PONE-D-19-20635

Cost-effectiveness of diagnostic algorithms including lateral-flow urine lipoarabinomannan for HIV-positive patients with symptoms of tuberculosis

PLOS ONE

Dear Dr. Nadia,

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.

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Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

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2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed:

https://doi.org/10.5588/ijtld.13.0630

https://doi.org/10.1371/journal.pone.0170976

https://doi.org/10.1371/journal.pmed.1002792

https://dx.doi.org/10.1371%2Fjournal.pone.0117009

https://halshs.archives-ouvertes.fr/halshs-01241824/file/2015.34.pdf

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed."

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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: Yes

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: The manuscript entitled “Cost-effectiveness of diagnostic including lateral-flow urine lipoarabinomannan for HIV-positive patients with symptoms of tuberculosis” investigates the cost-effectiveness of including lateral-flow urine lipoarabinomannan (LF-LAM) in TB diagnostic algorithm for severely ill or immunosuppressed HIV-positive patients with symptoms of TB. Ten diagnostic algorithms have been elaborated and compared, and make a conclusion that including LF-LAM in TB diagnostic algorithms is cost-effective for severely ill or immunosuppressed HIV-positive patients.

Series of data have been done by authors to confirm the conclusion. However, there are some drawbacks making the paper to be reconsidered, as detailed below, before it can become suitable for publication in “PLOS ONE”.

Specific comments to the paper:

1. HIV patients often have difficulties to produce sputum, thus only the GeneXpert, LF-LAM seem to be fast and effective ways to detect TB. What the purpose of the research? What the novelty of the research?

2. All the figures in the manuscript were not clear, need to revise.

Reviewer #2: Manuscript PONE-D-19-20635: Cost-effectiveness of diagnostic algorithms including lateral-flow urine lipoarabinomannan for HIV-positive patients with symptoms of tuberculosis

Key Results:

In the manuscript, Yakhelef et al. attempt to determine the cost effectiveness of the implementation of urine LF-LAM test for the detection of Tuberculosis (TB) positive patients whom are severely immunocompromised or are HIV positive using previous data from a study conducted at the Homa Bay County Hospital in Kenya. The authors used ten different algorithms, each containing a different combination of TB treatments starting from a smear alone up to combinations containing a mixture of LF-LAM, Gene Xpert from sputum, Gene Xpert from urine and X-ray detection. Their findings were reported in cost/patient/year in Euros as well as disability adjusted life year (DALY). From their analysis, the authors found that the greatest cost for treatment was anti-tuberculosis drugs (€41.42) and the cheapest costs was the chest X-ray (€1.12). When looking at the total cost/algorithm, the most expensive was A10 consisting of LF-LAM, Xpert from sputum and chest X-ray (€9758), while the least expensive was A2 consisting of LF-LAM alone (€5612). The mean DALY scores were found to be 1118 at its lowest for A1 and 1651 at its highest for A10. Using a cost effectiveness ratio, ICER, the authors determined that the two algorithms with the highest ratios were A2, detecting an additional 23 patients and decreasing costs by €87 as compared to A1, and A8, detecting an additional 10 patients and decreasing costs by €225 as compared to A7. Both of these findings indicate that adding LF-LAM to TB testing may decrease costs while increasing detection. Overall, the authors came to several conclusions: First, that adding LF-LAM testing to current methods is cost effective. Additionally, using LF-LAM in place of chest X-rays has the ability to detect more TB positive patients. Next, replacing Xpert in urine with LF-LAM is more cost effective and lastly, when comparing all of the algorithms to each other, A10 emerges as the most cost effective and most efficient overall if the country had the funds to implement it.

Validity:

After reading this manuscript, I believe that the concepts and findings of this study are valid and novel and may help provide further insight into the reduction of cost of TB diagnosis in resource deprived areas of the world.

Originality:

The results of this manuscript are original and significant. Further studies are needed to incorporate these findings into policy and influence policy makers, however, the authors address this issue in the paper.

Data and Methodology:

The data and methodology of this manuscript are valid and presented in a clear and concise manner. All data is presented clearly and are easy to interpret.

Appropriate use of Statistics:

The statistics in this manuscript are presented properly with a description of methods used, the proper numbers and significance values.

Conclusions:

Based on the experimental design and results presented, the conclusions present as valid and reliable.

Suggested Improvements:

Minor revisions:

- Introduction: This paper focuses on the LF-LAM assay, however, the assay is not described anywhere in the manuscript. Please consider adding a brief overview of the assay to familiarize the reader with what it does.

- Line 110: The title of your figure should give the reader a brief description of what they are looking at. Please consider revising this title as well as those in other figures and tables in the manuscript as many are very sparse in description.

- Cost estimation: Line 129: The acronym IPSOR is used without definition. Please define.

- Cost estimation: Line 163: The acronym CXR is used without definition. Please define.

- Cost estimation: Line 155: “pipette” should be plural in this case, should be “pipettes”

- Cost estimation: Line 164: Here and in several places in the manuscript you indicate that a 4% discount was applied, however, I could not find the reasoning for this discount. Please consider adding an explanation to the manuscript.

- Line 173: “Tables 1” does not need to be plural in this instance, should be “Table 1”

- Study population: Line 199: Are these all of the statistics that are available for the patients? Consider adding additional statistics if possible.

- Study population: Line 200: “patients had a confirmed TB” should not have an “a”. Should read “patients had confirmed TB”

- Line 218: “Tables 3” does not need to be plural. Should read “Table 3”

- Line 249: “Figures 2” does not need to be plural. Should read “Figure 2”

- Line 256: The acronym WTP is used without definition. Please define.

- Lines 274-279: This paragraph is very confusing the way that it is written, please consider revising.

- Line 326: The acronym GNI is used without definition. Please define.

References:

References are cited properly and addressed properly where needed.

Clarity and Context:

The abstract, introduction and conclusion contain the proper information that will engage the reader and provide insight to the paper as a whole.

Scope of Expertise:

None of the material presented were out of the scope of my expertise. All were logical and easily understood.

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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 to be viewed.]

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PONE-D-19-20635R1

Cost-effectiveness of diagnostic algorithms including lateral-flow urine lipoarabinomannan for HIV-positive patients with symptoms of tuberculosis

PLOS ONE

Dear Dr. Nadia,

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. 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

[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

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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 #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: The revised manuscrip covered all my comments, while there are still exist several minimal mistakes in the revised mauscript.

minimal comments:

1. In line 152, there are two dots, remove one.

2. In the revise manuscript, several references "underline", remove the underline. such as, in line 181, 185, 189, et al.

3. In line 156, reference [17], [19], should be changed into [17, 19].

4. In line 158, in the sentence “number of patients/day", should be changed into "number of patients per day".

5. In line 160, "First" should be changed into "Firstly".

6. In Table 1, in the setences "Age at oneset of disablity a" and "Age of death a", what the word a stand for?

7. In the line 201, the reference [23-24], shoukd be changed into [23, 24].

8. In the line 213, the reference [17-18], shoukd be changed into [17, 18].

9. In the line 222, 100~199 cells/u, should be changed into 100~199 cells/uL.

10. The references in this manuscript should be adjust to fit the PloS One. I saw many differences in the references, such as reference 10, 201-9, should be changed into 201-209. Please doubcheck the references.

Reviewer #2: None. The authors have addressed all of the suggestions that were put forth by me in the initial review. Thank you.

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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 #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 diagnostic algorithms including lateral-flow urine lipoarabinomannan for HIV-positive patients with symptoms of tuberculosis

PONE-D-19-20635R2

Dear Dr. Nadia,

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: 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: The revised manuscript covered all my comments.I have no comments to the authors. Thus, I recommend to accept this manuscript.

Reviewer #2: The authors had addressed my issues and concerns in a previous revision. I have no additional comments.

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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 #2: No