PONE-D-20-20339

Implementation of GeneXpert MTB/Rif proficiency testing program: A Case of the Uganda national tuberculosis reference laboratory/Supranational reference laboratory

PLOS ONE

Dear Kabugo,

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. In addition to reviwers comments, it is noted that the text has similarity to atleast one other study PMID : 30567748. So, the text must also be revised for oroginality. 

Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact.

==============================

Please submit your revised manuscript by November 28, 2020. 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:

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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.

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,

Pradeep Kumar, Ph.D.

Academic Editor

PLOS ONE

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2. Please upload a copy of Figures 1-5, to which you refer in your text. If the figures are no longer to be included as part of the submission please remove all references to them within the text.

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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: Yes

Reviewer #2: Partly

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

Reviewer #1: I Don't Know

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: No

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: • What is the reason behind author’s choice for using autoclaving as an inactivation method when SR reagent is a proven method of inactivation for Mtb? Did the authors conduct any studies to verify that autoclaving does not impact the GeneXpert results?

• Further, authors note that samples are stored at 2-8C for 42 days until results from MGIT are verified for inactivation. Does this long storage of samples have any impact on the results? Were any experiments conducted?

• It is noted in the supplementary section that samples are shipped at ambient temperature. Were overnight shipment methods used? What was the longest it took for samples to arrive at a designated laboratory? Was there any correlation with long transit times and discordant/invalid results? In other words, did long transit times lead to sample degradation and hence invalid results?

• Authors are requested to provide an original reference for lines 110-111 for the detection limit of GeneXpert MTB/RIF test.

• Under supporting information, authors listed figures 1 to 5 as S1 Fig 1, S2 Fig 2 etc., Please clarify which figures belong in the main manuscript and supplementary sections respectively.

• There is no information about the process behind obtaining ISO accreditation. Some detail about what changes were made to the SOPS to align with ISO’s requirements and how this aided in study’s success supporting lines 438-439 would be helpful.

• Authors note that the major cause of false results is clerical errors. Did the authors consider using automated GeneXpert test reports instead of manual reporting?

• Were the panel of strains freshly prepared during each around? Please clarify in methods section.

• How are the results reported when a test reports no MTB detected but RIF sensitivity/resistance is detected?

Minor comments:

• Authors are requested to expand the acronyms the first time they appear in the manuscript.

For example, PT in line 25, EQA in line 61, QMS in line 85 etc.,

• Similarly, authors use proficiency testing and PT interchangeably throughout the manuscript. For consistency authors should either stick to the acronym or the expanded version not both.

• Authors are advised to thoroughly revise the manuscript for grammatical errors and sentence formation for clarity in several areas.

• In lines 351-353, machine calibration is mentioned twice as one of the issues.

• Please rephrase lines 27-28 of abstract to “conducted between years 2015 to 2018” for clarity

Reviewer #2: Overall

This paper reports data from a cross-sectional study assessing the testing accuracy of the GeneXpert MTB/RIF assay in laboratories linked to the Uganda National Tuberculosis Reference Laboratory and assessing whether a program of GeneXpert proficiency testing in Uganda led to improved testing accuracy among participating laboratories. As the authors well describe in the introduction, national TB programs in resource-limited countries, especially in sub-Saharan Africa, have not generally established proficiency testing for GeneXpert MTB/RIF. This is a novel and interesting piece of work because it shows that setting up a persistent country-wide proficiency testing program for GeneXpert can lead to increased testing accuracy through root cause analysis and assistance and advice from a reference laboratory. However, a number of important inconsistencies and errors in the results section need to be corrected before the manuscript is suitable for publication, and I have concerns about the 80% threshold used to judge a laboratory as satisfactory. The manuscript would also benefit from a more in-depth discussion of the headline result that average laboratory scores increased the more rounds of the testing program they participating in. The article is intelligible but would nevertheless benefit from independent editorial assistance to improve the style and occasional grammatical errors. Below are my numbered comments and recommendations:

Introduction

1. Line 61: EQA should be defined as it is its first use.

2. Overall, the introduction explains the background to the study well, including the Uganda-specific situation and gives a good definition of proficiency testing.

Methods

I am unable to comment on the methods of the PT panel preparation as this is outside my area of expertise.

3. Line 242-4: I don’t understand why the scoring threshold in set at 80%, or even expressed as a percentage at all, because it gives the impression of greater accuracy than is truly available from your testing system, in which each laboratory tests 4 samples. 6 out of 8 points gives 75% (unsatisfactory) and 7 out of 8 gives 87.5% (satisfactory). So to be judged satisfactory, laboratories have to correctly test all 4 samples (100%), or correctly test 3 samples and have one error/invalid/no result (87.5%), but will automatically be judged unsatisfactory if they give one of more incorrect results. This system is fine, but it would be better would be to express the threshold as 7 out of 8 points for clarity.

4. Currently the names of the study rounds are very confusing and difficult to keep track of, with round 2 followed by round 1 followed by round 2 followed by round 1. Much better would be to make the numbering sequential, along the lines of: Pilot study, Round 1 (2016), Round 2 (2017), Round 3 (2017), Round 4 (2018). Or alternatively: Pilot study, 2016, 2017a, 2017b, 2018.

5. I have no ethical concerns, or concerns about the statistical methods.

Results

6. There are significant discrepancies between the numbers in Table 1 and Table 2. For the pilot study, Table 1 says that 48 results were returned but Table 2 has 48+3=51 results. Round 2 2016 and Round 1 2017 have consistent numbers between the two tables, but Round 2 2017 has 104 results returned in Table 1 but 100+5= 105 results in Table 2 and Round 1 2018 has 134 results returned in Table 1 but 115+4=119 results in Table 2. So 3 out of 5 are inconsistent.

7. Additionally, Line 288 says: “There were a total of 19 unsatisfactory results form 15 laboratories”. However, according to Table 2, there were 3+12+7+5+4=31 unsatisfactory scores. And then line 347-8 says: “3 out of the total 19 sites with unsatisfactory scores…”

8. Lines 308-310: These results are not in fact shown in Table 2 and Figure 3. Table 2 shows 29 discordant results, not 23. Presumably, those additional 6 discordant results came from laboratories which had more than one discordant result. Table 2 would be more useful if updated to show the number of laboratories with at least one discordant result in each round, rather than the total number of discordant results, possibly with the breakdown of false positives/negatives/resistant/sensitive below.

9. Lines 305-7: These lines are not results and should be moved to the discussion section.

10. Line 337-9: These lines are not results and should be moved to the discussion section.

11. Lines 275-6, 292-4, 298-300 and 310-11: These points are very interesting, and the odds ratio of 2.5 is one of the major results you report in the abstract, so I feel they deserve a graph or table of their own, showing the average scores (or number of satisfactory and unsatisfactory results) of laboratories in the first round they engaged in, and the second round, third round and fourth round for those which engaged in multiple rounds. One purpose of the study was to see whether continual participation in the proficiency testing program would improve the quality of TB testing results, which it appears to, and this graph or table would present this data in the clearest way.

12. Line 350-360: This list of issues could be made more useful if the frequency with which each issue arose was displayed.

13. It would be useful to see results broken down by whether the laboratory was inside or outside Uganda. I can see potential for the impact of the proficiency testing to be different for laboratories outside Uganda. Or if there was no significant difference, add a comment to say there was no difference.

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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-20-20339R1

Implementation of GeneXpert MTB/Rif proficiency testing program: A Case of the Uganda national tuberculosis reference laboratory/Supranational reference laboratory

PLOS ONE

Dear Dr. Kabugo,

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 addresss reviewers comments and I would like to draw attention to a thorough review of langauge.

Please submit your revised manuscript by Mar 06 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Pradeep Kumar, Ph.D.

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: (No Response)

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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: I Don't Know

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: No

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: In this revised version of manuscript titled “Implementation of GeneXpert MTB/Rif proficiency testing program: A Case of the Uganda national tuberculosis reference laboratory/Supranational reference laboratory” authors addressed most of the comments made by the reviewers. Important corrections were made in the results section and additional tables were included as per the suggestions of one of the reviewers. However, there are few additional corrections and discrepancies noted in the results section that need to be addressed before the manuscript is acceptable for publication. Further, the manuscript requires thorough revision to address typographical, grammatical errors and paraphrasing in certain sections for clarity. Following are my comments:

• In table 2, the percentage for round 2 should be corrected to 93.33 instead of 94.1

• Numbers in tables 3 and 4 do not make sense. For example, in table 3, how did the labs participating for the third time increase to 51 in round 2. Also, numbers 50 and 43 in round 4 also do not add up.

• Similarly, in table 4 how did the laboratory scoring unsatisfactorily for the 5th time appear while there are zero instances of 4th time. The results in the table also does not match the text in lines 335-338. Authors are requested to carefully revise and address.

• Lines 168-172: Authors performed a 20-fold dilution from 1.0 x 10^6 bacilli/mL. This will achieve a concentration of 5 x 10^4 bacilli/mL and not 1.0 x 10^4 bacilli/mL. Authors are requested to clarify. What is the final concentration tested on geneXpert?

Minor comments:

• Lines 51-54 and 210-211 may be rephrased for clarity.

• Please explain the relevance of lines 153-155

• Table 5 needs formatting adjustments for the headers to match the columns. Also, for consistency, authors may follow similar table formatting throughout the manuscript.

• Figure 1 has a typographical error in steps 4 and 5 (contious). The word pursued in misspelled in line 34 of abstract.

• Capitalization of words in the middle of a sentence is noted in several areas of the manuscript. For example – line 27 (Panels); line 29 (Laboratories); line 64 (Support Supervision). Authors are suggested to revise such areas.

Reviewer #2: The manuscript is much improved from the previous version. Figure 4, Table 5 and Table 6 are all good additions to the manuscript. However, there are still some errors and inconsistencies in the tables. My numbered points are below:

1.

Table 2:

Discordant results read: 3, 6, 5, 10, 7

Table 5:

Discordant results read: 3, 6, 5, 3, 5

2.

Table 5: Column values for false negative M. tb add up to 11 (1+2+1+3+4) but total says 10

3.

Table 5: Round 4 (2017) should read Round 4 (2018)

4.

Line 368-9: “The lowest number of errors/invalids/no results was reported in Round

369 4 (2018) and highest in Round 1 (2016) with errors reported as shown in Table 5”

This is misleading because from Table 5 one would say that the lowest number was in the pilot study or Round 3 (2017) and the highest was in Round 1 (2016). I presume you’re talking about the errors/invalids/no results as shown in Table 1. This comment should therefore be moved to Table 1.

5.

Line 64: First use of PT in the text (as opposed to the introduction) so should be “Proficiency Testing (PT)”

6.

Line 97: “Mycobacteria. Tuberculosis complex” should be “Mycobacterium tuberculosis complex”

7.

Line 154: is this supposed to have an error message?

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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.]

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-20-20339R2

Implementation of GeneXpert MTB/Rif proficiency testing program: A Case of the Uganda national tuberculosis reference laboratory/Supranational reference laboratory

PLOS ONE

Dear Dr. kabugo,

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 May 31 2021 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: http://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,

Shampa Anupurba, MD

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 (if provided):

Line 55- ' mycobacterium tuberculsosis ' to be corrected to 'Mycobacterium tuberculosis'

Line 168- ' mgit and lj' to be written as MGIT and LJ and also expanded.

Line 421- 'It is at this phase were...'- were may be replaced by 'where'

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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 #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: (No Response)

**********

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

Reviewer #2: (No Response)

**********

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: (No Response)

**********

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: (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.

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

[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.

Implementation of GeneXpert MTB/Rif proficiency testing program: A Case of the Uganda national tuberculosis reference laboratory/Supranational reference laboratory

PONE-D-20-20339R3

Dear Dr. kabugo,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 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,

Shampa Anupurba, MD

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: 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 #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: (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.

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