PONE-D-20-10082

Evaluating Equality in Prescribing Novel Oral Anticoagulants (NOACs) in England: Protocol of a Bayesian Small Area Analysis

PLOS ONE

Dear Dr. Ahmadvand,

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.

Reviewer #1 has made some relevant remarks. In particular, I recommend the authors improve the clarity of their writing in the Aims and questions section. 

Please submit your revised manuscript by Oct 03 2020 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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Michele Tizzoni

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

I apologies for the long time needed to complete the assessment but the COVID-19 pandemic has made very hard to find independent referees available for review.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper describes a protocol for a study that will estimate the equality in prescribing individual NOACs with high spatial resolution in Clinical Commissioning Groups (CCGs) across England from 2013 to 2019, using Bayesian spatio-temporal modelling.

The introduction is focussed on the positive aspects of NOACs and does not refer to the negative or adverse effects associated with these medicines. A balanced review would be useful.

Placement of references should be at the end of a statement/sentence not before e.g. ‘These NOACS… for (5-8) 1)…’ it is confusing to have the references and then numbering of points.

Page 4 – ‘epidemic of atrial fibrillation’ is used but ‘epidemic’ is probably not the right word to use here.

Aims and questions section appears very long. The first sentence requires re-wording – it may not be required since it is covered already.

Methods – is the prescribing data linked to diagnosis? Will other indications other than Afib be considered in the analysis?

A reference to the ‘non-optimal’ prescribing is required.

How is clustering within areas accounted for?

2019 is used as a reference year, but the data are available april 2013-april 2019, so is it the first 4 months of 2019 is reference or the year May2018-April 2019? Not clear

How far forward will be considered for predictions?

Could age/gender specific DDDs be considered as large differences in age and gender specific prescribing?

Analysis and modelling section – more explanation of the Bayesian models would be included and why they are used over non-Bayesian approaches? Also, a brief intro to Hierarchical modelling – not all readers may be familiar.

Statement ‘BYM introduced by (30)….’ Please give authors name etc and not a reference. Also how does BYM address the issue with inter-dependency? Some explanation would be helpful

How was the temporal term defined? Monthly, yearly??

SAE model – provide references or explain the Bayesian Hierarchical framework. This section could be much clearer – particularly when explaining ‘spatial variation due to different…. By this combined parameters’. This was not clear.

‘NOVAs’ instead of ‘NOCAs’ needs correcting.

Explain why using log normal used?

Formula is used without explanation of the meaning of the parameters, It is assumed the reader is aware of these.

For the explanation of Rstan ‘Stan used no … from posterior’ requires further referencing. Why does NUTs sampler make ‘appropriate estimate’ over others – the justification is not evident.

Assumptions – how will these assumptions be tested? Should sensitivity analysis be applied here?

Validation – presented in the ‘past’ tense which reads as if this work/analysis has been done already, even though this is a protocol for the analysis. Please correct.

Ethical considerations – similarly using ‘past’ tense. Is this appropriate?

Discussion – there is some repetition with what is included in the introduction - is this required in a protocol?

There is no mention of whether the data and/or models will be made available through open source platforms. This is required.

The level of English could be improved e.g. pg 2 discussion last sentence ‘ can be monitor for a long time’ rather than ‘monitored’. A thorough proof-read of the paper is required.

**********

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Reviewer #1: No

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PONE-D-20-10082R1

Evaluating Equality in Prescribing Novel Oral Anticoagulants (NOACs) in England: Protocol of a Bayesian Small Area Analysis

PLOS ONE

Dear Dr. Ahmadvand,

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 Reviewer has identified some minor issues that should be taken into account in a revised version of the manuscript.

Please submit your revised manuscript by Dec 31 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Michele Tizzoni

Academic Editor

PLOS ONE

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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

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

Reviewer #1: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Most of the previous points have been addressed - however, there are two further minor corrections required.

1. Original Question in first review: Could age/gender specific DDDs be considered, as large differences in age and gender specific prescribing?

The response and change to the manuscript text is not what was requested. I understand that the data are not available by age or gender, and therefore, the following sentence in methods can be removed as it adds confusion rather than clarity.

‘DDD is not age- or gender-specific, and therefore, it can suitably be used in our modelling which is on

population-level, aggregate prescription data without gender or age specifications.’

2. Thorough Proof-read: Despite a request for a thorough proof-read for English, some errors still need to be addressed. A list of examples is provided, but not exhaustive:

In the methods

‘Health economical ‘– change to health economics

‘In compliance with the copy rights,’ – change to ‘in compliance with copyright’

‘Due to insufficient sample size prescribed at the small levels, direct estimators are unreliable to provide adequate..’ - please rephrase ‘at the small levels’ so it is clear what this means?

‘In Bayesian approach’ – should be ‘In the Bayesian approach..’

‘These distributions control the parameters limits that they can vary in the model.’ – rephrase

‘Since the non-spatial random effect is included to capture for independent region-specific variation, most or all of the variation can be addressed.’ – rephrase e.g. ‘Since the non-spatial random effect is included to enable the capture of the independent region-specific variation,….’

‘precision parameter for combined component and a mixing parameter..’ – change to ‘precision parameter for the combined component and a mixing parameter’

‘The effects of clustering within the CCGs (….) will show itself in the remainder error terms of the model.’ – change to ‘the effect of clustering with the CCGs () will be present in the remaining error terms…’

‘If any of the assumptions seems to be true, the main way … through empirical defining counterfactual..’ – change to ‘ If any of the assumptions appear to be true, the main way … through empirically defining counterfactual’

**********

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

[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.

Evaluating Equality in Prescribing Novel Oral Anticoagulants (NOACs) in England: The Protocol of a Bayesian Small Area Analysis

PONE-D-20-10082R2

Dear Dr. Ahmadvand,

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.

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Kind regards,

Michele Tizzoni

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: No further comments to add to the paper. My review of this protocol is complete and I have no additional comments.

**********

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