PONE-D-19-32655

Epidemiology, mortality and prevalence of colorectal cancer in ulcerative colitis patients between 2010-2016 in Hungary – a population-based study

PLOS ONE

Dear Mr. Kunovszki,

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.

We would appreciate receiving your revised manuscript by Feb 14 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Valérie Pittet, PhD

Academic Editor

PLOS ONE

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2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed:

https://insights.ovid.com/pubmed?pmid=17156150

https://doi.org/10.1016/j.crohns.2014.06.004

https://www.ncbi.nlm.nih.gov/pubmed/10231311

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed.

3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

4. Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the authors of this manuscript have the following competing interests:

PK, JGO, PT, AB are employees / consultants of Janssen.

TM received speaker's honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer and Teva."

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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: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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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: Yes

Reviewer #2: No

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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: No

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5. Review Comments to the Author

Reviewer #1: Thank you for the opportunity to review the manuscript "Epidemiology, mortality and prevalence of colorectal cancer in ulcerative colitis patients between 2010-2016 in Hungary – a population-based study" Please find my comments below.

1. As many may be unfamiliar with your healthcare database it would be helpful to have either a better description or a reference to a description of the database in the manuscript and some highlights as it pertains to this manuscript.

2. Endpoints need to be described better. Primary endpoints are endpoints that your study is powered to detect. Secondary endpoints are those which the study is not powered to detect. Just stating that you had 3 endpoints is not adequate.

3. I would advocate removing figure 2 altogether since you state that you cannot adequately determine the incidence. You do a nice job of explaining why, but that essentially renders most of your data in that table questionable at best. I think keeping he descriptive language is good enough for this.

4. On Figure 3, the legend at the top has the male label over the female plot and vv. I would recommend switching that order to make it easier to understand.

5. Figure 5 is too difficult to interpret. Please either include the names on the cancers on the Y axis or highlight and name some key cancers within the figure.

6. Are deaths cancer-specific, disease-specific, or all cause? It seems like they are all cause but I think this needs to be highlighted better. This is also a big weakness of this manuscript because it is hard to know if these cancer patients had more severe disease, or accessed healthcare less and had other comorbidities. This should be discussed more in depth in the discussion.

7. Figure 8 is labeled poorly. It seems like it is CRC patients with UC, but from the labeling it appears to be all CRC patients in the country. This labeling should be improved upon.

8. It would be important to know whether the change in mortality from CRC in UC was unique to UC or whether this was similar as to the general population. This data should be collectable using your database and I would recommend including this as well.

Reviewer #2: This is a population-based national study on UC and associated CRC mortality, among others. Administrative data is used. The authors find an increased risk of CRC-mortality in UC patients.

Abstract

1. There is no clear description of the analytical methods used, including type of analysis, matching procedure.

2. The aim in the methods section should be more appropriately located in the background section.

General

1. The manuscript needs to be edited by a thorough English speaker.

Introduction

1. The introduction is winding and overly long and could be shortened considerably. What does this study add, why was it done? What gap of knowledge exists and how could this study help`?

Methods

2. The aim should be placed in the introduction section, along with a clear hypothesis.

3. The English is not up to par in the "Data Collection" section, making it difficult to follow. PLease revise.

4. The described algorithm for identifying UC patients seems reasonable, though validity is not mentioned. Has this algorithm been tested against e.g. chart data, and with what results?

5. Though I assume this to be the case, it should be mentioned that also the matched controls were also assessed for CRC using the described method for the UC patients (the cases).

6. In the statistics section, there is no mention of missing data and how this was handled. Also, was the Cox model tested for assumptions?

Results

7. The authors state that the decrease seen in UC incidence is a function of their diagnosis capture. This should be stated in the discussion, and how sure are the authors of this fact? MOreover, please analyse this statistically also (p value for difference/trend).

8. It would be interesting to see the incidence of CRC in the matched population also.

9. State p value for difference when comparing median survival in CRC UC versus non-CRC UC.

10. Survival curves should have Life tables and log rank tests, perhaps also confidence intervals.

Discussion

11. There is a paucity of other populationbased studies (apart from Hungarian ones) in the discussion. E.g. Rutegard 2016 Scand J Surg found 9% CRC incidence after 38 years of screening colonoscopy in a defined UC cohort and should be cited, along with the St Marks study (Rutter 2006 Gastroenterology). Is there any screening programmes for UC in Hungary?

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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.

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Reviewer #1: No

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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-32655R1

Epidemiology, mortality and prevalence of colorectal cancer in ulcerative colitis patients between 2010-2016 in Hungary – a population-based study

PLOS ONE

Dear Mr. Kunovszki,

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.

We would appreciate receiving your revised manuscript by Apr 30 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable 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/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

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 look forward to receiving your revised manuscript.

Kind regards,

Valérie Pittet, PhD

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: All comments have been addressed

Reviewer #2: All comments have been addressed

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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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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: No

Reviewer #2: 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

**********

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: Thank you for addressing our concerns. The introduction is still quite difficult to read and I would recommend having a native English speaker rewrite it prior to acceptance.

Reviewer #2: The authors have responded adequately to most questions and I can only recommend publication. Please note that Figure 6 seems to be inverted, i.e. have cases and controls been mixed up? Seems strange that the colitis should be both bigger and more prone to survive, given the increased HR for this group stated in the manuscript.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Epidemiology, mortality and prevalence of colorectal cancer in ulcerative colitis patients between 2010-2016 in Hungary – a population-based study

PONE-D-19-32655R2

Dear Dr. Kunovszki,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Valérie Pittet, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: