PONE-D-24-41844Diagnostic and treatment delay in extrapulmonary tuberculosis and association with mortality: experiences from Mbeya, Tanzania.PLOS ONE

Dear Dr. Grønningen,

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 Jan 09 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.

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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.

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We look forward to receiving your revised manuscript.

Kind regards,

Tebelay Dilnessa, MSc

Academic Editor

PLOS ONE

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Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

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Additional Editor Comments (if provided):

• The paper generally requires intensive revision. That is, it requires a through edition, revision and proofreading in terms of typographically, punctuation and grammatically.
• I would like to advise the author to structure the abstract as: Background, Objective, Method, and Conclusion.
• Add key words to the main document.
• In the abstract and result, the absolute number (numerator and denominator) is needed together with the percentage. For example, A/B (17.7%).

• In the introduction part, the rationale is not explained well. Why you did this research? What has been done before, what is known before and which you intend to fill?

• Statistical analysis
• All ‘headings and subheadings’ should be bold.
• Please bring the following contents with headings above the reference lists. Acknowledgment, data availability statement, conflict of interest and author contributions.
• Figures are too poor and you have to prepare them again.
• The references were not written properly. All references should be written correctly according to Vancouver style.
• Use the alignment ‘Justify’ for the text throughout the manuscript
• Follow the standard binomial nomenclature, italize journal name and the word ‘et al’
• Follow the guideline for manuscript writing protocol for 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: Partly

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

Reviewer #1: No

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 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: No

Reviewer #2: No

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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: Information on mortality associated with diagnostic and treatment delay in extra-pulmonary tuberculosis is valuable data for the TB program. The manuscript needed major revision before it proceeded to the publications.

Major comments

Provide a clear description of what information is extracted from the previous studies and the information collected for this study. A precise detail is required on the data collection methods such as the source data and verification methods/quality control used.

Make sure that only information relevant to this study is included in the definition, and include a citation for each term.

The exclusion criteria are not clear. Certain patients such as those who failed to provide information on diagnostic or treatment delay and who started on ATT before inclusion in the study/diagnostic sampling, have been excluded. But the reason is not indicated or the mortality rate in this group has not been analyzed.

The table’s presentation is not easy to follow. Example. Table 1 adds a p-value and uses a separate column for unadjusted and adjusted OR. What does it mean for antiretroviral therapy coverage? Please check the number of people who do not receive anti-TB treatment (23-table 1 vs 21-text).

The description on health-seeking behavior is mainly focused on the health facilities visited. Consider a different terminology for health-seeking behavior and a concise presentation of key findings.

The result presentation under diagnostic and treatment delay is not easy to follow. Focus on the main findings.

Classifying cases as adenitis and non-adenitis may not be appropriate, while the data showed that most deaths occurred among pleuritis (10/39, 26%), peritonitis (8/39, 20%), and adenitis (6/39, 15%).

The key findings summary (lines 333–338) are remarkable. Besides, add other key findings like proportion of death by site of infection, health system diagnostic delay, and structure the discussion based on the key findings.

Minor comments

Line 27-29: In the abstract introduction, add the major knowledge gap beside the unavailability of data.

Line 30: Add how those 111 EPTB patients are diagnosed.

Line 59: have not analyzed association of diagnostic delay with mortality. Rephrase.

Line 78: does nationally refer to the global or Tanzania?

Line 80-89: Move to method section. Part of the information can be used to describe the study area.

Reviewer #2: line 32; all the patients should be included, not only those that survived

line 34, 35, what corresponding numbers are these? are they percent? and what measure of dispersion is being used? is it IQR or 95% CI?

LINE 39-41; This conclusion is not aligned with the aim stated. how was the diagnostic delay, how was treatment delay. then mention mortality although the authors must make it clear to the readers that they had limited power to make firm conclusions due to small numbers

paper needs review by an English editor for grammatical errors

line 80-89; is about study setting. this should be moved to methods section

line 95: Be clear that this is All cause mortality

Authors should include the study endpoints and how they intended to report them. currently they are not clear

line 146: i recommend the authors rethink the definition of diagnostic delay which include patients history. the recall and reporting bias is almost impossible to control in this approach and the results will have limited relevance to the readers. i recommend the authors limit the time from first contact with a health worker including at other health facilities

line 147: authors should justify why ATT delay includes sampling time. ATT should only be initiated where a diagnosis has been made. this measure will confuse the readers. please clarify

line 163-163: is not clear at all. Authors should clarify how this score is reached for interest of the readers

authors have made no mention of sample size derivation. this is paramount for this prospective cohort study

line 181-188: this section is not clear. Authors have not provided the measurement and outcome variables in the write up. so it is difficult to assess the appropriateness of the proposed analysis.

line 185: this approach is not clear while reviewing the results, both bivariate and multivariate is included in all the tables, not easy to know which was significant at bivariate or not. authors should revisit the analysis plan and follow it in presenting results

line 197: Table 1 is for for descriptive display. authors are advised to show the analysis in subsequent tables. this is otherwise confusing to the readers

i recommend the authors present results in chronology starting with the main outcomes to other factors.

line 269: there is no Box plot figure

line 292: Authors should maintain the same outcome measure otherwise the readers will get confused. let the outcome measures be clearly defined

line 332: i recommend authors to revisit the discussion and focus on the main aims of the study, explicitly state the findings and focus on significant findings on multivariate as associations

line 398-403: It is not clear whether the authors were stating the limitations of the study.

i recommend that the limitations of this study be clearly outlined for the readers

line 405: the conclusion does not align with the presented results. the authors should review and align

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-41844R1Diagnostic and treatment delay in extrapulmonary tuberculosis and association with mortality: experiences from Mbeya, Tanzania.PLOS ONE

Dear Dr. Grønningen,

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 07 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,

Tebelay Dilnessa, MSc

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:

• It needs a through proofreading.
• Line 72: EPTB; a sentence cannot start by abbreviation, write its full form
• Line 181: The description of Fig 1should be described in terms of person, place and time.
• Line 201: Previously I commented to make a correction by saying, ‘Statistical analysis’. Do you have any justification?

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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: (No Response)

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 #1: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

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 #1: Yes

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 #1: Yes

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 #1: The manuscript is revised well. Only a few points are left unaddressed.

The description of the population and study design is extensive. It would be great to structure the information under subheadings such as enrollment, data collection, etc. Also, make sure the data source for the current study is clearly described.

Table 2: The category under referral to this facility is three, but the corresponding number is four. Please check.

Reviewer #3: No further comments. The authors have addressed all the comments.

I think the manuscript is now fit for publication.

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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: No

Reviewer #3: 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.

Diagnostic and treatment delay in extrapulmonary tuberculosis and association with mortality: experiences from Mbeya, Tanzania.

PONE-D-24-41844R2

Dear Dr. Grønningen,

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,

Tebelay Dilnessa, MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: