PONE-D-20-06975

Multidrug-resistant Tuberculosis and Its Associated Factors from Tuberculosis Patients in Tigray Region, Ethiopia: a cross sectional study

PLOS ONE

Dear Dr. Welekidan,

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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?

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: No

Reviewer #2: No

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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: This study attempted to describe the burden and factors associated with MDR-TB in Tigray, Ethiopia. I notified several things that should be clarified by the authors:

1. The study is a cross-sectional study, which is not adequate to analyse factor associated with MDR-TB. Temporality degree should be clearly defined between the factors and outcomes. Since the factors and outcome were identified at the one point in the cross-sectional study, temporality degree is not precise. I suggest changing the term “factors” to “characteristics” of MDR-TB patients.

2. I read that the study defined Tigray, Ethiopia, as the target population and sixth public hospitals were included as the source population in this study. The question is about the adequateness of the sample size. I read that there are many hospitals (private and public) in Tigray and around thousands of people were identified as suspected TB patients. How can you ensure 300 participants and the only public hospital included will represent the TB population in Tigray?

3. Although you explained the sample size calculation, it is still not clear for me. How you defined the sample size?. There is no sampling frame described and if we look at the figure 2, it only 4.2% suspected TB patient who had positive Gen expert. It is a very small proportion. In another side, your source population is the presumptive TB patients. Can you explain that?

4. Can you explain more detail why your data have a high proportion of negative gen expert test? Can you provide detail information about the excluded participants? And how you deal with the representativeness of your data?

5. Please follow standard reporting for observational study (e.g. STROBE)

6. One of your inclusion criteria is “new PTB patient” (line 120), but in the result, you provide data about previously treated TB patients (table 2)?

7. No clear information on how missing data was managed. Please describe it

Abstracts

8. The significant factors should be described in the result of abstract

9. Subject criteria should be described

Introduction

10. Line 92, reference? Adding evidence from another country is suggested. See PMID: 30394362, PMID:31338162.

Method

11. Line 119, please explain the reason to choose the selected hospital.

12. Line 122, the excluded participants should be reported in the result section? How many ? and what is the reason?

13. Line 166, how many TB-HIV patient?

14. Line 236, in which category patient with drug-resistant but not MDR-TB (e.g. mono resistance, IH-R, S-R, any R, etc.)?

Result

15. Line 264, it’s should be tested statistically, and the next is focus on the description only for the included participant

16. Table 1 it’s difficult to understand. Please revise

17. Table 3-5 can be combined. Did you analyse it separately? It should be interpreted in combination.

18. Line 331-343. Please ensure that you compare with the same duration and unit of measurement

Discussion

19. Some findings are different from the global risk factors of MDR-TB (PMID: 30339803), can you explain? It will guide for the specific problem in Tigray as compare with others and give insight for developing specific intervention in Tigray.

Reviewer #2: The prevalence of MDR TB is found to be very high in new and retreatment cases in the Tigray region in Ethiopia. This is an important result from public health standpoint in terms of allocation of resources and need to intervene to limit spread. It would be relevant for authors to discuss in methods section why the six hospitals were selected from the region and if there is a possibility that the population served by the hospitals may have a higher prevalence or risk of MDR TB, such has presence of hotspots, high HIV prevalence, historically poor TB control, etc. It should be discussed in the discussion why the prevalence of MDR TB is higher in the region than in most of the other parts of the countries.

In the methods, authors should describe the standard of practice in these hospitals and the region before this survey. Do all patients get Xpert or culture? Or with this study, are the patients getting systematic DST? If so, is there posssiblity this could influence the prevalence that was found.

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Reviewer #1: No

Reviewer #2: Yes: Kunchok Dorjee

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PONE-D-20-06975R1

Multidrug-resistant Tuberculosis and Its Associated Factors from Tuberculosis Patients in Tigray Region, Ethiopia: a cross sectional study

PLOS ONE

Dear Dr. Welekidan,

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. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

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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 #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: I suggest to change the title to "Characteristics of multidrug-resistant tuberculosis patients in Tigray region, Ethiopia".

Reviewer #2: 1) If the lower risk of DR-TB with alcohol consumption is likely a statistical noise, as the authors acknowledged and which likely is the case, then this may not be highlighted in the abstract.

2) In the discussion in lines 461-468, authors attribute the lack of association of sociodemographic factors to possible effect modification by geography. It is hard to conceive that the effect of age, residence, and education status on MDR TB would be different from region to region in Africa or Ethiopia. Looks like authors are using the term effect modification loosely without underlying reason or a basis. Authors can simply say they did not find association between sociodemographic factors and MDR TB prevalence. It is not necessary scientifically and biologically that MDR TB prevalence should be higher or lower in with increasing age; there are communities where actually MDR TB prevalence is higher in younger age group. There are many factors at play.

3) Lines 466-468: "Besides, our finding is different from the global risk factors review report, and this variation among regionally and globally could be due to Effect modification by geographical area". Please pay attention to grammar.

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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.

PONE-D-20-06975R2

Characteristics of multidrug-resistant tuberculosis isolates from pulmonary tuberculosis patients in Tigray Region, Ethiopia: a cross-sectional study

PLOS ONE

Dear Dr. Welekidan,

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. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

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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 #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: Regarding the title, I did not find that the authors described and discussed about charactersitics of isolate from MDRTB patient. If so, the manuscript should describe, discuss and explain more detail about microbiological aspects of the isolates. I read that the authors focused on the characteristics of the patients. Therefore, I suggest that the title should be revised to "Characteristics of pulmonary multidrug-resistant tuberculosis patients in Tigray Region, Ethiopia: a cross-sectional study". It will help the readers to understand the manuscript easily.

Reviewer #2: (No Response)

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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.]

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Characteristics of pulmonary multidrug-resistant tuberculosis patients in Tigray Region, Ethiopia: a cross-sectional study

PONE-D-20-06975R3

Dear Dr. Welekidan,

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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Kind regards,

Frederick Quinn

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 #1: 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

**********

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

Reviewer #1: 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

**********

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

**********

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: (No Response)

**********

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.

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Reviewer #1: No