PONE-D-24-19654An Updated Comparison of Standard and Novel FEV1 Indices’ Association with All-Cause MortalityPLOS ONE

Dear Dr. Russell,

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Academic Editor

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: Yes

Reviewer #2: Yes

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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: This is a timely and important study highlighting the limitations of utilizing Z-scores in interpreting PFTs, and comparing several approaches to PFT interpretation including raw FEV1, FEV1-Z scores, FEV1/H2 and FEV1/H3. The authors utilized the NHANES database to evaluate the association of different FEV1 indices with all-cause mortality. They found that FEV1/ht3 might have the best utility predicting all-cause mortality. The strength of the study is tackling an important topic, and utilizing large database and rigorous statistical methods to answer whether either one of FEV1 indices is more predictive of mortality.

However, the result section is somewhat difficult to read and interpret, and might benefit from simplification and additional explanation why did authors decide to divide FEV1 indices into deciles to evaluate association with mortality. Additionally, the authors should elaborate more on why they believe that their results were significant in unadjusted analysis but were not conclusive when adjusted for sex, age and tobacco use, and whether they believe the FEV1 indices therefore offer any information beyond these clinical indices. Additionally, the authors should comment on differences between looking at all NHANES cohort and then on patients with airflow limitations only.

The authors correctly identify a major weakness of the study which is only looking at mortality and not other clinically relevant outcomes, and should consider looking at frequency of exacerbations and hospitalizations either in NHANES or in a smaller cohort of patients with airflow obstruction. Since NHANES database includes lot of patients without pulmonary problems, the mortality might confounded by a lot of other factors and not directly related to effects of airflow limitation.

The authors should also elaborate on where they see clinical utility of FEV1/ht3 compared to Z-score, FEV1 or other indices of severity. Since their study focuses on mortality and not diagnostics or management, do they expect to use FEV1/h3 to better identify high risk patients and possibly change clinical management based on that?

Overall, this study raises an important topic, however the authors should focus more on potential clinical utility of their findings.

Reviewer #2: GENERAL COMMENTS

This a well-written manuscript reporting the results of a careful analysis of the associations between various FEV1 indices and all-cause mortality in a large NHANES population. The finding that non-traditional reference-range-independent indices performed as well or better than the traditionally employed reference-range-dependent indices is a potentially impactful contribution to the interpretation of spirometry results. The authors do a nice job of discussing the potential contextual limitation of their findings -- that all-cause mortality may not be the best outcome to study if one is interested in more respiratory specific outcomes re: severity and impairment rating.

Although the authors state that the inclusion of only spirometry which meets ATS A and B grades is a strength in terms of reliability, it is also a limitation in terms of generalizability. It is well known that persons who have respiratory symptoms perform spirometry less reliably than asymptomatic persons. Including grade C spirometry results in a sensitivity analysis would address this limitation.

SPECIFIC COMMENTS

lines 106-107 The sentence is unclear to which category of indices that "Such indexing strategies..." refers, reference-range-dependent or reference-range-independent. In addition, one reference-range-independent index, FEV1-Q, is also derived from large population samples.

samples of individuals which are costly to maintain.

line 140 The name, model number, and manufacturer of the spirometer used should be given.

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Reviewer #1: No

Reviewer #2: No

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An Updated Comparison of Standard and Novel FEV1 Indices’ Association with All-Cause Mortality

PONE-D-24-19654R1

Dear Dr. Russell,

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.

Please add/correct the following in your manuscript before submission:

1. Why were the grade D results from the sensitivity analysis included?

2. line 163 Should be "each FEV1 INDEX decile group"

3. line 274 Should be "intrinsic abnormalities OF lung function"

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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Kind regards,

Anindita Dutta, Ph.D.

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: All comments have been addressed

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 #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

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 #1: Yes

Reviewer #2: 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

**********

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: The authors adequately addressed some concerns of the reviewers by adding comments, edits and sub-group analysis results. There is still question of future utility of this specific index however as authors state this might be better addressed in future studies looking at specific events such as exacerbations, or specific patient subpopulations.

Reviewer #2: GENERAL COMMENTS

The authors have done a nice job in responding to the Reviewer comments. I appreciate the addition of the sensitivity analysis with less well performed spirometry. My only remaining issue is why were grade D spirometry results used. Grade C results make sense to me, but not grade. D results. The authors should either drop the grade D results from the sensitivity analysis or explain why they were included.

SPECIFIC COMMENTS

line 163 Should be "each FEV1 INDEX decile group"

line 274 Should be "intrinsic abnormalities OF lung function"

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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: Yes:  Eva Otoupalova

Reviewer #2: No

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