Dear Dr Pedron,

Thank you for submitting your manuscript entitled "The effect of population-based blood pressure screening on long-term cardio-metabolic morbidity and mortality: A regression discontinuity analysis" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Aug 12 2022 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Callam Davidson

Associate Editor

PLOS Medicine

Dear Dr. Pedron,

Thank you very much for submitting your manuscript "The effect of population-based blood pressure screening on long-term cardio-metabolic morbidity and mortality: A regression discontinuity analysis" (PMEDICINE-D-22-02708R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 us at PLOSMedicine@plos.org.

We hope to receive your revised manuscript by Oct 24 2022 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Callam Davidson,

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

Please include the setting in your title (i.e., “The effect of population-based blood pressure screening on long-term cardio-metabolic morbidity and mortality in Germany: A regression discontinuity analysis”).

Please add this statement to the manuscript's Competing Interests: "TB is editor-in-chief of PLOS Medicine.”

Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions). Please combine the Methods and Findings sections into one section, “Methods and findings”.

Abstract Background: Provide the context of why the study is important. The final sentence should clearly state the study question. Some of the content in the Introduction should be relocated to the Methods and Findings (e.g., outcomes, length of follow up).

Abstract Methods and Findings:

* Please include the population, years during which the study took place, length of follow up, and main outcome measures.

* Please quantify the main results (with 95% CIs and p values).

* In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Citations should be normal script, located within square brackets, and appear before punctuation (e.g., [1]).

Lines 24-25: Please add ‘to our knowledge’, or similar.

Please label and describe items in your Supporting Information as outlined here: https://journals.plos.org/plosmedicine/s/supporting-information

Please define the abbreviations in Table S1.

Please define "lost to follow-up" as used in this study. Other reasons for exclusion should be defined.

Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

Thank you for including a completed TREND checklist. Please use section and paragraph numbers rather than page numbers when completing the checklist, and cite the checklist in your Methods section (as S1 checklist, or similar).

Please remove the ‘Disclosures’ section from the end of the main text and relocate the content regarding ethical approval and consent to the Methods section. The Data Availability information can be removed as this is captured via your Data Availability Statement in the submission form.

Similarly, the Sources of funding section can be removed and the information instead entered in the Financial Disclosure section of the submission form.

Figure S1: Please update ‘Gender’ to ‘Sex’.

Line 396: Please temper claims to primacy by adding ‘to our knowledge’, or similar.

Comments from the reviewers:

Reviewer #1: This study evaluates the effect of blood pressure screening, in the context of a cohort study, on outcomes of blood pressure and fatal or nonfatal CVD events over some 16 years of follow-up. The study addresses a well-known issue and provides new information to inform ongoing debate. The data are analysed using sophisticated methods and the paper is well organised.

1. It is not clear what is the comparator. This is a single group study, but it appears that this intervention did not improve on existing blood pressure care. The paper needs to specify what the latter is. In the UK, general practitioners are encouraged to record the blood pressure of their patients every few years, and a recent cardiovascular health check programme has been found to provide limited additional benefit. Does a similar arrangement exist in Germany?

2. Use of the term 'screening' can lead to misunderstanding. While public health workers refer to 'popualtion screening', general practitioners and other clinicians use the term 'screening' when they routinely perform tests on specific groups of patients. It would be unfortunate if readers of this paper took from it the message that recording BP is not helpful.

3. The results are generally negative. However, the confidence intervals for the main estimates are very wide leading to questions concerning whether the power of the study is sufficient. Further, 'absence of evidence is not evidence of absence' so it may not be justified to conclude that screening 'did not reduce long-term fatal or nonfatal CVD events' - there is insufficient evidence to draw a conclusion. https://www.bmj.com/content/311/7003/485

4. In the Abstract where it concludes 'More intensive interventions, along with nudging and/or education, may be necessary to affect individual behavior and long-term outcomes.'. This needs to be set in the context of services that already exist (as noted above). No evidence is presented on nudging or education so these ideas need not be mentioned in the conclusion.

5. In the Introduction, this is generally good, but it needs to consider the medical care context as mentioned above. What access did participants have to routine BP care?

6. The Methods are described clearly and in detail. However, at line 127 the term 'bandwidth' is introduced without explanation and the meaning may not be clear. Later it refers to 'optimal bandwidth', with the meaning also unclear.

7. A flowchart detailing the sample selection would be helpful. Where it reads 'The follow-up data for secondary outcomes included 5,130 individuals', please explain why this is reduced as compared to the full sample.

8. Where it says 'The graphical inspection of these plots confirmed the absence of manipulation around the respective cutoffs.' please explain what is meant by manipulation and why the graphs demonstrate this.

9. The Figure legends could be more informative. For example, Figure 2 appears to show more than the effect at threshold. Figure 3, meaning of the x axis label of 'bandwidth' may not be clear.

10. In the Discussion, where it says ' The analysis indicated no effect of a population-based blood pressure screening intervention on long-term CVD mortality and morbidity in Germany.' It really means 'no additional effect' over and above existing BP care. But see also point 3 above.

11. The remainder of the discussion and referencing is generally good. It may be worth referring to the distinction of population-wide versus high risk approaches from G Rose, strategy of preventive medicine. It may also be useful to refer to behavioural science literature as finding that 'simply informing patients of their hypertension status is not enough' may not be surprising.

Reviewer #2: See attachment

Michael Dewey

Reviewer #3: In a longitudinal analysis based on 14,592 German adults from four population-based cohort studies free from cardiovascular disease (CVD) and drug treatment at baseline, the Authors investigated the impact of a blood pressure screening and personalized information treatment on CVD morbidity and mortality over a follow-up time of 16.9 years. They concluded no effect of a blood pressure screening intervention on long-term CVD mortality and morbidity and on the medium-term health behaviour or blood pressure intervention. This is a very well written and interesting paper. Statistical approach appears elegant. The discussion and conclusions are well balanced. In the Methods Section, a flow chart of the study design would be of interest. Methods should be improved with more details on information treatment and on the definition of "light touch" intervention. As it is, is it only a mail communication to the patient without direct information to the General Practitioner? If yes, please added a specific statement with explanation (i.e. privacy policy in Germany ecc…). Other studies have found a positive association between correct information about BP to GPs and impact on CVD mortality. Any further direct contact between the medical staff involved in the cohort studies and the participants? Other studies have investigated in longitudinal population-based studies the beneficial impact of observational epidemiological studies on the CVD mortality. On the other hand, some studies have outline that long-term negative psychological effects, as a consequence of the label of HT, exist. Therefore, clinicians might also consider appropriate positive health messages in participants with hypertension (doi:10.1136/openhrt-2015-000341). References should be implemented.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachments

Attachment

Submitted filename: pedron.pdf

Dear Dr. Pedron,

Thank you very much for re-submitting your manuscript "The effect of population-based blood pressure screening on long-term cardio-metabolic morbidity and mortality in Germany: A regression discontinuity analysis" (PMEDICINE-D-22-02708R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Dec 01 2022 11:59PM.   

Sincerely,

Callam Davidson,

Associate Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

In the last sentence of the Abstract Methods and Findings section, please describe the main limitations of the study's methodology.

Author Summary: Please include the headline numbers from the study, such as the sample size and key findings.

Line 115: PLOS Medicine does not permit use of footnotes, please relocate this information either to the main text or the Supporting Information.

Please ensure you have cited the relevant Supporting Information correctly in Table 1 legend.

Please ensure consistency in your Supporting Information titles (Figure S6 is inconsistent with the others).

Line 415: Please temper claims to primacy by adding 'to our knowledge'.

Comments from Reviewers:

Reviewer #1: The authors have given an extremely thorough and well considered response to the reviewer comments.

I agree with the authors that P values are not needed in the Abstract. Accordingly, it might be better to replace 'No significant effect' with 'No evidence of effect'.

In the conclusion section of the abstract, where it reads 'Future studies should consider larger datasets'; in terms of the future, would it be worth mentioning the evolving scope of digital health interventions (smarphone apps, wearable devices) that offer increased scope for intervention and evaluation, and whether evaluation of BP in the context of CVD risk (including smoking, cholesterol, diabetes etc) may offer a better approach?

Reviewer #2: The authors have addressed my points. Happy to accept their comment about mice, I was not clear whether that would work but worth a try.

Michael Dewey

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr Pedron, 

On behalf of my colleagues and the Guest Editor, Professor Martin Gulliford, I am pleased to inform you that we have agreed to publish your manuscript "The effect of population-based blood pressure screening on long-term cardio-metabolic morbidity and mortality in Germany: A regression discontinuity analysis" (PMEDICINE-D-22-02708R3) in PLOS Medicine.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Callam Davidson 

Associate Editor 

PLOS Medicine