Dear Dr Carrillo-Larco,

Thank you for submitting your manuscript entitled "Simplified hypertension screening: misdiagnosis, over-diagnosis and cardio-metabolic characterisation in 60 low- and middle-income countries" 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 Nov 19 2021 11:59PM.

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

Kind regards,

Beryne Odeny

PLOS Medicine

Dear Dr. Carrillo-Larco,

Thank you very much for submitting your manuscript "Simplified hypertension screening: misdiagnosis, over-diagnosis and cardio-metabolic characterisation in 60 low- and middle-income countries" (PMEDICINE-D-21-04705R1) 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 expect to receive your revised manuscript by Mar 18 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,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

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

Requests from the editors:

1) Please include line numbers in your next draft

2) Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible and include the setting of the study. Please place the study design (e.g., “a multi-country evaluation of surveys”) in the subtitle (i.e., after a colon).

3) Abstract:

a) Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions). Please merge Methods and Results into one section “Methods and Findings”

b) Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

c) Please include the study design, regions and setting, total number of participants, month/year during which the surveys took place

d) Please include the specific important dependent variables that are adjusted for in the analyses.

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

f) Abstract Conclusions: Please address the study implications without overreaching what can be concluded from the data.

4) 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

5) Introduction: Please conclude the Introduction with a clear description of the study question or hypothesis.

6) 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.

7) Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)." The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

8) Please provide 95% CIs and p values, where relevant, for all estimates in the text and tables.

9) Please do not report p values to 3 decimal points

10) In the Discussion section, please delete the titles “results in context” and “clinical medicine and public health implications”

11) Please define the abbreviations in Tables and Figure e.g., BMI in Table 5.

12) Please remove the “Conflict of Interests”, “Data availability,” and “Funding” statements at the end of the main text. This information is captured in the metadata obtained in the submission form

13) References:

a) Please select the PLOS Medicine reference style in your citation manager. In-text reference call outs should be presented as follows noting the absence of spaces within the square brackets, e.g., "... services [1,2]."

b) References should have no less and no more than six names before et al.

Comments from the reviewers:

Reviewer #1: This is a well-conducted study on simplified hypertension screening with regard to misdiagnosis, over-diagnosis and cardio-metabolic characterisation in 60 low- and middle-income countries. The study design, datasets, and statistical methods and analyses are mostly adequate. However, there are still a few issues needing attention, especially in presentation of the results.

1) The study is mostly descriptive and would be good to keep it descriptive to present all the facts on missing hypertentions in the 9 simplified screening approaches. The 10-year cardiovascular risk is just a risk score which itself has limitations in validation and accuracy, and they are a few others of similar kind. As all the surveys are cross-sectional studies, it would be good to focus on the observed facts rather than projections. Both Table 4 and Figure 2 are huge and not very informative and also on 10-year cardiovascular risk, suggest to move both to the supplementary information, and also tone down the claims on 10-year risks as subject to scrutiny and more work is needed.

2) Only around a couple of thousands paticipants in the survey in each country which is subject to variation and bias for the estimates. Can authors please go a bit comprehensive and critical in the limitation section to discuss the potential impact on the results of the study?

3) Table 5 on factors contributing to missed hypertension diagnosis. Age and BMI are mostly consistent but cadiovascular risk is not really, only 4 of 9 have significant results. Any interpretations and cautions to read the results?

Reviewer #2: This is a very well written, clear, and important paper.

The authors identified the share of misdiagnoses and over-diagnoses when using simplified hypertension screening approaches.

Given that hypertension screening needs to be increased globally in the fight against the epidemiological transition, more information on how screening efforts can be increased and made more efficient are highly relevant.

The authors use adequate statistical methods in answering their research question.

I have only minor comments and suggestions - and the authors may choose to ignore them.

- One sentence is a bit unclear (page 4 and 5): "We used the same predictors except for diabetes; the original model included history of diabetes whereas we included history and new diabetes cases (i.e., aware and unaware cases, the latter defined with fasting plasma glucose ≥126 mg/dL)"

It should be made clearer which predictors this is referring to.

- Perhaps the authors could add more details on how consequential simplified hypertension screenings may actually be for the CVD disease burden. This could be done by:

- including references for HTN screening being still too low in LMICs (see this study https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(19)30955-9.pdf )

- discussing how relevant it actually is to make screening time shorter. I wonder how much time is actually being saved by taking only e.g. only one measurement (could briefly mention wait time in between measurements). As the authors have pointed out, this may be particularly relevant in massive screening programs - but how frequent are these or should even be as screening efforts are being ramped up?

Reviewer #3: This is an interesting approach to an important question. It's a big paper with a lot of analyses. I have one substantial criticism and a few smaller ones.

The substantial criticism, which the authors responsibly describe in their limitations, is that the protocol-driven hypertension assessment of STEPS has poor alignment with real-world BP practices. A fair amount of evidence shows clinic values are less reliable, wider variability, and generally don't do the three-measure assessment this study is examining. It's testing a measurement approach that I basically think doesn't exist in the world. This makes the external utility of this work unclear to me.

The smaller complaints all stem from, to my reading, them not quite succeeding at making a hard topic simple enough for the reader. There are a lot of analyses and I never quite found the "story" in their outcomes. There are 3 things that make this hard to write about. First is that diagnostic testing is a difficult field. The established terms of sensitivity and specificity are confusing and unnatural. Seemingly to avoid that they used non-standard terms like proportion missed and over-diagnosed. But these were hard to track and weren't reported consistently. The core findings - the classic 2x2 table of missed and overdiagnosed relative to true and non hypertensive - was clear in the abstract, but not elsewhere.

Second, cross-national comparisons are hard to write because it's hard to see the story. A table of 60 countries is very hard to get a feel for or read, especially because it's unlikely that 2 countries of the same region actually have different phenomena. The manuscript dealt with this difficulty 3 different ways. They had a few tables with 60 countries, a few divided by continent, and some organized internationally with multilevel modeling (Table 5). I can see the urge for all of these, but it didn't help me understand what was going on. What do we learn from each? Do we think it's a national, regional, or single international phenomenon?

This became especially difficult in the figures, which don't really work for me. They showed statistical significance, which is a feature of sample size, effect size, and random chance. In this case we know the effect is real - that the new measures do not precisely match the old - so there's no question we'd reach significance with enough sample. But I don't know the sample size of each of the 60 rows and this obscures the effect size, which is more interesting. I generally didn't find the story behind the figures that compelling compared to the general issue of learning how reliable the techniques are. (Though the fact, which appeared in a few ways, that the errors were larger in those with high risk and history of CVD is both concerning and interesting.)

The third difficulty was just that nine is a lot of comparisons. This made some tables feel overwhelming. But to address that, they didn't include all 9 at all spots in the paper, like the figures, even though we'd just seen them in a table.

I think if this paper is resubmitted, I would recommend really deciding what the story is and telling that. Then, putting the details in the supplement and acknowledging in the paper that what is presented is post-hoc. I would put the missed and overdiagnosis in the same tables. I would report sensitivity and specificity somewhere. I would recommend grouping the countries in a way that feels meaningful and only putting all 60 in the main paper once. (Put more in an appendix.)

I have a few questions:

1. Table 5 seems to show that higher risk people are are likely to have missed HTN. But Table 4 seems to show that missed hypertension have a risk of CVD that is roughly half the risk of those with consistent hypertension. How?

2. In table 5 the HR of CV risk is ~3 in all examples except one where it's 0.89. Is that right?

3. I would benefit by having them talk through the implications of the random effects findings in table 5.

4.Table 2 could use something like "by country" somewhere. I struggled to understand what the SD was the SD of, though I now see it's of the results of each country.

5. I would probably merge tables 2 and 3, remove the min and max, and add columns for overdiagnosis into that table.

Reviewer #4: Blood pressure measurement is key in the screening and management of high blood pressure. In the most comprehensive scenario patients would need multiple BP measurements

on separate occasions, and in the most pragmatic approach would require three BP measurements and taking the average of the last two which is standard approach. Three BP measurement may however be challenging in resource-constraint settings because of shortage health care workforce. Therefore, it will be necessary to have fewer BP measurements that would have values as close as possible to taking the average of the last two measurements which is currently the gold standard. Although attempts have been made to find simplified BP screening approaches, these simplified approaches were tested in three countries only and BP may vary between countries. The authors then decided to analyse national surveys in 60 low- and middle-income countries giving a large dataset. The authors further went ahead to relate the different measurement to their effect on cardiovascular risk score.

This paper is well written and a stimulation at looking for ways that can make blood pressure measurement especially during mass screening programmes to be more pragmatic.

Apart from country to country variations as stated by the authors is there any regional differences to the variation? Although one-size-fits will be applicable to different countries it will be nice as a more pragmatic approach for the authors based on their study to state the 2 or 3 methods out of the nine tested that they will recommend for countries to be tested.

Reviewer #5: Authors considered only BP measurement for hypertension diagnosis but currently having BP lowering drugs, earlier suggestion by a practitioner about hypertension as well as life style modification for hypertension management are part of hypertension definition which are ignored by authors.

Reference 15 seems incorrect or broken.

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

[LINK]

Dear Dr. Carrillo-Larco,

Thank you very much for re-submitting your manuscript "Simplified hypertension screening: a multi-country evaluation of surveys" (PMEDICINE-D-21-04705R2) 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 expect 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 Mar 29 2022 11:59PM.   

Sincerely,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

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

Requests from Editors:

1. Please consider the suggested title, e.g., “Simplified hypertension screening methods across 60 countries: An observational study,” or similar.

2. Thank you for providing your STROBE checklist. Please replace the page numbers with paragraph numbers per section (e.g. "Methods, paragraph 1"), since the page numbers of the final published paper may be different from the page numbers in the current manuscript.

3. Please include p-values in tables where appropriate e.g., Table 4

4. Please replace the term “predictor” with “independent variable.” e.g., table 4

5. References – please include access dates for references with a weblink e.g. ref #6

Comments from Reviewers:

Reviewer #1: Many thanks authors for their great effort to improve the manuscript. The authors have addressed my comments very well. I am satisfied with the response and revision. No further issues needing attention.

Reviewer #5: Congratulations for great work

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

[LINK]

Dear Dr Carrillo-Larco, 

On behalf of my colleagues and the Academic Editor, Dr. Joshua Z Willey, I am pleased to inform you that we have agreed to publish your manuscript "Simplified hypertension screening methods across 60 countries: An observational study" (PMEDICINE-D-21-04705R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

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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, 

Beryne Odeny 

PLOS Medicine