PONE-D-22-07328Interpreting Polygenic Score Effects in Sibling AnalysisPLOS ONE

Dear Dr. Fletcher,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Heming Wang, PhD

Academic Editor

PLOS ONE

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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: Yes

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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: No

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: In this manuscript, the authors explored these expectations by using family (quad) data and simulations that include indirect genetic effect processes and evaluates the ability of sibling analysis to uncover direct genetic effects of polygenic scores. They pointed out that interpreting results from sibling analysis aimed at uncovering direct genetic effects should be treated with caution.

Overall, it is a solid manuscript. The authors conducted a variety of simulation scenarios to demonstrate the bias. The methodology and procedures were proposed and clearly described. The results and conclusions were clear and logical. The limitation is that the results are from a “simple” data generating processes, where they assumed no assortative mating, no gene-environment interaction or correlation, and sibling genetic correlations of exactly 0.5. But I understand that it is much more complicate in the real world.

My comments are:

1. the authors did 15 simulation repetitions, for me 15 times is kind low. I would expect that the results are generated from at least a few hundreds of repetitions.

2. In each of the boxplot, we can see that some groups have larger variations then others. Is there any explanation?

Minor comments:

1.The reference style is not consistent. For example, Introduction, second paragraph.

2. The authors should fix all the math symbols and letters. They are not showed on the pdf file.

Reviewer #2: The authors use simulated and real-world data (from parent-children quads), to determine whether within-family analyses using polygenic scores can truly separate direct and indirect genetic effects. This analysis seems especially important given that this is a claim that is often made, but not previously tested. The authors find that even under the ideal scenario (all direct, no indirect effects), within-family analyses tend to underestimate the true effect. As indirect and direct genetic effects become more correlated, estimate from within-family models become more biased in an unpredictable manner. This is an important investigation of a common assumption: that within family models are robust estimates of true direct genetic effects. It would be a welcome addition to the literature. My comments are mostly minor in hopes of clarifying some of the information provided in this manuscript.

Major points

Is this really a limitation of genetic analyses only? Could this be a broader issue of family fixed effects models in social and behavioral sciences more broadly? Is there any reason to think that the issues raised in these simulations do not also apply to phenotypic or environmental analyses within family?

Minor points:

Moving the data and methods into the main text would be helpful. I know that it helped orient me to the analyses.

The axis labels in the figures could be a bit clearer, maybe “estimated/expected”? Something that helps the reader quickly distinguish what the ratio is comparing.

Additionally, I think the figure labels could better differentiate the comparison. For example, rather than “between/between” and “within/within”, why not “between/indirect” and “within/direct”? This may better orient the reader to the fact that it is a comparison of an estimate to the true population parameter.

It might help to provide some specific examples of when we might expect different scenarios of different combinations of direct and indirect effects (e.g., height vs educational attainment).

I hope the authors take these comments in the constructive manner in which they are intended. This is a valuable analysis and important to those in the filed using polygenic scores.

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Reviewer #1: Yes: Xiaoyin Li

Reviewer #2: No

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PONE-D-22-07328R1Interpreting Polygenic Score Effects in Sibling AnalysisPLOS ONE

Dear Dr. Fletcher,

Thank you for submitting your manuscript to PLOS ONE. We are happy to tell you your revised manuscript in provisionally accepted. However, in order to publish your paper, please revise the format your math equations such that they will be displayed correctly.

Please submit your revised manuscript by Oct 27 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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.

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

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Heming Wang, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Please see the note from Reviewer 1 and double check the display of math formula in your final version.

[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: (No Response)

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: The authors addressed most of my comments. Some of the math formulas still did not display correctly.

Reviewer #2: (No Response)

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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.

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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.]

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

Interpreting Polygenic Score Effects in Sibling Analysis

PONE-D-22-07328R2

Dear Dr. Fletcher,

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.

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Kind regards,

Heming Wang, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: