PONE-D-20-21709

Coffee consumption and risk of breast cancer: a Mendelian Randomization study

PLOS ONE

Dear Dr. Ellingjord-Dale,

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.

First of all I want to apologize with the authors as the peer review process takes a long time. One of the reviewer who initially accepted to review the manuscript did not eventually do the review. The manuscript has now been reviewed by two external evaluable referees, who suggested minor revisions. I am agree to, this is a well written and as per state of the art conducted investigation. The reviewers’ comments are attached below. In addition to such comments, I would ask to the authors to specify all the parameters involved in the computation of the study power (page 7), including the type I error. It’s also not clear to the reader what parameters 0.89, 0.87 and 0.80 represent, i.e. regression coefficients? Or what else?

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We look forward to receiving your revised manuscript.

Kind regards,

Matteo Rota, Ph.D.

Academic Editor

PLOS ONE

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3.Thank you for stating the following in the Acknowledgments Section of your manuscript:

[The

breast cancer genome-wide association analyses were supported by the Government of

Canada through Genome Canada and the Canadian Institutes of Health Research, the

‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome

Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065,

18

X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and

The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935).]

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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: Yes

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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: Yes

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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: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I think this is an interesting research with large genetic data in Europe.

#1 What kinds of subtypes did you assess? I understand that you investigated the relationship between genetically predicted coffee consumption and risk of breast cancer overall as well as breast cancer subtypes incorporating several MR methods to assess the impact of potential MR assumption violations. However, there were no information about subtypes you assessed in method. There are several subtypes in breast cancer, so please state which subtypes you assessed in method section.

#2 Have you considered the dose-response analysis, especially for the postmenopausal women? There is a dose-response meta-analysis regarding the association between coffee intake and breast cancer risk. (Nutrients. 2018 Jan 23;10(2):112) The result showed that consumption of four cups of coffee per day was associated with a 10% reduction in postmenopausal cancer risk. If you have done, please include it in the results.

#3 You mentioned that you have considered some potentially important confounders of coffee and breast cancer association (BMI, age at menarche, alcohol, smoking, and age at menopause). How did you choose these factors? There are more factors potentially associated with breast cancer, as parity, age at first birth, family history of breast cancer, and use of menopausal hormone therapy. (Biochim Biophys Acta. 2015 Aug;1856(1):73-85) Is it possible to consider these factors in the analysis?

Reviewer #2: Ellingjord-Dale, M. et al performed a 2-sample Mendelian randomization analysis, accompanied by comprehensive sensitivity analyses to investigate the association between coffee intake and risk of breast cancer. Authors observed null associations in both primary and sensitivity analyses. The manuscript is well written and easy to follow. Below are my suggestions/concerns that need to be addressed in the revision.

• Given substantial heterogeneity in ratio estimates between variants, it is misleading to present results from the fixed IVW analyses. I suggest to remove “IVW fixed” results from figure 1, 2 and 3.

• In the conclusion, authors state “…, but we cannot rule out existence of weak inverse association”. I agree with authors that there could be a weak association which was not picked up by the study, but I do not think it is appropriate to infer directionality of such association.

• In the discussion, authors should also acknowledge linearity assumption with their MR analyses. If there is a threshold adverse effect, this could have been masked by fitting a linear model.

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Reviewer #1: No

Reviewer #2: No

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Coffee consumption and risk of breast cancer: a Mendelian Randomization study

PONE-D-20-21709R1

Dear Dr. Ellingjord-Dale,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Matteo Rota, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This editor judged as resolved the comments raised by Reviewer #1. Reviewer #2 suggested to accept the manuscript for publication, too. We are pleased to inform you that your manuscript can now be published in PLOS ONE.

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 #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 #2: Yes

**********

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

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 #2: Yes

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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 #2: Yes

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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 #2: 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) (Limit 100 to 20000 Characters)

Authors have addressed all my concerns.

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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 #2: No