PONE-D-22-04944Reduction in medical costs for cardiovascular diseases through innovative health awareness projects in a rural area in JapanPLOS ONE

Dear Dr. Shoji,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 20 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,

Yoshihiro Fukumoto

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 in the Competing Interests section: 

"The potential competing interests of authors (if any) are otherwise summarized in the following sentences. AS is employee of Medilead Inc. KK is COE of Integrated Clinical Care Informatics, Inc. AI has received grants from Abbott Japan Inc., Abbvie G.K., Becton, Dickinson and Company, Creative-Ceuticals Inc., Eli Lilly Japan K.K., Gilead Sciences K.K., Intuitive Surgical G.K., Milliman Inc., Pfizer Inc., Sanofi Pasteur Inc., and Terumo Corporation, and personal fees from Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., CSL Behring Japan Inc., FUJIFILM Corporation, Sanofi K.K., and Takeda Pharmaceutical Co., Ltd. outside the submitted work."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. 

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

[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: Yes

**********

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: Overall, the manuscript is well written. However, there are several points that should be improved in terms of potential additional analyses and justifications of the proposed methodology.

1) It should be clearly stated what is the novelty of this study and what it adds to the existing literature.

2) It is not clear what kind of data were used. It is stated that data were obtained from the Iwaki cohort, so presumably the analysis was based on patient’s level data, but this is not stated. It maybe that aggregate data were used, but again, this is not stated or justified. This is somewhat explained in the limitation section, but it should be explained clearly and in greater details in the methods section.

3) The method section is not clear, a good way to explain the clinical and economic impact of the CHAP programme is a before and after econometric method. The authors should explain why this was not possible considering the data limitation.

4) The risk score to estimate the 10-year incidence risks of CHDs and stroke is referenced, but a brief explanation of what is it and how it works should be provided (perhaps as supporting information).

5) Costs are calculated by multiplying the incidence of CHDs and stroke by medical costs. The estimation is based on assumptions and not on a costing methodology. It is not clear why, if patents level data are available, costs were not estimated with, for instance a two-part model (accounting for 0 costs and skewed distribution of healthcare costs) or any other sound methodologies.

6) Table and figures could be presented in a more appealing way. E.g., in Table 1, numbers and percentages could be presented within one single cell. Similarly, mean and SD could be presented together. E.g., age in years in 2008 could be presented in the following way 56.97 (13.10). Figures 2 should be fully labelled to aid the reader.

7) In the Conclusions, it is stated that the innovative project for awareness and encouragement contributes to a significant cost reduction in the treatment of CVDs and reduces the economic burden on the local government. In reality, this is based on assumptions as a formal econometric analysis was not conducted. It could be said, however, that the innovative project has the potential for cost reduction etc. etc.

Reviewer #2: Major comments:

This study was revealed the effect of CHAP as an innovative project on the prevention of stroke and coronary heart disease as well as to contribute to a cost reduction in the treatment of these diseases. The concept of the present study was valuable but there are some concerns as described below.

1. In Table 1, the subjects appear to be younger after 2012 than before. Author described that “The mean age, which is an important risk factor of CHDs and stroke, did not show any significant change in either period but decreased by about 3 years around 2012” in page10, line 182-184.

It is questionable whether there is any statistical discrepancy in age before 2012 and after.

2. In Table 1, the author showed significant trend changes in SBP, DBP, and HbA1C, before and after 2012, but I wonder if they are adjusted for age, because the mean age seems to be younger after 2012 than before.

3. I don't understand how you could show “a more remarkable increase in risk factors (Table 2C).” in page16, line 207-208. Could you explain more about it?

4. In page 22; line 262-263, the author described that “the effect of CHAP was remarkable for SBP, DBP, and HbA1C, but not for other risk factors or lifestyle factors.”Is it possible that there was a bias in the content of lifestyle interview or guidance in CHAP? It would be better to mention standardization of instructional content.

5. In figure 3 & 4, the differences between B and C were understood, but the results for A and C seem to be very similar. Careful explanations are needed about the results for A and C.

Minor comments:

1. Page 16; line 196-197. This figure legend showed the definitions of risk groups in Figure 3. It should be in Figure 3.

**********

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: Yes: Giorgio Ciminata

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-22-04944R1Reduction in medical costs for cardiovascular diseases through innovative health awareness projects in a rural area in JapanPLOS ONE

Dear Dr. Shoji,

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 authors should respond Reviewer 1, and would be encouraged for re-submission.

Please submit your revised manuscript by Oct 12 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,

Yoshihiro Fukumoto

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. 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: (No Response)

Reviewer #2: 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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: No

Reviewer #2: 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: Yes

Reviewer #2: Yes

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 #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: Overall, most comments have been addressed, however there are still two points of major concern:

1)It was previously suggested to use a before and after econometric method to explain the clinical and economic impact of the CHAP programme. The author responded saying that “Because CHAP was intended to change overall attitudes and behaviors of participants and it has been offered all participants since 2013, therefore we did not directly compare between the periods by using one model”.

The all point of a public health intervention such as the CHAP programme is to change overall attitudes and behaviours of participants. So, it is still not clear why a single before and after econometric model was not used. Also, it is understood that “the period with CHAP was set from 2012 to the end of the observation period” and that CHAP was offered to all participants since 2013. In this case, is not clear how the trend for risk score can be evaluated in the “before” model. If a single before -after econometric model cannot be used, I would have expected to see a risk score calculation at baseline (before CHAP introduction) then a “trend for risk score” for the years following the introduction of CHAP.

It maybe that this is provided in the existing analysis, but it is not clearly presented or framed.

On a minor note, the sentence could have been constructed better (e.g. “therefore” after “because” is not correct grammar).

2)This comment refers to an issue not previously picked up but of a major concern:

On page 7 (line 133-136 of the revised copy) the following is stated: “Participants who lacked checkup results of risk factors for CHDs and stroke were not excluded. We assumed no risk and counted a score of 0 for every missing risk factor. Detail information is shown in Supporting information”. It is not clear what this means. Are there missing records (e.g., if a patient did not have a risk factor for CHDs, 0 should be reported) or simply if the risk factors were not identified they were not reported? I believe that latter applies. In this case, I would simply delete the whole sentence, somewhat misleading.

However, if the former applies, assuming that patients with missing records on risk factors have 0 risk is quite a big assumption. This “dilutes” the proportion of patients with none or little risk. If it is a complete case (but this should be stated) the missing records should be reported and discarded. Alternatively, a multiple imputation should be carried out. It is appreciated that this for whatever reason may not be feasible, but if so, it should be clearly stated. At the minimum, the number of patients with missing records should be reported, and a sensitivity analysis excluding these patients should be conducted.

Reviewer #2: All comments have been addressed. Authors replied adequately to my questions. I think the revise manuscript is much better.

Reviewer #3: After reviewing the revised version of this manuscript, I believe that authors have satisfactorily answered the queries raised by reviewers. The manuscript is well-written, has excellent-quality data and statistical analyses. I have only but one minor suggestion, that is:

In lines 36,37 of the abstract, authors state that "CHDs and stroke were significant even after CHAP (+ 0.413, p < .001; + 0.169, p < .001, respectively), but slightly more compared to before CHAP" I believe that authors meant to write "slightly less" instead of "slightly more".

I also recommend authors to perform a final check on English and grammar.

**********

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: Yes: Giorgio Ciminata

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.

Reduction in medical costs for cardiovascular diseases through innovative health awareness projects in a rural area in Japan

PONE-D-22-04944R2

Dear Dr. Shoji,

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,

Yoshihiro Fukumoto

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: