PONE-D-19-15042

Cost-Effectiveness of QuantiFERON®-TB Gold In-Tube Versus Tuberculin Skin Test for Diagnosis and Treatment of Latent Tuberculosis Infection in Primary Health Care Workers in Brazil

PLOS ONE

Dear Dr. Braga,

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.

We would appreciate receiving your revised manuscript by Aug 31 2019 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

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

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

[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: 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 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: No

Reviewer #2: No

**********

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 was an interesting and informative study comparing cost effectiveness of 5 strategies for diagnosis of latent TB in health care workers in Brazil. The evaluation was based on a hypothetical cohort of 10,000 HCW. Outcomes evaluated included number of individuals correctly classified and number of TB cases avoided. The conclusions of the study were that TST with a ≥10 mm cutoff was the most cost saving strategy for diagnosis of latent TB in this population.

Overall: The text is a bit difficult to read with some issues with word order, etc that I believe are a byproduct of the translation to English. I would suggest having a native English speaker edit the manuscript if possible.

Minor points:

Authors use both 10 mm and ≥10 mm throughout the manuscript. ≥10 mm should be used consistently.

Line 49: Suggest editing to say “preventing active disease” or “identification of latent and active disease in an effort to reduce transmission”

Lines 51-53: Suggest updating to more recent statistics.

Lines 118-122: This text is repetitive with the figure legends and unnecessary.

Line 129: Please edit title of Figure 2 so that it is not identical to the title of Figure 1.

373-375: The effectiveness of all strategies in regard to number of tuberculosis cases avoided is very similar. Is the difference between the strategies statistically significant? Mention should be made of the closeness of all strategies for this measure of outcome effectiveness.

Line 440: “…the change in the most cost-effective strategy was a result of the substantial increase in costs.” Suggest describing which costs were increased.

Line 494: define STF

Table 1: I do not understand the calculation for “Cost of Complete LTBI Treatment(6months)”, “Cost of Partial LTBI Treatment (3 months)” or “Cost of Active TB Treatment”. Why do line items for the drug(s) used for treatment have “(month)” beside them? Does this mean that this is the cost for one month? If so, the calculations for the total cost of treatment are incorrect since the values have only been included once. If these values actually represent the cost of drug for the entire duration of treatment why do they have “(month)” beside them?

Discussion: There is no discussion of the comparable results for all the tests for number of cases avoided.

Other Suggestions:

• I think that the addition of number-needed-to treat (the number of people treated for LTBI to prevent an active TB case) for each strategy would be an interesting and valuable addition to the study.

• Authors mention that adherence to LTBI treatment by HCW is low due to the known false-positivity rate of TST. Is the adherence rate to LTBI treatment for individuals diagnosed with QFT known or can it be realistically estimated? Would it be possible to do a cost calculation for TST vs QFT using different adherence rates for each test? This could be really important since the rate of adherence to LTBI treatment was one of the most impactful variables in the cost effectiveness calculations and would also likely impact number of active TB cases avoided.

Reviewer #2: The paper present interesting data investigating the cost effectiveness of QuantiFERON®-TB Gold In-Tube and Tuberculin Skin Test for Diagnosis and Treatment of Latent Tuberculosis Infection in Primary Health Care Workers in Brazil. The method section is well explained, however the result and discussion sections need to be restructured in a better way.

The tables in the results section (especially table 4) are too large, they need to be presented in a more efficient way. a summarizing table can be used and the rest of the data can be attached to the paper as supporting information.

The manuscript need to be English edited in a very detailed way. Many of the sentences are too long and contain grammar and formulation mistakes.

Some suggestions and comments below:

Line 59: add more recent statistics

Line 65: is considered as a priority by WHO in controlling the disease ??

Line 138: do you mean true positives and true negatives?

Line 181: cut-off

184-185: data based on...

351-352: column 2 in table 2, is it the total cost, if so mention it

453: what do you mean by study contacts?

471: are you comparing the study results to other studies performed outside of Brazil? if so, find a good way to make the transition between this paragraph and the previous one

549-550: this paragraph is out of context, you will need to develop it further and find a way to link it to the previous paragraph (or you can delete it)

**********

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: 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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Cost-Effectiveness of QuantiFERON®-TB Gold In-Tube Versus Tuberculin Skin Test for Diagnosis and Treatment of Latent Tuberculosis Infection in Primary Health Care Workers in Brazil

PONE-D-19-15042R1

Dear Dr. Braga,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With 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

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: (No Response)

Reviewer #2: Yes

**********

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

Reviewer #1: (No Response)

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: (No Response)

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: (No Response)

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 going over the manuscript again for correct English translation. Please check reference numbers throughout the manuscript for accuracy...I do not believe that the references indicated in lines 54 and 56 are the correct references for these statistics. Additionally, an analysis of the additional cost incurred by the high number of false-positives that would be inappropriately treated using the TST>=10mm strategy vs. other strategies and the total impact of this on the cost effectiveness would be beneficial.

Reviewer #2: I suggest to go through the manuscript one more time and correct the typos (e.g: 145-146: treatment of TB....)

**********

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 #2: No