PONE-D-22-30639Influences of age and gender on operative risks following carotid endarterectomy: a systematic review and meta-analysisPLOS ONE

Dear Dr. Rerkasem,

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.

Please submit your revised manuscript by Feb 18 2023 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,

Athanasios Saratzis

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 this manuscript is a systematic review or meta-analysis; our author guidelines therefore require that you use PRISMA guidance to help improve reporting quality of this type of study. Please upload copies of the completed PRISMA checklist as Supporting Information with a file name “PRISMA checklist”.

Additional Editor Comments:

The 3 expert Reviewers have identified some major issues relating to the methodology as well as the presentation of the article. Please consider all points raised by the Reviewers, especially relating to the way the analyses were conducted and clinical translation/impact of variables that might have influenced the results.

[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: Partly

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

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

**********

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: No

Reviewer #3: No

**********

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: Many thanks for the opportunity to review this manuscript reporting the results of a meta-analysis of studies reporting age and/or sex associations with outcomes following carotid endarterectomy. This is a large and apparently rigorous review of available literature which has included and pooled data from a large number of studies. Whilst this offers breadth, my main concern with the methodology of this meta-analysis is heterogeneity, particularly in the meta-analysis of associations of age with outcomes. Whilst I commend the authors on their work, I think major revisions are required to the analyses before I could recommend this manuscript for publication. Please find detailed comments below:

1. It is very rare that fixed-effect analyses are suitable. I do not think fixed-effects analyses are appropriate in this type of meta-analysis. The authors have used a mix of observational and randomised data and as such the heterogeneity of study designs is too great for fixed-effects analyses to be used. It is also not clear from the reporting which meta-analyses the authors have performed have used a fixed-effects model. The authors should repeat any analyses where a fixed-effects model has been used and instead use a random effects model.

2. Whilst I accept that the use of I^2 as a measure of heterogeneity is widely used in the literature, it is frequently used and interpreted inappropriately (https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/1471-2288-8-79). It definitely should not be used to decide on whether a fixed- or random-effects analysis should be used. As above, please use a random-effects model for all analyses. Consider reporting Tau^2 in addition to I^2 as this represents the ammount of between-study heterogeneity whilst I^2 estimates the % of variability due to between-study heterogeneity and precision of the effect estimates has a big impact on I^2.

3. I do not think the meta-analyses of age in its current form is valid. At the very least the forest plot should be presented in subgroups of studies that compared ages at different cut points (<65 and 65+; <70 and 70+; <75 and 75+; <80 and 80+). However I'm not sure that pooling all these studies with different cut points is appropriate as this pools data from different age cohorts. The most robust way to investigate the influence of age would be to perform separate meta-analyses pooling data from studies that have used the same cut-point only.

4. Similarly I have concerns about the meta-analyses of short- and long-term outcomes. The time points for these outcomes are not defined in the methods. Given that the outcomes are reported as odds ratios then the outcome measures themselves need to be measured at the same timepoint (e.g. 30 day mortality pooled together, 1 year mortality pooled together, 5 year mortality pooled together). Studies reporting outcome measures at different timepoints should not be pooled in the same analysis.

5. There is a notable lack of table summarising included studies presented in the manuscript or supplementary material. The authors state all the data that has been extracted but this is not presented anywhere. I think there should be a table included which describes the data included. Of particular note, there is no information of sample size for each individual study presented anywhere in either the manuscript or supplementary material. A table presenting the raw data extracted from each study as detailed in the methodology and also including the sample size should be presented in the supplementary material. This would provide important context to enable readers to interpret the results appropriately.

6. Are the authors confident that there is no double-counting of participants? For example, have more than one study utilised data from the same registry e.g. ACS-NSQIP, VSQIP, NVR etc. The authors need to take care not to include studies that have utilised the same database with overlapping timeframes in the same meta-analysis as this risks potentially including the same participants and outcome events in the same meta-analysis multiple times. This risk is highlighted in this recent paper by Hussein et al (https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-022-14213-6).

7. I presume all of the data extracted and pooled are unadjusted for confounders. If so, this is a significant limitation to the study and should be mentioned. There is a very high risk that any observed effect is due to confounding in the individual studies and that pooling data magnifies this effect. It would be interesting, if possible, to include a meta-analysis of suitable outcome measures using effect estimates from studies that used comparible adjutment models to reduce the impact of confounding. This would also have limitations (especially as it is unlikely adjustment models were the same between studies) but may increase the confidence of findings.

8. I am unclear from the methods and reporting of results what sensitivity analyses have been performed. Subgroup analyses are usually presented as a single forest plot divided into relevant subgroups. Sensitivity analyses are reporting of the pooled analyses with only studies with specific characteristics removed from the analyses. Please could the authors be more specific about the subgroup analyses performed and what sensitivity analyses have been performed with their justification?

Minor comments:

1. The objectives in the abstract merely describe the methodology. Please describe the purpose of the meta-analysis based on the PICO question(s) i.e. investigate associations of age and sex on outcomes following CEA.

2. Please include the dates when the searches were last completed. They are mentioned in the abstract but not included in the manuscript that I can see (apologies if I've missed it).

3. I'm not sure what this means: "Hand searching which was proceeded via contacting expertise to further obtain published and unpublished studies." (lines 109-110) Please revise.

4. The order of reporting results seems strange. Whilst reporting risk of bias before presenting the results of the meta-analyses is usual, reporting the risk of publication bias and the GRADE assessments before presenting the actual results of the meta-analyses themselves seems strange. I think the more appropriate order would be to present the publication bias results after the results from the meta-analyses and then the GRADE assessments as the final part of the results.

Reviewer #2: This study aimed to stratify by age and gender, the 30-day and 5-year stroke and mortality outcomes following carotid endarterectomy. The authors undertook an extensive search of the literature including 133 studies. They concluded that individuals over the age of 80 and those with asymptomatic disease had a higher mortality rate within 30 days of carotid endarterectomy. Additionally, women had a higher incidence of stroke within 30 days of carotid endarterectomy than men. While this study is of interesting and beneficial value, the article is, at times, difficult to read and to interpret with grammatical errors. Below are detailed reviews of each section and include suggestions to improve the manuscript.

ABSTRACT:

Objective to determine the outcomes of CEA however the authors only reported the stroke and mortality rates. The word outcomes suggest that other factors were included such as TIA and MI. Please reword this throughout the paper to make it clear to the reader that stroke and mortality were the only outcomes assessed.

Line 47: First time CEA is mentioned, should be written out

INTRODUCTION:

Line 82: Please provide a reference for this statement

The second paragraph reads like a discussion proving an argument rather than setting the scene for the research undertaken. Consider rewording and restructuring.

Objective – Please provide a definition for what is meant by short-term and long-term (i.e. 30 days post CEA and up to 5 years). This should also be clearly defined in the methods. The first time the reader reads this is in the results.

METHODS:

Line 140: Please explain what was meant by ‘Incomplete data was clarified by contacting an author of the study’. Was there a standard protocol followed? i.e. An email was sent to the author and if no response was heard within 2 weeks the results were not included.

Statistical analysis: A random effect model should be used throughout rather than a fixed effect model.

RESULTS

Results section is difficult to read. If Odds Ratio and CI are reported in a table which is referenced then don’t include in the main body of the text as it is hard to follow. The effect of age and effect of gender are particularly difficult paragraphs to read, please restructure.

Line 165: Split the studies into; age, gender, age and gender. This will make it easier for the reader

Line 186: Where does this number come from? First time referenced.

Table 2: Should define what their presenting symptoms were and carry out subgroup analyses accordingly as there are important differences in risk between different symptomatic indications. E.g. categorising symptomatic patients as; stroke, ocular event, cerebral TIA. Carrying out analysis by symptomatic or asymptomatic is too vague. This should be reflected in the discussion.

DISCUSSION

Line 250: It is unclear where these percentages come from, is this from your data?

Line 269: Reference

Line 300: Reference the current Guideline

Reviewer #3: A priori women and older people do worse in elective vascular surgery.

Although gender may be associated with worse outcomes, are there any clinical confounding variables that may contribute to this?

Please ask an English speaker e.g. Dr Howard to correct the English in the document please. It is substandard for a good scientific journal.

Line 82 please reference ESVS carotid guideline

Endpoints: one of the clinical concerns long term, is whether women with smaller arteries have a higher restenosis rate. Can the authors include this outcome please?

It is interesting to see the peri-operative stroke risks are similar. This is reassuring in terms of efficacy of surgery.

I think the odds ratios may be scientifically interesting but are too low (OR<2) to really influence clinical practice.

Older people with asymptomatic disease are not offered surgery – the ACST finding that older people have higher risks is the explanation, therefore this finding is redundant.

It is no surprise that older people have more strokes and die more frequently than younger people. This finding does not require a meta-analysis.

There are several studies demonstrating the lower risk of stroke or death follow treatment of asymptomatic patients – e.g. ACST1 and 2, in comparison to symptomatic patients. Please comment.

I do not think that you can say that the risks are higher in asymptomatic females v symptomatic females as the 95%CI of the OR actually overlap. Please comment.

Similar comment for older patients. Please comment.

Rothwell’s subgroup paper suggested that older symptomatic patients benefit more from CEA – would the author’s like to comment - i.e. procedural risks may be higher, but non-operated stroke risks are also higher.

**********

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: Yes: John Houghton

Reviewer #2: No

Reviewer #3: Yes: I do not see the clinical need for this study. The overlapping OR do not appear to show any separation between older and female asymptomatic v symptomatic patients.

**********

[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.

Influences of age and gender on operative risks following carotid endarterectomy: a systematic review and meta-analysis

PONE-D-22-30639R1

Dear Dr. Rerkasem,

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.

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,

Athanasios Saratzis

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: