Peer Review History

Original SubmissionJuly 16, 2020
Decision Letter - Adya Misra, Editor

Dear Dr Song,

Thank you for submitting your manuscript entitled "Healthy lifestyle, endoscopic screening, and colorectal cancer incidence and mortality in the US: a nationwide cohort study" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff [as well as by an academic editor with relevant expertise] 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 .

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,

Adya Misra, PhD,

Senior Editor

PLOS Medicine

Revision 1
Decision Letter - Emma Veitch, Editor

Dear Dr. Song,

Thank you very much for submitting your manuscript "Healthy lifestyle, endoscopic screening, and colorectal cancer incidence and mortality in the US: a nationwide cohort study" (PMEDICINE-D-20-03426R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and 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 Sep 17 2020 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. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

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,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions - "methods and findings" is a single subsection).

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

*In the abstract conclusions, the text currently reads "Healthy lifestyle may reduce CRC incidence and mortality independent of

endoscopic screening", but this assumes that the effect sizes seen in the main analyses represent causal effects, and given the study design we can't assume this. It would be better in the abstract to use more moderate language and to present the findings consistently as associations - in the main discussion you can then go on to say that, if those effects were causal then the implications might mean (xyz...), but this conclusion shouldn't be leapt to.

*Please use the following style for the author summary - https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary - this should use bullets and the headers need to be different. See also an example, https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002416

*We'd suggest ensuring that the study is reported according to the STROBE guideline; when doing so, please 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/. When completing the checklist, please use section and paragraph numbers, rather than page numbers.

*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.

*In the discussion section, as noted above for the abstract, some of the language should be moderated so it doesn't assume causal effects. Eg, "Approximately 32% of CRC cases and 34% of CRC deaths could potentially be prevented by endoscopic screening alone" - this could be presented later, but with the caveat that these estimates are based on assuming the effect size seen in your analyses are entirely reflective of a "true" causal effect (which may not be true). The discussion in general should be careful about where it uses causal language and it would be better to ensure the main part of the discussion presents the findings as associations, only going on later to discuss the implications **if these associations are indeed causal**.

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Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper. The general approach is OK but I have a number of issues to resolve before I can recommend publication.

First, quoting a "per unit" estimate is misleading, as the trend in both groups was non-linear (and nonlinear in different ways).

Second, the interaction term added is not adequate, as it does not address the above. Consider CRC incidence (as shown in fig 1A). If the factor of 0.85 was correct, then the nonscreened group would have HRs of 1, 0.85, 0.72, 0.61, 0.52 and 0.44; while the screened group would have values of 0.37 0.31, 0.27 0.23 0.19 amd 0.16. These are not accurate (and the two lines are not parallel)

Third, it's an interesting question whether the appropriate measure for reduction in risk is the ratio or the difference. Reducing a large risk by (say) 15% is not the same as reducing a small risk by 15%.

More specific points: On p. 5 at the top, give a rate of CRC death per person, not just "3rd highest"

Also on p. 5, the huge range of risk reduction for liefestyle (20 to 70%) makes these claims less credible (at least to me).

p. 7 Please define "metabolic equivalents"

p. 7 I'm not altogether happy with the way the lifestyle factor was computed. Dichotomoizing risk factors is kind of silly. People don't go from "normal" to "high" risk when they cross some threshold. E.g., for BMI (a very flawed measure of obesity) you aren't fine at 24.9 and then high risk at 25.1. Also, 31 minutes of exercise is not dramatically different from 29 minutes. It would be better to develop a measure of risk that left all measures continuouis (and maybe nonllinear).eith based on data or based on literature.

p 10 How was the "per unit" number calculated, given that there were 5 different logistic regressions run for each group?

Peter Flom

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Reviewer #2: Wang and colleagues address an important topic- the associations between screening and/or healthy lifestyles and the risk of colorectal cancer incidence and mortality, using the Nurses health Study and Health professionals follow-up study, two large, important cohorts that have been sources for many important observational studies. They found that the protective effects of screening and health lifestyle (based on a healthy lifestyle score) were independently associated with lower risks of CRC incidence and mortality. These findings are important and timely. The study is well-executed and the supplementary analyses helpful. I would make a few suggestions to better put them in context:

1) I would ask that the language be changed to highlight these are associations, not interventions or trials: For example, instead of concluding: "Healthy lifestyle may reduce CRC incidence and mortality independent of endoscopic screening." I would suggest "Healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening." Similarly, saying "First, we provide empirical evidence for the substantial benefit of lifestyle modification, independent of endoscopic screening, for improved CRC prevention." is probably less accurate than "First, we provide empirical evidence for the independent association of healthy behaviors and endoscopic screening with lower CRC incidence."

2) It would be helpful to discuss the rationale for turning the actual, sometimes linear measures included in the healthy lifestyle score into dichotomized scores. Giving the same weight to 3 drinks per day and 10 drinks per day, for example, seems to underweight extreme scores.

3) What is the relationship between the lifestyle score and all-cause mortality? I am assuming the the effects go beyond that of CRC.

4) The discussion talks about "lifestyle modification" which is an intervention framing, but I think it is important to reiterate the associations are with given levels of healthy behaviors moreso than the results of chnages in those behaviors. This framing is important because while both screening and healthy lifestyles are associated with less incidence and mortality, the effort required to achieve the protective levels of lifestyle (medium to high intensity counseling interventions) may be considerably greater than those required to get endoscopic screening (a discrete event).

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Reviewer #3: From non-randomized studies on colonoscopy screening as well as from randomized studies on sigmoidoscopy and FOBT studies we have learned that endoscopic screening is a sufficient tool to reduce incidence and mortality from colorectal cancer. Furthermore, epidemiologigal studies have identified various life style associated risk factors for colorectal cancer, including BMI, smoking, nutrition. Probably up to 50% of colorectal cancers could be prevented by a healthy life style. Whereas both a healthy life style and screening can reduce the colorectal cancer burden and both are recommended by various national and international guidelines, it is so far not known whether individuals undergoing screening colonoscopy can further reduce their colorectal cancer risk by maintaining a healthy life style.

Wang et al. provide an answer to this important question in their study. Based on the analysis of well-known and thoroughly studied cohorts, the nurses health study and the health professionals follow-up study, they are able to demonstrate that the reduction of colorectal cancer incidence and mortality by maintaining a healthy life style is independent of participating in colonoscopy screening. Furthermore, individuals who undergo colonoscopy and follow a healthy life style are able to further reduce their colon cancer risk. Therefore, the recommendation will be to participate in bowel screening and to maintain a healthy lifestyle in oder to minimize risk. To the best of my knowledge, this ist he first study to provide this evidence.

The study is well designed, the analyzes have been properly performed and the manuscipt is well written. I only have some minor issues:

1. Is there data available on the adenomatous polyp count / size in the colonoscopies? If yes, is there a difference regarding life style? I would expect that a healthy life style is associated with a lower polyp count.

2. Were the colonoscopies primary screening colonoscopies? Or did some patients have sigmoidoscopies or FOB testing before with a finding that resulted in referral to secondary screening by colonoscopy? How did you include negative screening by sigmoidoscopy or negative FOBT screening in your analysis? Somebody having negative sigmoidoscopy and/or negative FOBT every other year has undergone screening that will also reduce the risk of a diagnosis of colorectal cancer and will usually not undergo colonoscopy. If data on FOBT screening is available, data for sigmoidoscopies is obviously available, it would be important to study the group with no screening at all as the unscreened group currently comprises no screeing at all + screening other than colonoscopy.

3. How did authors account for changes in life style, e.g. unhealthy lifestyle in the beginning of the study and changing to a healthier diet over time?

4. Was there a difference in Duke`s or UICC staging of the cancers diagnosed between groups? As a stage shift towards lower stages by screening is known, it could be speculated that the group with screening + healthy diet not only has less cancers but also cancers at earlier stages.

5. Was there a difference in risk of a colon cancer diagnosis between individuals receiving one or more negative screening colonoscopies over time?

6. Page 8: Participants were considered as endoscopically unscreened until the first time they reported undertaking endoscopy for screening purpose and as endoscopically screened thereafter… How did authors account for diagnostic colonoscopies performed for complaints that did not provide any pathologies? A person undergoing colonoscopy for other reason than screening with no significant findings will usually not undergo screening colonoscopy within the next couple of years.

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

[LINK]

Revision 2

Attachments
Attachment
Submitted filename: Response to reviewers.docx
Decision Letter - Adya Misra, Editor

Dear Dr. Song,

Thank you very much for submitting your manuscript "Healthy lifestyle, endoscopic screening, and colorectal cancer incidence and mortality in the US: a nationwide cohort study" (PMEDICINE-D-20-03426R2) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and 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 Dec 14 2020 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. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

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,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

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

Requests from the editors:

Please compare the spline fit and linear fit as suggested by Ref1 in order to check what the differences are and if they are of practical importance rather than statistical significance. Please look at the reduction in error between the two models and then judge whether it is big enough to make the more complex spline model worth the effort.

Please add "our results indicate" or "our study suggests" in order to tone down the language throughout.

Please avoid implying a causal relationship between healthy lifestyle, endoscopic screening and colorectal cancer as this is an observational study

Please introduce all acronyms on first view. For instance the study cohorts are mentioned in the methods but it is not clear what the "NHS" stands for, for example.

Please add participant demographics in the abstract

Comments from the reviewers:

Reviewer #1: The authors have addressed most of my concerns. The remaining issue is about the splines.

I checked "proceed without recommendation" because what to do depends on non-statistical issues.

Here is the statistics part:

The authors tested a cubic spline for statistical significance and found it was not significant. But the p value of a test for linearity is not really the point. P values, in general, are problematic (see the American Statistical Ass'n Statement https://medium.com/@peterflom/some-thoughts-on-9-11-4f746ae9bdcb) and, here, as often, the real issue is effect size. That is, are the curves shown in the figure in their response to me straight or not?

The same effect size will be significant with more subjects. The key issue is whether it is meaningful and important.

And that's a non-statistical question. It depends on whether the difference between a straight line estimate and a spline estimate is "worth it" in terms of complexity.

One way to help answer this question is to see how well the two models do - how much does the spline model reduce the error? Is it enough that people in the field will care?

Peter Flom

Reviewer #3: The revised version of the manuscript has been strongly improved. My questions have been sufficiently answered.

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

[LINK]

Revision 3

Attachments
Attachment
Submitted filename: Response to editors and reviewers.docx
Decision Letter - Adya Misra, Editor

Dear Dr. Song,

Thank you very much for re-submitting your manuscript "Healthy lifestyle, endoscopic screening, and colorectal cancer incidence and mortality in the US: a nationwide cohort study" (PMEDICINE-D-20-03426R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx 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.

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 15 2020 11:59PM.   

Sincerely,

Adya Misra, PhD

Senior Editor 

PLOS Medicine

plosmedicine.org

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Requests from Editors:

Please revise to "United States" in the title

Please capitalise "W" in whites

Page 6- paragraph 2 suggest revising “high quality diet” as it is currently ambiguous

Page 7 suggest removing “prospectively”

Please add citations to or copies of the questionnaires used in both NHS and HPFS cohorts

Page 12 Results 1st paragraph should say “multivitamins”

Page 16- please remove "remarkable"

Discussion-I suggest removing all iterations of “causal” as this is an observational study. In addition, I suggest removing the speculation about biological pathways linking healthy lifestyle and CRC incidence.

Late in the paper you note that colonoscopy can include removal of CRC precursors. Please mention this as a possible basis for the preventive effect in the author summary and/or introduction. I assume there are no data on this.

Please remove funding and conflicts of interest information from the main text. These should be provided in the relevant sections of the article submission form.

Presumably, those less likely to be screened are less likely to have a healthy lifestyle - please mention this as a possible limitation?

Discussion- please avoid labels like “unhealthy lifestyle” I suggest replacing with less healthy lifestyle or similar

STROBE checklist- some information appears to be missing, for example page 3

Comments from Reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication

Peter Flom

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

[LINK]

Revision 4

Attachments
Attachment
Submitted filename: Response to editors and reviewers.docx
Decision Letter - Richard Turner, Editor

Dear Dr Song, 

On behalf of my colleagues and the Academic Editor, Dr Kolligs, I am pleased to inform you that we have agreed to publish your manuscript "Healthy lifestyle, endoscopic screening, and colorectal cancer incidence and mortality in the United States: a nationwide cohort study" (PMEDICINE-D-20-03426R4) 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. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

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

Sincerely, 

Richard Turner, PhD 

Senior Editor, PLOS Medicine

rturner@plos.org

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