PONE-D-19-21348

Exposure to Formaldehyde and Asthma Outcomes: A Systematic Review, Meta-Analysis, and Economic Assessment

PLOS ONE

Dear Dr. Woodruff,

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.

We would appreciate receiving your revised manuscript by Jan 30 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable 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/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

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 look forward to receiving your revised manuscript.

Kind regards,

A. Kofi Amegah, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

The justification for the work is weak in light of the previous systematic reviews on the topic. Tighten up the introduction to help gauge the paper's contribution to the existing literature and its public health relevance beyond the US population.

Is there a reason why SCOPUS database was not searched?

Studies that met the included criteria as evident are those in bin1 and should be profiled as such. Subsequently, delete all text referring to the other bins in the methods, results and discussion section. The flow diagram should be revised accordingly

Did the case reports (n=4) considered in the bin1 studies satisfied the PECO guidelines in terms of the "Comparator"?

The Risk of bias assessment section is too winding and confusing. Please, simplify

Elaborate the plausible biological mechanism of the relationship in the Discussion section. Prune down the Discussion to make room for the mechanistic pathway

The conclusion should touch on the far-reaching implications of the findings (if any). It appears it has no relevance beyond the US population.

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5. Please note that your currently uploaded Table 2 has the title “Table 3. Summary of included studies (n=85)”. Please amend as necessary.

6. Thank you for stating the following financial disclosure:

"JPB Foundation, Grant #681, https://www.jpbfoundation.org: JL, EK, PS, MDC, HV, MD, ND, EW, TJW.

NIEHS, P01ES022841, https://www.niehs.nih.gov/: JL, PS, AMP, ND, TJW

USEPA, RD 83543301, https://www.epa.gov/: JL, PS, AMP, ND, TJW"

a. Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

If this statement is not correct you must amend it as needed.

b. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

7. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files

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10. Please upload a copy of "Supplemental Materials 3" which you refer to in your text on page 11.

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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: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

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?

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

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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: The topic of this paper is scientifically interesting and potentially relevant to a regulatory process in the United States. In prior work, some of the authors have taken thoughtful steps toward adapting popular systematic review guidelines for environmental health evaluations. While I have major reservations about the appropriateness of highly-structured review methods, like the GRADE method used here and related approaches, my comments on this paper are not founded on these objections, as such protocols are established in the literature.

Overall, this paper is technically well-executed. The authors establish explicit, state-of-the-art protocols for their systematic review and meta-analysis and follow them carefully, with full reporting of the methods and results. The findings are credible, but I have several suggestions for improving the paper, outline below.

Study selection. I doubt the decision to include very small studies and case reports. These studies are unlikely to contribute significantly to assessing causality or to quantitative analysis. Nothing in systematic review methodology requires including them as long as inclusion/exclusion criteria are explicit and applied consistently.

Data extraction. While contacting authors for unpublished data gives an appearance of thoroughness, it actually detracts from transparency and reproducibility of the results, as the information obtained would not necessarily be available to others. It is preferable for studies missing key data to be excluded.

Temporality. About half of the included studies are cross-sectional. This appears consistent with the PECO statement, which says that formaldehyde exposure can be “prior or concurrent to” any of several outcomes. However, there is an implicit assumption that current exposures are representative of those before the outcomes appeared, which may be more tenable for symptoms and exacerbation than for diagnosis. The authors should clarify how they assessed the temporality of exposure.

Writing. The paper is clearly written, but very long. There is a lot of descriptive information and some sections overlap (e.g., the descriptions of data extraction on p 8 and analysis on p 10). Readers would be grateful if the text were shortened by a third, omitting many of the descriptive details. For example, it’s obvious that only the “Bin 1” studies are informative, so there is no need for details of the others.

Risk of bias assessment. It is puzzling that many studies, notably cohort studies according to the authors, were rated “probably high risk of bias” for blinding. Blinding is exceedingly rare in observational studies of environmental exposures and knowledge of participants’ exposure status is not usually seen as an important source of bias. The authors should explain why they believe it is important to downgrade studies on this basis.

Discussion. The authors make an important point that many papers lack data needed for quantitative meta-analysis or risk assessment. However, this is not a simple problem of reporting that can be solved with checklists like STROBE. It is a problem of study conceptualization and data analysis. Journal reviewers and editors could help to address this by asking authors to report quantitative data and to do so in a form that can be used for further analysis.

Reviewer #2: I applaud the authors for identifying a public health problem (e.g., EPA proposed formaldehyde rule does not consider asthma as a health outcome) and conducting a comprehensive approach to improve public health. This approach consisted of a series of systematic reviews and associated meta-analyses, and an economic assessment on exposure to formaldehyde and asthma. I agree that excluding established health effects from the economic analysis can underestimate the benefits of regulations. However, the quality of the health hazard assessment is not adequate or transparent to support the level of evidence conclusions, and thus, opens the door for major criticism and compromises potential public impacts from the economic assessment.

Please see the attached file for details

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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: No

Reviewer #2: 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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: PLOS review Lan et al. formaldehyde and asthma Reivew .pdf

PONE-D-19-21348R1

Exposure to Formaldehyde and Asthma Outcomes: A Systematic Review, Meta-Analysis, and Economic Assessment

PLOS ONE

Dear Dr. Woodruff,

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 Sep 11 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

A. Kofi Amegah, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The organization and quality of the figure and tables poses a lot of challenges to the review process and should be improved. The font size for instance is too small and I recommend creating smaller tables to help increase the font size and enhance the presentation. A summary table with results for each assessment is also recommended. Please ensure that the responses to the reviewer's comments are systematic and come immediately after the comment to help better interrogate the revised manuscript. Further, the authors should ensure they have adequately addressed all the additional comments raised to help bring finality to the review process as quickly as possible

[Note: HTML markup is below. Please do not edit.]

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 #2: (No Response)

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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 #2: Partly

**********

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

Reviewer #2: 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 #2: 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 #2: 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 #2: I appreciate the authors’ efforts to improve the transparency and strengthen the scientific rigor of the systematic review. However, the revised manuscript is still not adequate to determine whether the body of evidence supports the authors’ conclusions using their systematic review method. comments and recommendations are in the attached file.

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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 #2: 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.

Attachments

Attachment

Submitted filename: PLOS review Lan et al. formaldehyde and asthma ReivewRevision.pdf

PONE-D-19-21348R2

Exposure to Formaldehyde and Asthma Outcomes: A Systematic Review, Meta-Analysis, and Economic Assessment

PLOS ONE

Dear Dr. Woodruff,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

A. Kofi Amegah, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The manuscript suffers from poor organization and formatting of tables especially table 3 which is too voluminous. Suggestions by reviewer 2 to improve readability of the manuscript and address transparency issues to enable readers to evaluate whether the conclusions of the study are supported by the data has not been adhered to. In the current state, it is extremely difficult to gauge the public health impact of the work

[Note: HTML markup is below. Please do not edit.]

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 #2: (No Response)

**********

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 #2: Partly

**********

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

Reviewer #2: 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 #2: 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 #2: No

**********

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 #2: The revised manuscript remains difficult to review primarily due to poor organization and formatting of tables. As stated in my previous comments (on the original and R1 version), ideally, the manuscript should have been divided into four separate systematic reviews, with each review discussing the study characteristics, risk of bias, and findings, and including summary tables and figures.

The authors did not address the recommendation by myself and the journal editors to create a summary table for each assessment. Because of inadequate formatting, organization, and presentation of the information, I am not able to review table 3 (findings for all studies combined) or critically review this manuscript. Well-designed summary tables are needed for each assessment to understand the discussion of the results and whether the database of studies supports the authors' conclusions. (See recent IARC monograph tables for examples on presenting results and study characteristics). Reasons include the following:

• The meta-analysis includes only 9 of 24 studies of childhood asthma and formaldehyde; the strength of the evidence of the other 15 studies is not transparent. The supplemental figures mix findings from studies included in the meta-analysis (additional risk estimates) and studies with those not included in the meta-analysis. The scatter plots are not self-explanatory without information from a summary table (e.g., table 3, which is difficult to read). The discussion of the findings of the studies not included in the meta-analysis is inadequate.

• The meta-analysis of childhood asthma exacerbation and symptoms included only 5 of 23 studies. The presentation of results suffers similar problems as discussed above.

• The discussion of the findings from adult studies is more comprehensive than that of the childhood studies not included in the meta-analyses. However, there is no comprehensive resource for the findings across studies in adults (except in Table 3, which is hard to read). Results from the studies are reported in multiple figures that are in the supplement files and thus not reader-friendly. The authors note the variety of exposure categories made it challenging to easily compare across different studies, thus, it is unclear why the authors are reluctant to make changes to improve the presentation of the data.

I appreciate that the authors address several comments made in my previous review. However, I feel the authors ignored (e.g., did not provide a rebuttal or make changes) other comments by either not extracting them into the response document or mistakenly stating they addressed them (e.g., Table 3 was not divided into 4 separate tables).

As the manuscript has the potential to have a public health impact, it is disappointing that the authors are reluctant to improve its readability and transparency to enable readers to evaluate whether the science supports their conclusions.

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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 #2: 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.]

- - - - -

For journal use only: PONEDEC3

PONE-D-19-21348R3

Exposure to Formaldehyde and Asthma Outcomes: A Systematic Review, Meta-Analysis, and Economic Assessment

PLOS ONE

Dear Dr. Woodruff,

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.

In order to improve the readability of the article, please move tables 3a and 3b to the supplementary material. In addition, please consider dividing table 3b by study design.

Please submit your revised manuscript by Apr 04 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.

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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

A. Kofi Amegah, PhD

Academic Editor

PLOS ONE

Davor Plavec

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

My concern still relates with Table 3b which is very lengthy (193 pages) and will be extremely difficult for readers to digest this table which presents information on study characteristic of the included studies. The authors should consider breaking down this table according to Study Design (i.e. Cohort, Cross-sectional etc.) to improve the readability

[Note: HTML markup is below. Please do not edit.]

[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.

Exposure to Formaldehyde and Asthma Outcomes: A Systematic Review, Meta-Analysis, and Economic Assessment

PONE-D-19-21348R4

Dear Dr. Woodruff,

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,

A. Kofi Amegah, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: