PONE-D-22-33822Musculoskeletal misdiagnoses in children with brain tumors A nationwide, multicenter case-control studyPLOS ONE

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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: Yes

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

Reviewer #1: No

Reviewer #2: 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

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: 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: General comments:

This study examined whether prior musculoskeletal diagnoses in childhood brain cancer are misdiagnosed and affect diagnostic delay. The topic and nationwide medical chart data are interesting. However, the major limitations of this study include a small sample size, which cannot draw a firm conclusion for observed non-statistical differences. Below are comments about this manuscript.

Major comments:

#1. How did the authors manipulate the year of diagnoses in the matching process? Because the study period extended 21 years from 1996 to 2018, the diagnostic procedures/modalities and treatments must have advanced. If comparing cases in the earlier cohort to later controls without considering diagnostic periods, confounding of those medical advances may arise.

#2. The discussion and conclusion sections, including the abstract and main text, should be cautious about concluding a strong interpretation, such as “musculoskeletal misdiagnoses in childhood brain tumors do not affect the diagnostic delay.” One primary reason for this non-significant result is the weak statistical power. In fact, in Fig 3 and Fig 4, the results suggest that cases tended to have better survival and total interval outcomes. For safer to say that this study did not find a significant association. With insufficient statistical power, please be advised to tone down such decisive conclusions/messages.

Minor comments:

#1.Page 6, Result section, the first paragraph: “From January 1996 … 46% (39/84) were girls.” This whole paragraph may be moved to the Method section (probably, in between the Data collection and Statistical analysis parts), with some subheadings such as “Cases and controls.” Because in the Method section, details for the matching process should be described, which helps readers understand the design easily.

Reviewer #2: Thank you to the editor for the opportunity to review this interesting manuscript entitled “Musculoskeletal misdiagnoses in children with brain tumors:

A nationwide, multicenter case-control study”

It is important to get so called negative findings to published, too.

Regarding abstract: I would suggest to add to results the finding of “7-fold risk of musculoskeletal symptoms in infratentorial tumors”. This is given on page 13.

In introduction, second row:… overall survival rate has shown…”. Please add survival rate of brain tumors in Denmark. This because you only refer to the Danish data (ref 3).

On row 5 about diagnostic delay you may consider to add a recent reference from Swedish register data (Rask o et al, Pediatr Blood Cancer. 2022 Nov;69(11):e29850)

About study designs, could you please provide reasoning for choosing only 2 control patients per each case as you, however, had more than 900 patients with BT-diagnosis.

In discussion, you could add the data on Swedish patients regarding the time intervals (even though no big discrepancies seem to be evident).

The strengths and limitations of this study are well discussed.

Tables and figures seem to be appropriate and their headings, too.

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Reviewer #1: No

Reviewer #2: No

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Musculoskeletal misdiagnoses in children with brain tumors: A nationwide, multicenter case-control study

PONE-D-22-33822R1

Dear Dr. Brix,

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,

Sethu Thakachy Subha, M.S

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: (No Response)

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: (No Response)

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: I Don't Know

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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: (No Response)

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: (No Response)

Reviewer #2: Yes

Reviewer #3: No

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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: I thank the authors. All concerns raised in the previous version have been revised appropriately—no further comments.

Reviewer #2: Thank you for the responses.

two minor comments:

page 5 under title cases and controls, the first sentence does not read fluently. Pleae check the verbs/ word orders.

page 7, table 2, check that all %-marks are in place

Reviewer #3: After a thorough review of the manuscript I strongly suggest some additional major comments should get addressed and a number of central points would benefit from further clarification.

Introduction

The authors state, that they aimed to “identify any patterns or red flags” in terms of the musculoskeletal misdiagnosis. However, throughout the entire manuscript it was never touched on “the red flags” again – a brief discussion on this part of the aims was entirely lacking.

Methods

The musculoskeletal diagnoses were classified according to ICD-10. It would be however very helpful to also clarify how the brain tumours have been classified (ICCC-3, ICD-10?).

Results

Indeed, the differences between misdiagnosed vs non-misdiagnosed cases did not reach statistical significance (table 4), I suggest, however, to mention the tendency of larger time intervals among misdiagnosed children in the results and discussion section.

The authors state only one odds ratio in the results section. I suggest adding a table or a figure where the all odds ratios are transparently displayed. This would be very helpful for a better understanding of the associations between potential risk factors and the musculoskeletal misdiagnosis.

Discussion

Although the low sample size hardly allows for statistically significant findings, the authors may consider carefully those values indicating potential deviations in cases and controls. Therefore, I wondered whether the authors may add a paragraph where they discuss their own findings and speculate on potential underlying mechanisms possibly driving their findings, e.g. longer time intervals among misdiagnosed children or why the proportion of sequelae was lower among cases than controls (against expectation)

Since the small sample size of the study has clearly influenced the precision of the estimates, I suggest adding this point to the paragraph on strengths and limitations.

Figure 4:

I wondered why the number of days in the pre-diagnostic symptomatic interval in controls is higher than in the total interval (92 vs 90). It should be vice versa – shouldn’t it?

In addition: what is the meaning of the numbers – Mean, Median? I suggest to add this information to the figure caption.

General

I would ask the authors to use consistent word usage for sex/ gender

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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: No

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