewers raised some questions regarding your submission. After careful consideration, we feel that it has merit and therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Please submit your revised manuscript by Dec 20 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Ravi Prakash

Academic Editor

PLOS ONE

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Additional Editor Comments:

Reviewer 1

Minor Revision

This manuscript provides very good information and clarifies further gap in the low economic countries like Ethiopia. The manuscript can be considered for publication after required minor corrections given below. The manuscript is meeting the PONE requirements. Statistical analysis was executed properly. All the required data provided in tales and supplementals.

Reviewer 2

Major Revision

The manuscript addresses an important public health issue by examining active TB detection through door-to-door household contact investigations in Ethiopia. It highlights a significant gap in active TB case detection and provides insights into how home-based interventions might improve detection rates among high-risk groups. But the study design to result is not new, just add a piece of evidence to the established public health knowledge.

Specific Comments:

1.Introduction:

References such as those on TB incidence and the 'missing millions,' could benefit from more recent data to reflect any changes in global trends.

2. Methods:

1)The study mentions using the Xpert Ultra assay and TB culture for diagnosis. It would be helpful to briefly describe the sensitivity and specificity of these methods.

2)Consider adding more details on how "presumptive TB" was defined during the household evaluations.

3)Actually its Spearman's rank correlation coefficient or Spearman's ρ, not "Spear’s man correlation".

3. Results:

1)The section detailing the correlation between the index case’s cycle threshold (Ct) values and household contacts is intriguing. It would be beneficial to include a brief explanation of why this correlation is important in the context of TB transmission.

2)The comparison between DS-TB and MDR-TB households is valuable. However, the discussion of the similar yield in active TB detection between the two groups should address the potential for misclassification or under-diagnosis of MDR-TB in the HHCs.

3)Consider highlighting key findings in bullet points or using summary tables for improved clarity.

4)Figure 1 is useful in showing the contact investigation cascade. However, it could be enhanced with a visual distinction between DS-TB and MDR-TB groups to make differences more apparent.

4. Discussion:

1)The limitations are acknowledged, such as the lack of clinical screening (e.g., chest X-rays). However, the authors could further discuss how the use of such diagnostic tools might alter the study's conclusions.

2)The study's impact on future TB control strategies could be emphasized more. For example, what specific recommendations can be made for integrating door-to-door TB investigations into existing public health frameworks?

[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: Yes

**********

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: This manuscript provides very good information and clarifies further gap in the low economic countries like Ethiopia. The manuscript can be considered for publication after required minor corrections given below. The manuscript is meeting the PONE requirements. Statistical analysis was executed properly. All the required data provided in tales and supplementals.

Reviewer #2: The manuscript addresses an important public health issue by examining active TB detection through door-to-door household contact investigations in Ethiopia. It highlights a significant gap in active TB case detection and provides insights into how home-based interventions might improve detection rates among high-risk groups. But the study design to result is not new, just add a piece of evidence to the established public health knowledge.

Specific Comments:

1.Introduction:

References such as those on TB incidence and the 'missing millions,' could benefit from more recent data to reflect any changes in global trends.

2. Methods:

1)The study mentions using the Xpert Ultra assay and TB culture for diagnosis. It would be helpful to briefly describe the sensitivity and specificity of these methods.

2)Consider adding more details on how "presumptive TB" was defined during the household evaluations.

3)Actually its Spearman's rank correlation coefficient or Spearman's ρ, not "Spear’s man correlation".

3. Results:

1)The section detailing the correlation between the index case’s cycle threshold (Ct) values and household contacts is intriguing. It would be beneficial to include a brief explanation of why this correlation is important in the context of TB transmission.

2)The comparison between DS-TB and MDR-TB households is valuable. However, the discussion of the similar yield in active TB detection between the two groups should address the potential for misclassification or under-diagnosis of MDR-TB in the HHCs.

3)Consider highlighting key findings in bullet points or using summary tables for improved clarity.

4)Figure 1 is useful in showing the contact investigation cascade. However, it could be enhanced with a visual distinction between DS-TB and MDR-TB groups to make differences more apparent.

4. Discussion:

1)The limitations are acknowledged, such as the lack of clinical screening (e.g., chest X-rays). However, the authors could further discuss how the use of such diagnostic tools might alter the study's conclusions.

2)The study's impact on future TB control strategies could be emphasized more. For example, what specific recommendations can be made for integrating door-to-door TB investigations into existing public health frameworks?

**********

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: Yes:  Ramgopal Sivanadham

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: Review comments.docx

PONE-D-24-35318R1Active Tuberculosis in Household contacts of Bacteriologically confirmed Pulmonary Tuberculosis patients: A Multicenter Study Finding the ‘Missed One' in Central Ethiopia.PLOS ONE

Dear Dr. Abegaz,

Thank you for submitting your revised manuscript to PLOS ONE. After careful consideration, the reviewers still has some concerns in the manuscript. 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 15 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,

Ravi Prakash

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.

Additional Editor Comments:

Reviewer 1:

No Comments

Reviewer 2:

Minor Revision

1. The definition of diagnostic is undoubtable following the guideline in line 141-145. "An active pulmonary TB case is a TB case confirmed by either smear microscopy, Gene Xpert MTB/RIF Ultra, or a TB culture test. Bacteriologically confirmed pulmonary tuberculosis: case referred to a pulmonary TB patient with biological specimen positive by Acid-Fast Bacilli (AFB) smear microscopy, Xpert MTB/RIF assay or TB culture, indifference with drug susceptibility profile."

Now what worrying is the diagnosis of bacteriologically confirmed pulmonary tuberculosis in HHCs, which means that the test may not covered all of three methods of AFB, Xpert, and culture simultaneously, it is a "OR" in your diagnostic criteria. The results may include false positive of dead bacteria patients, on the basis of the screening produce also not included the chest X-ray, which may bias the results.

This should be discussed and should be put forward in limitation, not only simply narrate in limitation line 389-390 "We did not use clinical screening like chest X-rays which might increase the sensitivity of screening. "

2.Line 292-294 "Whereas among thirty presumptive household contacts of MDR-TB patients, 2 (6.67%; 95% CI: 1.16- 23.51) were MTB detected Rifampicin resistance was not detected." this need to discuss in depth, is any other evidence or report that the MDR-TB HHCs not infected with MDT-TB strains, it should be addressed and clarify the primary and secondary drug resistance in this case.

3. line 300 "There was a positive correlation between the ct values of the index case and the corresponding HHC ct) value at each probe ", This bracket seems superfluous.

4. last time comment "Consider highlighting key findings in bullet points or using summary tables for improved clarity.

Author Response: Thank you for the suggestion. We tried to put key findings of the study at the end of result section. Page 12 line 309-315"

Lets make it clear that authors could embeded the key findings in the article, not only list and summary in the back of results, which is a bit redundant and may overlap with the discussion. Author should also be associated with the journal's editorial policy and format.

[Note: HTML markup is below. Please do not edit.]

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

**********

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

**********

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 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

**********

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

**********

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 recommendations in minor revision have been addressed. The manuscript can be proceeded for next steps in publication.

Reviewer #2:  1. The definition of diagnostic is undoubtable following the guideline in line 141-145. "An active pulmonary TB case is a TB case confirmed by either smear microscopy, Gene Xpert MTB/RIF Ultra, or a TB culture test. Bacteriologically confirmed pulmonary tuberculosis: case referred to a pulmonary TB patient with biological specimen positive by Acid-Fast Bacilli (AFB) smear microscopy, Xpert MTB/RIF assay or TB culture, indifference with drug susceptibility profile."

Now what worrying is the diagnosis of bacteriologically confirmed pulmonary tuberculosis in HHCs, which means that the test may not covered all of three methods of AFB, Xpert, and culture simultaneously, it is a "OR" in your diagnostic criteria. The results may include false positive of dead bacteria patients, on the basis of the screening produce also not included the chest X-ray, which may bias the results.

This should be discussed and should be put forward in limitation, not only simply narrate in limitation line 389-390 "We did not use clinical screening like chest X-rays which might increase the sensitivity of screening. "

2.Line 292-294 "Whereas among thirty presumptive household contacts of MDR-TB patients, 2 (6.67%; 95% CI: 1.16- 23.51) were MTB detected Rifampicin resistance was not detected." this need to discuss in depth, is any other evidence or report that the MDR-TB HHCs not infected with MDT-TB strains, it should be addressed and clarify the primary and secondary drug resistance in this case.

3. line 300 "There was a positive correlation between the ct values of the index case and the corresponding HHC ct) value at each probe ", This bracket seems superfluous.

4. last time comment "Consider highlighting key findings in bullet points or using summary tables for improved clarity.

Author Response: Thank you for the suggestion. We tried to put key findings of the study at the end of result section. Page 12 line 309-315"

Lets make it clear that authors could embeded the key findings in the article, not only list and summary in the back of results, which is a bit redundant and may overlap with the discussion. Author should also be associated with the journal's editorial policy and format.

**********

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: Yes:  Ramgopal Sivanadham

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.

Active Tuberculosis in Household contacts of Bacteriologically confirmed Pulmonary Tuberculosis patients: A Multicenter Study Finding the ‘Missed One' in Central Ethiopia.

PONE-D-24-35318R2

Dear Dr. Abegaz,

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,

Ravi Prakash

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 #2: All comments have been addressed

**********

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 #2: Yes

**********

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

Reviewer #2: 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 #2: (No Response)

**********

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 #2: 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 #2: All minor revision suggestions have been implemented, and the manuscript is now ready to move forward with the publication process.

**********

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 #2: No

**********