PONE-D-21-01797Improved survival of non-small cell lung cancer patients after introducing patient pathway management: a retrospective cohort study with propensity score weighted historic controlPLOS ONE

Dear Dr. Vokó,

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 Oct 28 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Samer Singh, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Dear Dr Zoltan Voko,

The manuscript has been reviewed by three reviewers. Their overall comments have been positive.

However, some issues and concerns have been underlined for improving the manuscript. The comments from reviewers are appended below the message for addressal.

Additionally, elaborate on statistical (counterfactual) analysis, and why alpha = 0.05 for HR and PETCT analysis would be sufficient for decision making, given the potentially severe consequences of such a decision in the current case.

In case extra time is required to revise the manuscript and address the concerns/comments you may request it through system.

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2. In your Methods section, please ensure that all variables included in the analyses have been adequately defined.

3. Thank you for stating the following in the Competing Interests section: "I have read the journal's policy and the authors of this manuscript have the following competing interests: the described research was conducted as part of the H2020 SELFIE project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634288. JGP, MCs, MRM, KI, ZK, and ZV are employees of SELFIE beneficiaries. The employer of JGP, MCs, ZK, and ZV received additional EU research grants related to the evaluation of smoking cessation interventions and national cancer screening programs.  MM, ÉSE, GL, and ASz are employees of Móritz Kaposi General Hospital, this Hospital initiated the OnkoNetwork program and received study funding from the SELFIE grant."

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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 authors use a retrospective cohort study to evaluate the implementation of the OnkoNetwork on overall survival for patients with non-small cell lung cancer. This is a single institution study conducted at Moritz Kaposi General Hospital. The authors should be commended for rigorously evaluating a care delivery implementation that has the potential to improve care for oncology patients. I have the following recommendations for strengthening this manuscript.

1) The introduction should define in specific terms the "patient pathway management." After reading the manuscript, I was uncertain about how the authors define patient pathway management. For example, the American Society of Clinical Oncology defines a pathway as "detailed, evidence-based treatment protocols for delivering cancer care to patients with specific disease types and stages." Are the authors referring to the same type of treatment pathways? The main thrust of the introduction is around timeliness of care and biases. I think this could be shortened and further detail could be added around clinical pathways and how this study seeks to add to the pathways literature in oncology. The authors could cite various studies that have evaluated pathways in oncology and lung cancer such as DM Jackman, Journal of Oncology Practice, 2017 along with Neubauer MA, Journal of Oncology Practice, 2010.

2) The components of the OnkoNetwork are not well described. I was uncertain of what the OnkoNetwork intervention was in practice. I think the manuscript would benefit from revising lines 85 - 88 to more specifically list the components of the intervention. How is the Onkonetwork different from standard of care. Perhaps the authors could include a diagram or figure as well.

3) In lines 115 - 177, the authors write the intervention cohort was defined as patients with a "new solid tumor" diagnosis. However, wasn't it actually patients with a new non-small cell lung cancer diagnosis? I would revise to make more clear.

4) The data for the 2 cohorts are from 2014 - 2015 and 2015 - 2016. It is now 5-years old. The authors should provide some detail on why they are using data from several years ago to conduct their analysis and how this could impact their findings.

5) In the results section (line 190 - 191), the authors write that enrollment into the OnkoNetwork was 0% in the control and almost 100% in the intervention. I had assumed that to be expected given the design of the study. I was confused why the intervention group wasn't 100% enrolled in OnkoNetwork. Furthermore, do the authors need this statement given the methodology of the study design.

6) The description of the overall survival in the results could benefit from further clarification. Specifically, did the implementation of the Onkonetwork lead to the improvement in survival or did the intervention group include a greater proportion of earlier stage patients and that is what led to the improvement in survival. I would ask the authors to review lines 248 - 249 where this is discussed and add further clarity. This is also discussed in the conclusion, lines 313 - 315.

7) I think the conclusion would benefit from further discussion of how this manuscript adds to our knowledge of oncology clinical pathways and pathway management.

Reviewer #2: Overall the manuscript is well written and have addressed importance of health care management in patient outcome.

However, there are few points need to be taken care of before accepting the manuscript for publication.

This is an observational study where the authors have compared the overall survival of patients with NSCLC either have treatment delay or not. The exclusion and inclusion criteria used for the study patients are clear; however, the recruitment of patients to control and intervention cohorts were non-randomised. This process could have introduced biased in the cohort selection. The authors have used propensity score to reduce bias, yet it is important to highlight the impact of randomisation in this study.

Was the treatment regimen across the cohort uniform? If not, then it is important to discuss that how could different regiment impact on survival. In the intervention cohort, more patients underwent surgical resection, this could have contributed to the overall survival of the patients compared to those only have received chemotherapy. While comparing overall survival, uniformity in treatment regimen should be considered amongst the groups.

The quality (resolution) of the graphs need to be improved, it is difficult to read and interpret.

Reviewer #3: Overall the paper is well presented although the language should be improved to increase readability.

Major:

Line 240: The p-value of the HR is given as p=0.039. What test has been used? I assume alpha = 0.05 which then it is significant. However, in a medical context a significance level of alpha = 0.001 should be used in which case it is not significant. Discuss!

Line 250: P-value = 0.055 for PETCT. This is even not significant for alpha = 0.05 and not at all significant for alpha = 0.001.

It seems the key results of the paper show no statistical significance. Discuss!

Minor:

The language of the paper should be improved.

Section title 'Descriptive analysis'. In this section a survival analysis is discussed which is not a descriptive analysis. I suggest to change the section title.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-21-01797R1Improved survival of non-small cell lung cancer patients after introducing patient navigation: a retrospective cohort study with propensity score weighted historic controlPLOS ONE

Dear Dr. Vokó,

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 19 2022 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,

Samer Singh, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The study finding would be an excellent addition to the existing knowledge base. However, appropriate statistical treatment of the data remains desirable. For this reason alone, I am inclined to place it as a major revision.

The authors would like to suitably address the concerns of Reviewer number 3.

Additionally,

The statistical methods/methodology be sufficiently elaborated, and the discussion enriched accordingly to make the point.

The authors would like to be conservative while drawing the conclusion from their data.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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 #2: Partly

Reviewer #3: Partly

**********

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #3: No

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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 #2: 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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The following review relates to the statistical analysis.

Overall, the paper uses advanced methodology to address an interesting problem. The main problem of the paper is that the methodology is not motivated nor alternative approaches are discussed. Furthermore, the statistical methods are not presented in a way as needed for such an article.

Propensity score: A discussion of the propensity score needs to be presented explaining why it is needed and why there are no alternatives. Add citations to methodological papers disucussing this in detail.

Counterfactual analysis: The same needs to be provided for the counterfactual information.

Rubin's B and R statistics: Same as above.

Results section:

What are the p-values for the Kaplan Meier analysis?

For each analysis it needs to be clear what samples have been used.

A statistical hypothesis test is not a descriptive analysis! (page 10, line 191) This is wrong and needs to be corrected.

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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

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.

PONE-D-21-01797R2Improved survival of non-small cell lung cancer patients after introducing patient navigation: a retrospective cohort study with propensity score weighted historic controlPLOS ONE

Dear Dr. Vokó,

Thank you for submitting your manuscript to PLOS ONE. The reviews of the manuscript are appended below. Some minor clarification regarding the sample size, statistical analysis and its presentation as raised by the reviewers is required. 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 Oct 01 2022 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,

Samer Singh, Ph.D.

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.

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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: (No Response)

Reviewer #4: (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 #2: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #4: 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

Reviewer #4: 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

Reviewer #4: 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: Minor revision:

For counterfactual analysis, please mention if the baseline characteristics were selected from control cohort or intervention cohort.

If selected from control cohort, is it possible that the survival benefit difference may increase or reduce between intervention and hypothetical cohort?if yes, then one of the possible explanation may be that owing to the propensity score matching using control group baselines characteristics may not make a difference for the analysis. Is there any other possible explanation? This should be discussed in the discussion.

Reviewer #4: The authors present results from a study on the impact of patient navigation for non-small cell lung cancer patients in Hungary on survival. Authors use propensity score weighting to address imbalance in the group that had access to patient navigation and the historical control cohort that did not have access to patient navigation. Authors demonstrate improved survival in the group that had patient navigation, though this difference did not remain after accounting for post-baseline clinical measures (which showed some potential imbalance (though not statistically significant) even after weighting). The manuscript will be strengthened if authors consider the following points.

1. To avoid confusion between Table 1 sample sizes and the at risk numbers given for the K-M curves in Figure 2 for the weighted sample, authors may want to clarify that the weighted sample size is 120.

2. It is not clear to me why authors included all of the baseline variables in the Cox model, since the propensity score weighting was done to approximately balance these variables between groups.

3. Throughout the manuscript, authors state that groups are "similar" or distributions are "similar". A non-significant p-value does not prove a lack of difference between groups. This is a minor point, since readers can refer to the tables to evaluate how "similar" they feel groups are on certain characteristics, but authors should keep this in mind when reporting results.

4. In my first read of the manuscript, I was a bit confused by Figure 3, since it wasn't clear to me what percentages were being shown. I thought initially it had to do with survival in the groups among those who had particular characteristics, since this was being shown after the Cox results. I realized that these are just the observed/weighted percentages in the two groups (as is presented in Supplementary Table S4a). Authors may want to refer readers to this table when mentioning Figure 3 in the text, to clarify.

Minor edits:

1. line 82: authors need to add a ")" after "groups" to close the parentheses from earlier in the sentence.

2. line 162: "Study data was" should be "Study data were"

3. line 190: "study data is" should be "study data are"

4. lines 238, 240: STATA should be Stata: https://www.statalist.org/forums/help#spelling

5. line 239: "using a" should just be "using"

6. Table 2: There are a couple of significant results that are not bolded, and a non-significant result that is bolded. Authors should be consistent in their use of bolded results. Also authors are missing a "]" for the CI for Urban residence in the multivariate baseline characteristics model.

7. line 397: "(Table 3) was" should be "(Table 3) were"

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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 #2: No

Reviewer #4: 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.

Improved survival of non-small cell lung cancer patients after introducing patient navigation: a retrospective cohort study with propensity score weighted historic control

PONE-D-21-01797R3

Dear Dr. Vokó,

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,

Samer Singh, Ph.D.

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 #4: 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 #4: (No Response)

**********

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

Reviewer #4: (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 #4: (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 #4: (No Response)

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Reviewer #4: (No Response)

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Reviewer #4: No

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