PONE-D-20-02997

Addressing Missing Data in Randomized Clinical Trials: A Causal Inference Perspective

PLOS ONE

Dear PhD van Klaveren,

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.

==============================

I agree with the reviewers, and would say minor revision.  But I do have one other comment to add.  Specifically, this statement here:

In other words, randomization enables internal validity (Rubin, 1974), such that

differences between participants in a clinical trial assigned to different treatment arms can,

apart from random error, be attributed to the treatment under investigation (Jüni, Altman &

Egger, 2001).

This claim is categorically untrue.  The reason for it being false should be discussed, as opposed to just deleting it, since this is a common sentiment, and needs to be refuted.  It is somewhat disgraceful that authors are still making this claim even today, when we know better.  I would refer the authors to my book:

Berger, VW (2005). “Selection Bias and Covariate Imbalances in Randomized Clinical Trials”, John Wiley & Sons, Chichester.

==============================

We would appreciate receiving your revised manuscript by Jun 15 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,

Vance Berger

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Additional Editor Comments (if provided):

I do have one other comment to add. Specifically, this statement here:

In other words, randomization enables internal validity (Rubin, 1974), such that

differences between participants in a clinical trial assigned to different treatment arms can,

apart from random error, be attributed to the treatment under investigation (Jüni, Altman &

Egger, 2001).

This claim is categorically untrue. The reason for it being false should be discussed, as opposed to just deleting it, since this is a common sentiment, and needs to be refuted. It is somewhat disgraceful that authors are still making this claim even today, when we know better. I would refer the authors to my book:

Berger, VW (2005). “Selection Bias and Covariate Imbalances in Randomized Clinical Trials”, John Wiley & Sons, Chichester.

[Note: HTML markup is below. Please do not edit.]

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

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

**********

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

**********

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: The paper addresses an important topic - missing data and related causal inference in RCTS.

The paper is well-written but could be improved further with more relevance to readers with the inclusion of (1) simulations with different baseline covariate distributions under different treatment effect sizes: small, medium and large and (2) relevant data and syntax to enable replication of authors findings.

Reviewer #2: The manuscript by Cornelisz et al. takes a causes inference approach to address selection bias and missingness in outcomes due to MCAR, MAR, and MNAR in clinical trials. To do this, the authors provide causal inference-based strategies for estimating the average treatment effect, improve precision, and to test some underlying assumptions related to missingness.

The article was well written and easy to follow.

See below for my comments.

\\begin{enumerate}

\\item On page 10, change "demonstrate" to "demonstrated" in the sentence "The potential of exploiting RFLB...".

\\item On page 11, the sentence "Individuals are randomly assigned to one of both treatment conditions, such that always only one of both potential outcomes...." seems a little confusing. Can the authors clarify this sentence?

\\item On page 15, the sentence "The term 'missing at random' therefore does not defines missing outcomes as random events" also needs to be clarified. Can the authors double check this sentence?

\\item On page 17, can the authors say more about the monotonicity assumption since the assumption of the bounding procedure depends on this. What happens when the monotonicity assumption is violated?

\\item Are there certain assumptions/conditions that need to be met in order to apply the RFLB - this was not clear. Can you say more about the assumptions?

\\end{enumerate}

\\end{document}

**********

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.

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.

Addressing Missing Data in Randomized Clinical Trials: A Causal Inference Perspective

PONE-D-20-02997R1

Dear Dr. van Klaveren,

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.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Vance Berger

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: