PONE-D-24-01070Identifying primary-care features associated with complex mental health difficultiesPLOS ONE

Dear Dr. McInerney,

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 Apr 18 2024 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,

Enzo Pasquale Scilingo, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

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

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. 

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following financial disclosure: 

"Funded by the National Institute for Health Research Research for Patient Benefit - "Mental Health in the North" call ( NIHR203473)"

Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" 

If this statement is not correct you must amend it as needed. 

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

4. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

5. Please include a separate caption for each figure in your manuscript.

Additional Editor Comments:

The manuscript needs to be improved before it can be recommended for publication. In particular, some issues about the protocol design need to be carefully addressed. 

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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: No

Reviewer #2: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an interesting attempt to identify cases of complex mental illness in medical records. While not completely successful in doing so, it does add to the literature in this area. However, I have concerns regarding the inclusion and exclusion criteria, in particular the way that certain items were operationalised. I feel "chronic depression" will not have captured many with chronic depression; while "severe mental illness" excluded many incentivised terms for psychotic illness, and only four antipsychotics were considered. I feel these issues require some more detailed justification and explanation in the text. Specific comments in relation to these points and others are below. There were also quite a few editorial issues, such as the lack of graph titles/footnotes, mislabelled supplements and tables, and the broken link to github.

1. Line 63: The prevalence appears to vary substantially in the WHO study with >7% in the US And Colombia and only 2% in Western Europe. This study in the UK suggests around 4% which may be more accurate: https://pubmed.ncbi.nlm.nih.gov/16648528/

2. Lines 68-72: This study uses THIN, which does not have full UK coverage. The methods of this paper state at the time of the study it had records for 744 GP practices, accounting for approximately 6% of the UK population. Therefore, if you assume a population of 60 million, the denominator should be 6% of this, and this study identified around 1.3% of patients with codes for PD (46,210 / 3,600,000), rather than 0.008%. Likewise, the Norwegian study was only looking at diagnoses made in a one year period, and so was not looking at the prevalence of PD in the sample, but those who had a consultation for PD in that one year.

3. Line 73: This study is based in the US which is a very different EHR system to ours. Depression (as a clinical code or prescription of antidepressants) is recorded relatively well in the UK, it is the determining whether it is a persistent depression that is harder. This may be a better reference for how much is recorded for depression/PTSD in the UK, though it doesn’t detail persistent depression: https://bmcmedinformdecismak.biomedcentral.com/articles/10.1186/s12911-023-02296-z/tables/3

4. Line 81: Another really important reason the authors may want to consider is that as of Jan ’24 NHS England advise “ICSs are strongly encouraged to consider the physical health needs of all people severely affected by their mental illness…This includes, but is not limited to, those with a diagnosis of personality disorder, eating disorder or severe depression, and people with mental health rehabilitation needs”. However, without these diagnoses recorded in primary care the GP will be unable to act upon this: https://www.england.nhs.uk/long-read/improving-the-physical-health-of-people-living-with-severe-mental-illness/#the-smi-register-and-smi-annual-physical-health-checks

5. Line 110: Note, this link does not currently work so I have been unable to review anything on the github.

6. Line 161: This data is in S2 Table, not S1.

7. Table 1: This data is in S2 Table, not S3.

8. Table 1: dementia is listed as an exclusion but not justified in the text.

9. Line 161 you state “a SNOMED-CT diagnostic code for caseness (see link associated with "Mental disorder | SCTID: 74732009 + child codes" but then in Table 1 you have much more stringent inclusion criteria. Referring to Figure 1 I see that this is a stepped approach, and assume a case is a patient with a diagnosis as per the inclusion in Table 1? This could be clearer in the text.

10. Controls: Were controls those that met neither the diagnosis or the medication criteria, or could they meet one criteria but not the other? Were controls able to have diagnoses such psychotic disorders? We know a lot of patients with codes for psychosis go on to receive a code of schizophrenia, and so I wonder whether removing them may have given a “cleaner” control group. GPs in England are incentivised to keep a record of patients with SMI (including schizophrenia and bipolar disorder but also other psychoses – e.g. schizoaffective schizophrenia, first episode psychosis). Because of this, people with any of the SNOMED codes included in the NHS incentivised definition are likely to be well recorded, but not all meet your criteria of SMI. The Hardoon paper from your introduction found that of people with personality disorder, 20% had an SMI (schizophrenia, bipolar disorder, other psychosis) diagnosis, so the cross-over between SMI and PD needs some careful thought. Excluding them from cases removes potentially quite a few people with PD, while not fully excluding them from controls (i.e. including those with other psychoses) may be contaminating your control group.

11. Table 1: Could the authors justify their selection of antipsychotics? I was interested that only four were chosen. While quetiapine, olanzapine and risperidone are very commonly prescribed, the paper by Hardoon et al lists chlorpromazine, aripirazole and haloperidol as more commonly prescribed to patients with personality disorder than flupentixol, while more recent analysis of patients with SMI shows that aripiprazole is now the second most commonly prescribed.

12. Line 190: Could the authors justify the age 30 as a cut off for “antecedent” events? If a patient has an “antecedent” event such as ADHD under 30, do they automatically also have a concurrent event for ADHD? As obviously diagnoses such as these may be recorded by the GP very infrequently, but still be present.

13. Line 269: Could the authors also report the exact number of controls? Some basic descriptive information on cases and controls would be useful here.

14. Line 276: It is not clear which feature sets are shown in these figures.

15. Figure 2a: What does the true/false relate to?

16. Figure 3a: Is this a count of all figures?

17. Figure 5: What do a, b and c refer to? I think the titles/footnotes for these figures are missing?

18. There is no table 4 in the manuscript, and S3 Table is not referenced anywhere.

19. Table 5: While SMI is defined here, I think the use of the same abbreviation to mean two different things (severe mental illness and scaled mutual information) is going to confuse readers.

20. Table 5: I was surprised you excluded obesity, and there was no consideration of smoking. I would have thought, alongside alcohol and drug misuse these would be useful predictors of mental health conditions. While I agree these are not specific to complex mental illness, possibly in combination with other things they may have been useful.

21. Line 329: While I agree there is a great deal of under-reporting/under-diagnosis in primary care; you did exclude patients with SMI and we know co-occurrence is common (around 20% in the Hardoon paper). The WHO prevalence calculated by Huang et al is in adults, whereas I think you are calculating yours over the whole population, and Huang et al estimated a prevalence far lower for Western Europe (2.4%). This study in the UK suggests around 4% which may be more accurate: https://pubmed.ncbi.nlm.nih.gov/16648528/. Could the authors take some of these nuances into consideration? That being said, I think the biggest under-reporting is “chronic depression”. I suspect that is because this is rarely coded for. Other colleagues have instead looked at persistence of standard depression codes over time, or long-term prescription of antidepressants. This means many with chronic depression are potentially in your control population. There are also SNOMED CT codes such as “persistent depressive disorder” which suggest chronic depression.

22. Line 424: But you didn’t include “other psychosis” in your exclusions, and therefore there could well be people with psychosis in your cases cohort. The list of SNOMED codes used for incentivisation is here, if you select PCD refsets” and set Cluster ID as “MH_COD”. You will see many conditions that you did not exclude which may warrant antipsychotic prescription: https://app.powerbi.com/view?r=eyJrIjoiNDRmYjEwMzQtZGE3MS00ZGE5LTgwMTUtNjQ2NGE1NTZiYmEzIiwidCI6IjM3YzM1NGIyLTg1YjAtNDdmNS1iMjIyLTA3YjQ4ZDc3NGVlMyJ9 .

23. General: I wonder if it warrants a comment regarding validation in other datasets?

Reviewer #2: This manuscript studies health records to assess What features within patients’ primary-care

electronic healthcare records might indicate that a patient has complex mental health difficulties .

Complex mental health difficulties is defined as difficulties more persistent or disruptive than the common mental disorders but which do not meet current definitions of severe mental illness like psychosis or bipolar disorder. It is an interesting paper that tries to understand what distinguishes a complex case from a non-complex case.

They also used a large dataset including all patients registered for at least 1 year in a practice and have some indication of mental illness because of diagnoses or medication. Severe mental illness diagnoses were excluded.

I have problems with understanding the cases in their case-control design. Cases were those records demonstrating recent, active, complex mental health difficulties, defined by having 1) a SNOMED-CT diagnostic code for caseness from at any time prior to 31st December 2021 and 2) a prescription for medicines of interest within ten years prior to 31st December 2021.

- What happens with patients that did not have registrations for that period of time ? Because they were registered in a practice for less than 10 years? Or does the dataset also includes data from there patients from their former practices?

- Why is this defined as cases? Why not also the ones with only a prescription \? As the authors mention GPs might not always be accurate in registering the diagnoses. So including this group with only prescription as control might not really be a good control.

- Cases could also be defined as the ones with having longer period of time of either registration of diagnoses or prescriptions. As the definition suggest a persistency of symptoms.

The authors use an information-theoretic approach. This could explained more in the introduction; why is that innovative? They discuss it in the discussion but this could be introduced more in the first part.

They could explain more why it is important to know the features of registered complex mental health problems. As they already mentioned that registration is not accurate. So what does it tell us these features?

The findings support the idea that complex mental health difficulties are difficult to identify and operationalise, leading to an underecording of cases that limits the use of electronic healthcare records to support identification, study, and provision of appropriate and timely care. Partly I agree that GPs under record mental health problems. But in present study about 13% had either a diagnosis or a prescription. How is that in line with prevalence in the general population?

Why for the concurrent feature findings or behaviours are concurrent after 30 years of age, e.g. self-harm, risk, substance misuse or dependency? What about patients younger than 30?

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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-24-01070R1Identifying primary-care features associated with complex mental health difficultiesPLOS ONE

Dear Dr. McInerney,

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. The manuscript needs minor revisions before it can be recommended for publication. Please submit your revised manuscript by Apr 11 2025 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,

Enzo Pasquale Scilingo, 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.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

**********

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 #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #3: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #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: Thank you for considering the points raised in the first review. I have just three very minor clarifications.

1. Line 151-154: “who have been registered with their general practice for at least one year; who, additionally, either have a record of a SNOMED-CT diagnostic code of interest within ten years prior to 31st December 2021 (see link associated with "Mental disorder | SCTID: 74732009 + child codes" in S2 Table), and who have a record of prescriptions for medicines of interest (Table 1) within ten years prior to 31st December 2021”

Should this be “either have a record of a SNOMED-CT diagnostic code… or who have a record…”, or if they needed both perhaps the word “either” needs removing?

2. Line 192: “Controls’ were those records that did not meet these two criteria.”

I presume this is anyone that didn’t meet either of these criteria? So someone with recent medication but no diagnosis becomes a control as does someone with a diagnosis in the absence of medication, and people that have neither? This could be a little clearer.

3. Thank you to the reviewers for providing a table 1 in the supplement. While I agree these tables may be mis/over interpreted they do provide useful context; for example for other researchers who may want to do similar in other regions. I am not sure your labels match your numbers for age in this table though, with e.g. max age listed as 30/40.

Reviewer #3: Thank you for the opportunity to review this interesting paper on the features of complex mental health difficulties in primary care records, which makes an important contribution to the literature. Key strengths of the study include the use of multiple feature types with several levels. Even though many of the patients with complex mental health difficulties remain ‘unseen’ following this methodology, the authors provide thoughtful reflections on the challenges of using electronic health record data to identify these patients. I have also read the reviewer reports and author responses from the first round of review, where the authors have addressed the reviewer feedback. I have minor points for the authors to address.

1. The antecedent feature set includes adverse childhood experiences; however, these experiences are not defined/specified in the text. Which adverse childhood experiences were included in the antecedent feature set? The authors cite a study in the discussion which found substantial under-coding of adverse childhood events, therefore we would expect high missingness in this feature set.

2. In the discussion, the authors refer to qualitative work undertaken as part of their wider work in this area and say that this was used to inform the quantitative study. From what I can see, this qualitative study is currently unpublished. The mixed-methodology should be made clearer - please add further information around how the findings from the qualitative study informed this study in the methods, for example if this informed the selection of features?

3. The article requires careful proof-reading for typos/phrasing issues, particularly:

o Line 55, comma needed after (dysthymia).

o Line 71, ‘,,,’ should be one comma, with a lower-case S for ‘similarly’.

o Line 137, remove ‘the’ before England.

o Line 187, removing ‘excluding those from our exclusion list’ as this phrase is redundant.

o Figure 1 title is quite long – may I suggest adding the sentences after ‘our records-based definition…’ as a footnote. Same for figs 2 and 3, after A). It seems a few of the figures have footnotes (e.g. Fig 5 includes a footnote entitled ‘10’, while others don’t). These figures are not titled/footnoted consistently, please can authors proof-read all figure titles/footnotes.

o Table 4, following ‘Active…’ should also be a footnote.

o Line 407-408, thirdly and fourthly repeated in same sentence.

**********

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 #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.

Identifying primary-care features associated with complex mental health difficulties

PONE-D-24-01070R2

Dear Dr. McInerney,

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Sreeram V. Ramagopalan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

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

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #3: No

**********

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 #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 #3: The authors have addressed my comments and I recommend this paper for publication. The author has requested for the editor to make a final decision on the formatting of the figures.

**********

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 #3: No

**********