PONE-D-21-28288Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumorsPLOS ONE

Dear Dr. Milbury,

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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ACADEMIC EDITOR: 

This is a MS with significant relevance. Please respond to the comments of 3 reviewers’ item-by-item to satisfy the reviewers' concerns. Please carefully edit the MS for English corrections and typos.

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PLOS ONE

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"All authors received funding for this work from Foundation Medicine, Inc. This is the only funding source for this work."

At this time, please address the following queries:

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"All authors are or were employees of Foundation Medicine, a wholly owned subsidiary of Roche, and have equity interest in Roche."

We note that you received funding from a commercial source: Roche

Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. 

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https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019S017C.pdf

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Additional Editor Comments:

This is a MS with significant relevance. Please respond to the comments of 3 reviewers’ item-by-item to satisfy the reviewers' concerns. Please carefully edit the MS for English corrections and typos.

[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

Reviewer #3: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: 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

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: In this manuscript, Mibury et al. report Clinical and analytical validation of FundationOne. Since it is important to validate NGS sequencing data for clinical use, I agree to the authors’ point make of this manuscript. I think the manuscript is carefully written. Therefore, I basically do not have conceptual problem to this study. However, the manuscript is too long. I do not think people will read through the manuscript, except the reviewer like me, because peoples are usually interested in specific cancer types. In addition, the style of the manuscript is very unusual. I would recommend to revise this manuscript to “reader friendly style”.

Specific recommendation:

1: I would recommend to divide into several manuscripts.

2: Although the major part of the text in this manuscript is “Methods and Results”, this is very unusual. I somehow understand why the authors wrote with this style. However, as a reader, this makes hard to understand the study. I would recommend to write Methods and Results separately. In the result section, please just briefly describe their methods that are required to understand the results.

Reviewer #2: This is an important MS in the era of precision medicine. CGP is designed to provide accurate genetic alterations by virtue of reducing complexity of biomarker(s) testing and enabling precision medicine to improve outcome/management of cancer patients. May be it is important beyond the cancer patients.

This is an important MS but minor revision is needed before publication.

Minor comments:

1. Please discuss about variant of unknown significance (VUS), Tumor fraction (TF) and variations of allele frequencies (VAF)

2. Authors also provide a comparison between customized gene panel NGS vs WES vs WGS

3. Authors may also provide a simple methodology flow chart. It is good for the readers especially for new clinical researchers, residents and clinical fellow

4. Also need a table for abbreviations

Reviewer #3: Well written, carefully prepared validation Report of an important genetic test on its way from avant-garde to becoming gold standard. While there is no surprise and little novelty in this manuscript the data are important enough to be published and well discussed in a high quality journal.

Minor criticism:

To better appeal to the general reader the manuscript would profit from being shortened and becoming a bit more concise.

A list of abbreviations used should be included for easier readability.

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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

Reviewer #3: No

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Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors

PONE-D-21-28288R1

Dear Dr. Creeden,

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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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,

George Vousden

Staff 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

Reviewer #2: All comments have been addressed

Reviewer #3: 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

Reviewer #3: Yes

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

Reviewer #1: N/A

Reviewer #2: I Don't Know

Reviewer #3: N/A

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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: Yes

Reviewer #2: Yes

Reviewer #3: 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 #1: Yes

Reviewer #2: Yes

Reviewer #3: 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 #1: (No Response)

Reviewer #2: Revised MS is much better and informative than the original one. After revision the MS is much improved and good for Physician scientists and researchers. Also after adding the flow chart in the methodology, it is much easy to follow.

Reviewer #3: In the revised manuscript the authors have made a good job in making it shorter and more concise without loosing valuable information. The paper will give the field and even clinicians the possibility to gain additional and developing insight into tools they are starting to use in their daily practice.

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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

Reviewer #3: Yes: Prof. Dr. Michael W. Krainer, Medical University Vienna