PONE-D-21-10921Principal Investigators Over-optimistically Predict Scientific and Operational Outcomes for Their Clinical TrialPLOS ONE

Dear Dr. Kimmelman,

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 would like to thank all 3 reviewers for providing a fast and interesting feedback on this manuscript. I must acknowledge that it took me some times to secure reviewers for this paper and apologize for the delays. I wanted to have a clear understanding of the statistical approach used and have asked a specific advice to a 3rd reviewer about these aspects. Please try to take into account all the comments made by the 3 reviewers by detailing as much as possible your methods in order to make sure that it will be understandable by a large audience.  

I have a few additional comments : 

- In the abstract : please add a few words in the conclusion about the limitations in order to avoid any spin ;

- I appreciate the transparency in the manuscript and in the appendix but I missed a mention of a pre registration : 

. If the study was registered, please provide a specific number of registration ; 

. If the study was not registered, please make it explicit ;

. I would also suggest to edit the method section in order to move any change to the initial protocol in a dedicated paragraph "changes to the initial protocol". 

I agree with the reviewers that the paper is about an important issue. 

Please submit your revised manuscript by Nov 29 2021 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.

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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.

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We look forward to receiving your revised manuscript.

Kind regards,

Florian Naudet, M.D., M.P.H., Ph.D.

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: Partly

Reviewer #2: Partly

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: 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: No

Reviewer #3: 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

Reviewer #3: 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: ***************************************************************************************************

please see the attached report

***************************************************************************************************

Reviewer #2: Benjamini and colleagues aimed to assess the accuracy of principal investigators’predictions about three events for their own clinical trials: positivity on trial primary outcomes, successful

recruitment and timely trial completion. The topic is of interest but the manuscript needs major revisions before being considered for publication.

The main remark is the difficulty to read the results due to multiplicity and the unusual statistical methods used. The Brier score is well explained but the utility of the comparison of PI scores to predictions algorithms is difficult to understand. I wonder if a simpler analysis could show similar results. For example, for the primary endpoint, authors could show the percentage of studies for which PIs expected statistical significance and finally were negative.

Table 1: why adding columns 2 and 3 (with respective n= 281 and 536)? What is their utility regarding the aim of the study? In the same way why showing column 4 (match sample of 100 trials). This is confusing for me; the footnote does not mention the origin of the different columns.

Fig 3 needs clarifications. At least, foot notes should be added. The results section says that when referring to figure 3, PI showed moderate discrimination for primary outcome but not for recruitment or timeline attainment. Please explain how you can say that when looking at the figure.

The utility of sensitivity analysis needs also to be clarified, especially the ROC curves shown in fig A3.

Reviewer #3: The article is interesting and well-written. However, a think there is the room for a further improvement. In particular, it is well-known that there are several decompositions of the Brier score which provide a deeper insight. Therefore, I wonder if one of these decompositions may be useful to obtain further insights on the data analyzed by the authors. Moreover, I have the additional minor remarks:

1. Captions of tables and figures are too long.

2. In sentences like “timely closure for trials.(15)”, “metrics in prediction studies:(16) calibration”, and “measured using the calibration index;(13)(16) the”, the numbered citations should be placed before the punctuation.

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Reviewer #1: Yes: Leonhard Held

Reviewer #2: No

Reviewer #3: No

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PONE-D-21-10921R1Principal Investigators Over-optimistically Forecast Scientific and Operational Outcomes for Clinical TrialsPLOS ONE

Dear Dr. Kimmelman,

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 still think that this is an important paper, thank you for submitting it. I really appreciate your edits.

I would like to thank the 3 reviewers. As you will see they were pleased with your edits. One of the reviewers still raise a few comments. I must say that I agree with him and I'm looking forward to reading your responses. 

Please submit your revised manuscript by Feb 06 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,

Florian Naudet, M.D., M.P.H., Ph.D.

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.

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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

Reviewer #3: All comments have been addressed

**********

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

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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 Response)

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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: Comments on the response to my comments on PONE-D-21-10921. The

numbers refer to the order of my original comments.

1) Thanks for giving more details on the elicitation procedure. Your

explanation indicates the presence of digit preference bias with all

percentages divisible by 5, except for 1, 99, 33 and 67. This should

be mentioned as a limitation of the study.

3) Thank you for your explanation, I was inaccurate in my point. Yes,

the probability of a significant (positive) finding is

Pr(sig) = Pr(sig | H0) Pr (H0) + Pr(sig | H1) Pr(H1)

Now Pr(sig | H0) = usually 5% and Pr(sig | H1) is the assumed power

(say 80%). Therefore, if the clinician reports Pr(sig) it is possible

to infer her personal prior probability Pr(H0) (or equivalently Pr(H1)

= 1 - Pr(H0)). For example, if Pr(sig)=70% is reported by the

clinician we obtain Pr(H0) = 13% and so Pr(H1)=87%. Not sure if this

is helpful for the manuscript but I just wanted to make my point clear.

Minor point "Brier scores": Maybe I wasn't clear but I still think it

does not make sense to report Brier scores of extreme forecasts

because, under the null hypothesis of perfect calibration, the

expectation of the mean BS is (sum p_i*(1-p_i))/n, see Spiegelhalter

(1984, p. 427). If you only look at extreme forecasts (p_i very small

or very large), the mean BS will (under H0) therefore be on average

smaller than overall.

It seems that you need to enlarge the upper limit of ylim in Fig 2, as

one bar currently touches (or crosses?) the limit.

General comment: The absence of a study protocol is a weak point. How

can we criticize the design and reporting standards of clinical trials

if our own standards are not any better? Surely, study protocols have

been very common in medical research prior to 2013. Not just for

clinical trials, but also for other study types (e.g. PRISMA was first

published in 2009).

Reviewer #2: I would like to thank the authors for their responses to reviewers comments and modifications that clarifed the manuscript and allow now its publication.

Reviewer #3: The authors did a good job in revising the paper according to the received comments. Therefore, the paper can be accepted as it is.

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Reviewer #1: No

Reviewer #2: Yes: Bruno Laviolle

Reviewer #3: 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.

Principal Investigators Over-Optimistically Forecast Scientific and Operational Outcomes for Their Clinical Trials

PONE-D-21-10921R2

Dear Dr. Kimmelman,

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.

First I would like to thank the reviewer for his super fast feedback. 

And importantly, kudos for this nice piece of work that I am pleased to accept for publication.

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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.

Kind regards,

Florian Naudet, M.D., M.P.H., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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

**********

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: (No Response)

**********

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

Reviewer #1: (No Response)

**********

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 Response)

**********

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: (No Response)

**********

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: (No Response)

**********

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: Yes: Leonhard Held