PONE-D-22-17578Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy.PLOS ONE

Dear Dr. Ayyar Gupta,

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. Your manuscript has been assessed by two reviewers whose reports can be found below. As you will see from the comments, the reviewers have raised a number of concerns that need attention. They request additional information on methodological aspects of the study and clarifications to the statistical analyses/results. Could you please carefully revise the manuscript to address all comments raised?

Please submit your revised manuscript by Sep 29 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.

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Staff Editor

PLOS ONE

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2. 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:

Senior authors in the study have been involved in clinical trial as PI or have been involved in advisory boards but has no influence on the topic reported in this study and does not alter our adherence to PLOS ONE policies on sharing data and materials.

Dr Niks reports consultancies for BioMarin, Summit and WAVE for which reimbursements were received by the LUMC. 

Dr de Groot has received consulting and education fees from PTC Therapeutics, Santhera, Biomarin/Prosensa. 

Dr Hogrel has received consulting fees from Biogen, Sarepta and Minoryx.

Prof Servais has received consulting fees from Roche, Biogen, Avexis, Cytokinetics, Sarepta, Biomarin, Santhera, Servier, Biophytis and Dynacure. He is coordinating natural history studies funded by Valerion, Dynacure and Roche. 

Dr Mayhew has received consulting fees from Roche, Novartis (Avexis), Biogen, Rehenxbio, PTC, BMS/Roche, Sarepta, Italfarmaco, Pfizer, Summit, Catabasis, Santhera, Vision, Mallinckrodt , Lysogen, Modis and Wave 

Prof Straub received speaker honoraria from Sanofi Genzyme and has participated in advisory boards for Audentes Therapeutics, Biogen, AveXis, Pharmaceuticals, Pfizer, Roche, Sanofi Genzyme, Sarepta Therapeutics, Summit Therapeutics and Wave Therapeutics. 

Dr Ricotti is co-founder, EVP , CMO of DiNAQOR, and served as a consultant for Solid Biosciences and Antisense Therapeutics.

Prof. Muntoni reports grants from Sarepta, grants from Wave, grants from PTC, personal fees from Avexis, Roche, Pfizer, Dyne Therapeutics, Sarepta, outside the submitted work."

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3. 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. 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

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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: Dear Dr. Gupta and colleagues.

Thank you for the opportunity to review this manuscript. I find this manuscript incredibly important, and attempts to address the very difficult topic of minimal clinically important differences in quantitative functional skills, specifically the Northstar Ambulatory Assessment (NSAA). As the field of Duchenne muscular dystrophy continues to evolve with emerging clinical trials, the importance of outcome measures remains critical for governmental approval agencies, private Biopharma corporations, and public academic research groups. I really appreciate, and acknowledge the authors attempts to include patient perceived differences in attempting to quantify a qualitative measure.

I share all of my constructive feedback with the best of intentions, not only to improve this manuscript, but to also help the field in a more broad sense. The manuscript overall is written very well, and the authors express their findings in a clear, coherent, and concise manner, which is always appreciated by reviewers. Several broader questions, which may not be able to be applied to this manuscript in a post-hoc manner are raised, for both my academic curiosity, and to plant the seeds for future investigations. I have attempted to highlight my suggestions in a methodical manner as laid out below.

General:

1. Please make sure that the figures and tables are labeled appropriately. Oftentimes I noticed that they are referred to as “Table1” instead of “Table 1”.

Introduction:

- Paragraph 2: when discussing the standards of care for treatment, it may be worthwhile two add in the multitude of clinical trials in process (different ASO targets, small molecules, biologics, AAVs, etc…) To highlight the importance of outcome measures in clinical trials.

- Paragraph 4: please consider adding these reference to the supplemental figure of the north star ambulatory assessment when discussing the NSAA.

- Paragraph 5: The importance of age is loosely referred to when interpreting the NSAA, but it may be worthwhile to include an explicit statement and what longitudinal studies of the NSAA have shown in DMD, and the impact of age dependency when interpreting NSAA results in this paragraph.

Methods:

1. Is it possible at all to combine cohort one and two? Certainly this may not be possible given differences in data collected of each of the groups, but may simplify latter analysis.

Results

1. Table 1: This table can be made much clearer, and should include information such as age, baseline NSAA scores, baseline 6 minute walk test data, clinical trial involvement, type of mutation (and location if known), age of diagnosis. If keeping two cohorts, statistical information comparing the two cohorts would be warranted To show if there are significant differences between the two groups.

2. Table 2: What does “Age band” mean? This is an interesting word choice. Table 2 is Overall hard to interpret with multiple empty boxes, repeated rows of “1/3 SD” and “SEM”, and no clear separator between “NSAA – Cohort 1” and “NSAA – Cohort 2”, and “6MWD – Cohort 2”. For the reader, I think this table can be significantly cleaned up to improve its visual appearance. Also, please remain consistent when abbreviations “SD” vs “sd” throughout the chart.

3. Table 3: Please put a space between “1/3SD” to read “1/3 SD”. try to not have words split between lines such as MCID/Mea ---- n” but rather MCID/Mean”. Similar to Table 2, this table is not very visually appearing, and though important, can be cleaned up for visual purposes for the readers, As it has multiple empty spaces, unusually spaced rows (very large “SEM” and very small “1/3 SD” rows, for instance.

4. Table 4: In the “N” column (2nd column), you say (% of sample), but only a few data points have percentages included. In NSAA, you list 34/34; I assume it means 34 of 34 patients did the NSAA?

5. Figures 2-4: these figures are very important and I am glad that the authors included them, however I think that they can be improved. First the resolution is blurry, please consider uploading higher resolution images. Imaging software such as Prism may be able to make more visually appealing figures. Consider changing the Y axis to say “Number of Responses” rather than “Count” to sound more professional.

Discussion:

1. What do you think accounts for discrepancies between participant responses between patients and parents?

2. At this point may be worthwhile to elaborate on. Would the variability amongst patient responses be an important factor to report for clinical trial outcome measure purposes? This may suggest that the objective current outcome measures (such as NSAA) it could be better than patient reported outcomes. This would also highlight the different patterns of patient perceived disease progression (such as losing complete function and two items versus partial function in four items).

3. Is it worth discussing the point that clinical trials are being targeted for younger populations and how this will impact NSAA interpretation?

Limitations

- Forgive me if I misinterpret or misunderstand the author is methodology, but the linearized scale method may weigh all contributing parts equally which may not be clinically relevant.

- Using the anchor based approach, annual decline of 30 meters for the six minute walk test may not be appropriate for all age groups, as boys naturally improve their strength until plateauing before precipitous decline. Age differences of NSAA assessment are an important limitation to consider, given age dependency of all functional tests.

- Please include a brief statement about other outcome measures that are used in clinical trials, such as biopsy, other functional tests, magnetic resonance imaging/spectroscopy, ultrasound, and electrical impedance myography.

Reviewer #2: This manuscript describes multiple analyses that were performed to assess the MCID for the NSAA in Duchenne muscular dystrophy. The authors first used retrospective data to calculate age-specific MCIDs based on the distribution of the data and the correlation between the NSAA and the six-minute walk distance. The authors also surveyed patients and parents to assess the minimal change in the NSAA that would be meaningful to them in the context of a clinical trial. My comments and questions are detailed below.

Introduction: “This leads to progressive loss of motor function with loss of the ability to walk typically by the age of 12 years…” This is a minor point, but the way this sentence is phrased makes it seem like all but a few patients lose ambulation by age 12. However, 12 is actually the mean age of loss of ambulation, meaning that many patients remain ambulatory beyond this age. Recent data from the TREAT-NMD cohort suggests that among steroid-treated Duchenne patients, a large percentage of patients remaing ambulatory until the age of 16.

Methods: Please include the dates during which the data for these analyses was collected.

Methods: It seems more common to have ½ the SD be the cutoff in distribution-based MCID calculations. What was the rationale for selecting ⅓ SD in the distribution based approach?

The survey questions ask what degree of change would justify participation in a two-year trial. I’m not sure how useful these survey responses are in a practical sense because the premise is not a realistic one. Trial design is predicated on the fact that the degree of efficacy is unknown, and a key element of informed consent for trials is that the participant understands that no benefit is possible (even probable) and is willing to participate anyway. We have also seen in past trials in DMD that participants/families were willing to support any amount of change that could be perceived as improvement, whether it corresponded with change in the NSAA or not. A more common approach for using patient/parent impressions to determine MCID would be to measure the NSAA at different time intervals and then ask if respondents have perceived improvement, worsening, or no change during those intervals.

Table 1: A large percentage of patients are on an intermittent steroid regimen. This is somewhat surprising, as there is evidence that intermittent dosing is not as effective as daily dosing and this schedule is rarely seen in practice now. Are there any unusual features about these cohorts that could explain this?

Was there any assessment of whether or not the data points within each age stratum were normally distributed? This would be important to know when implementing measures based on standard deviations and standard errors.

Results: The organization of Table 2 is a bit unusual. Since the data is being summarized based on age, I would expect to see age as the first column, followed by the N, mean, SD, ⅓ SD, SEM (with the row split here), MCID, and MCID/Mean.

Results: Within cohorts and 1 and 2, are there any patients who were measured multiple times at different ages? It seems that there must have been, since cohort 1 is listed as having 626 participants, but the sum total of all the participants in each age group is 1,166. If there are a significant number of non-independent data points, this could lead to underestimation of the variability between age bands.

Results: “Responses from 40 patients including 7 boys with DMD and 33 parents (7 parents of the boys that participated and 26 parents) were obtained…” This section could be clarified in a couple ways. I would avoid referring to the survey respondents as “patients” since the parents are presumably not being seen as patients and readers may interpret this to mean that 40 Duchenne patients participated when there were only 7. The phrase “7 parents of boys that participated and 26 parents” also sounds a bit incomplete. Consider changing to something like “...33 parents (7 of whom were parents of boys that participated).”

Since there are only 33 distinct DMD patients being described in the survey analysis, the descriptive statistics in Table 4 should not merge the patient and parent responses as if there were 40 distinct DMD patients. I would expect both the parent and the DMD patient to give similar answers with regards to their mobility status, but if there are discordant answers, this should be noted.

The Discussion section includes an explanation of the linearised NSAA scale. I would recommend moving this to the Methods. Otherwise, the rationale for using the linearised scale isn’t really clear at the time it is presented in the Results. It might also be useful to discuss in greater detail the reasons or scenarios in which the raw scores or the linearised scores might be preferred.

It might be useful to discuss how the MCID estimates from this analysis should be applied to clinical trial design, particularly as it relates to power and sample size calculations. The authors also point out that complete loss of function (1 to 0) may be assigned a different level of clinical importance compared to the deterioration of function (2 to 1). However, both would result in a change in the NSAA of 1 point. How would the authors suggest analyzing the NSAA data such that these distinctions can be recognized?

The section on strengths and limitations doesn’t seem to list any limitations. The sample size, particularly in the patient group, is a significant limitation in the survey study and should be noted. The analysis also doesn’t include patients younger than 7, who are the primary target population for ongoing gene therapy studies. Similarly, the MCID estimates would not apply to patients who are older.

Figure 4: The labeling of the y-axis should extend at least as high as the tallest column.

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Reviewer #1: Yes: Stephen Chrzanowski

Reviewer #2: No

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PONE-D-22-17578R1Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy.PLOS ONE

Dear Dr. Ayyar Gupta,

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 respond and revise the manuscript to address the minor issues remaining that have been identified by one reviewer. I think this should be a small modification to your manuscript for clarification.

Please submit your revised manuscript by Feb 16 2023 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,

Stephen E Alway, 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.

Additional Editor Comments (if provided):

Please respond and revise the manuscript to address the minor issues remaining that have been identified by one reviewer.

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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 #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 #2: Partly

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

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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 #3: Yes

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

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

Reviewer #2: Yes

Reviewer #3: Yes

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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: Most of my comments have been addressed. I did have some additional comments on the revision.

In the new Table 1, the range for the NSAA score is listed as 2-34. Please verify that the low score of 2 is correct. Given that the oldest participant in the cohort is listed as being 10.5 years old, this would be an unexpectedly low NSAA score for a group of Duchenne patients this age.

It was not apparent in the original manuscript that only 31 participants were included in the distribution-based MCID analysis of the six-minute walk test. Since the original cohort from the IMDEX natural history study had 56 participants, only about half of the cohort is represented in this analysis. This rather alters my perception of the robustness of this analysis. It would be useful to get a better understanding of the reasons that so much of the data is missing from this cohort. Has there been any analysis to determine how representative these 31 participants are with respect to the larger cohort being described here? Is there any reason to believe that participants were excluded for reasons relating to their physical function?

Results: “Based on 62 observed annual changes in 24 boys (54 observations) above the ages of seven years….” Please clarify how the 62 changes were counted from 54 observations. If the 24 participants were each measured at baseline and after 1 year, that would be 48 observations. If 6 of those participants had an additional measurement after year 2, that would make 54 observations, but this would only end up being 30 annual changes, not 62. There also appear to be more than 62 points plotted in Figure 1, which is supposed to correspond to this analysis. If participants are contributing multiple data points to the analysis, please describe any adjustment for non-independent data used in the correlation analysis.

Reviewer #3: (No Response)

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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 #3: Yes: Jennifer L Lammers

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Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy.

PONE-D-22-17578R2

Dear Dr. Ayyar Gupta,

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. Congratulations!

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards, and thank you for your contribution of your interesting manuscript.

Stephen E Alway, 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 #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 #2: Yes

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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

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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 #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: The authors have been very thorough in their responses to my comments. I have no further recommendations for this revision.

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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

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