Peer Review History

Original SubmissionFebruary 3, 2020
Decision Letter - Adya Misra, Editor

Dear Dr Funston,

Thank you for submitting your manuscript entitled "The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: a population-based cohort study" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff [as well as by an academic editor with relevant expertise] and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Adya Misra, PhD,

Senior Editor

PLOS Medicine

Revision 1
Decision Letter - Emma Veitch, Editor

Dear Dr. Funston,

Thank you very much for submitting your manuscript "The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: a population-based cohort study" (PMEDICINE-D-20-00302R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jun 05 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***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 ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that 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/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*Some minor reformatting is needed to the article structure to fit better with PLOS Medicine's format. In the abstract, we'd ask the authors to restructure this using the PLOS Medicine headings (Background, Methods and Findings, Conclusions) - "Methods and Findings" is a single subsection.

*In the last sentence of the Abstract Methods and Findings section, please describe some of the key limitation(s) of the study's methodology.

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*Ideally, please reformat the in-text reference callouts to use the PLOS Medicine style (numerals in square brackets) rather than superscript numerals- this should be fairly quick and easy if using referencing software.

*Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

*The two subsections at the very end of the paper, 'What is already known on this topic' and 'What this study adds' should be deleted (and any unique material from there incorporated into the paper) as these aren't needed for PLOS Medicine publication.

*It's good that the paper has been reported according to both STARD and RECORD reporting guidelines - we'd suggest the authors include as supporting information the completed checklist for just one of these, ideally STARD as that would be the relevant guideline for the overall framework of the study.

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Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper.

Overall, I think they were outstanding and I wish other authors of similar studies could be made to read these methods and adapt them. I've been saying stuff like this for years but little has changed. Good to see.

But I do have some issues to resolve before I can recommend publication.

NOTE: There were neither page numbers nor line numbers - this makes things tricky for the reviewer

Intro: Give numbers for stage II and III

Model building: The sentence starting "The number of polynomial terms ...." Whether to use splines or polynomials is an interesting question. Using AIC to decide is one reasonable way. I tend to like splines, but polynomial terms can also work. But I would set an upper limit on the order of they polynomial (maybe cubic but no higher) because beyond that they lose the main advantage over splines - interpretability. Please list the terms used here (and give details in the appendix).

Rather than dichotomize age, leave it contnuous and investigate it the same way you did CA125. Then include the terms (spline or polynomial) in the model. This would give a probability for every combination of age and CA. And the plts could be changed to trellis plots.

Section on cutoff: Maybe add a discussion of why 3% was chosen and the costs of the diferent errors.

figure 2 is too small to read, at least on a printout. I needed a magnifying glass.

Peter Flom

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Reviewer #2: This is a very informative study reporting the estimated probabilities of ovarian cancer and all cancers are reported for a wide range of CA125 levels. The findings will allow assessment of the probability of undiagnosed cancer, other than ovarian, enabling the expedited investigation and referral in the UK.

The only critique is that the first paragraph of Abstract is very confusing and should be revised.

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Reviewer #3: Funston G and colleagues present their findings on the diagnostic performance of Cancer Antigen 125 (CA125) to detect ovarian and non-ovarian cancer. Being able to effectively diagnosis ovarian cancer at early stages has remained one of the most significant challenges in managing ovarian cancer. Nearly 80% of patients are diagnosed at late stages, which confers a poor prognosis. The authors recognize that most cancer care starts with the general practitioners and there is a urgent need to better define cancer risk associated with elevated CA125 levels. Specifically, while the risk threshold for investigating a potential cancer was been redefined at 3%, the guidance for ovarian cancer remains largely dependent on CA125 levels (35 U/mL). The authors performed a large (n=50,780) retrospective study on patients being treated in the English system. The data is intriguing and will provide strong evidence to shift clinical interpretation of CA125 levels. The manuscript is well written, concise, and clear. Overall, the research study significantly contributes to the field of ovarian cancer. There are a couple of noted weaknesses that should be addressed.

1) The authors note that a limitation of this study was that only contains patients being evaluated in the English system. This limitation should be expanded upon at minimum in the discussion and potentially in the results. For instance, there several confounding factors that contributes to CA125 levels including race, smoking, hysterectomy, menstrual cycle, etc. (PMID: 11352859). Changes in menstrual cycle can account for CA125 change up to 22%. It is unclear from the manuscript whether beyond age these factors contributed or detracted from the findings.

2) Different histological subtypes for ovarian cancer should be noted, because different histotypes are not likely to have the same CA125 threshold. It is interesting that in women <50 y.o. required a CA-125 level of 179 U/mL to equate to a 3% probability of invasive ovarian cancer, which is likely due to different (other than high grade serous) and less invasive histotypes being more prevalent in pre-menopausal women.

3) Figure 2 is difficult to read, the text is too small, and the y-axis different for each graph.

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Revision 2

Attachments
Attachment
Submitted filename: Editor and reviewer responses.docx
Decision Letter - Clare Stone, Editor

Dear Dr. Funston,

Thank you very much for re-submitting your manuscript "The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: a population-based cohort study" (PMEDICINE-D-20-00302R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by the statistical reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***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.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Aug 18 2020 11:59PM.

Sincerely,

Clare Stone, PhD

Acting Chief Editor

PLOS Medicine

plosmedicine.org

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Requests from Editors:

Please avoid use of itals for emphasis

The checklist should have sections and paragraphs instead of page numbers as these can change during formatting etc.

Comments from Reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication.

Peter Flom

Any attachments provided with reviews can be seen via the following link:

[LINK]

Revision 3
Decision Letter - Clare Stone, Editor

Dear Dr Funston,

On behalf of my colleagues and the academic editor, Dr. Steven D Shapiro, I am delighted to inform you that your manuscript entitled "The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: a population-based cohort study" (PMEDICINE-D-20-00302R3) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

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A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Clare Stone, PhD

Managing Editor

PLOS Medicine

plosmedicine.org

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