PONE-D-20-30805

Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): a pilot randomised controlled trial

PLOS ONE

Dear Dr. Jones,

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.

It is somewhat astonishing that you would use the worst possible randomization method even in this day and age, when so much has been published about the shortcomings of permuted block randomization, even with varying block sizes.  What possible justification can there be for this?  Before you respond, please carefully review the following:

Berger, VW, Ivanova, A, Deloria-Knoll, M (2003). “Minimizing Predictability while Retaining Balance through the Use of Less Restrictive Randomization Procedures”, Statistics in Medicine 22, 19, 3017-3028.

Berger, VW (2005). “Selection Bias and Covariate Imbalances in Randomized Clinical Trials”, John Wiley & Sons, Chichester.

Berger, VW (2006). “Do Not Use Blocked Randomization”, Headache 46, 2, 343.

Berger, VW (2006). “Varying Block Sizes Does Not Conceal the Allocation”, Journal of Critical Care 21, 2, 229.

Berger, VW (2006). “Misguided Precedent Is not a Reason To Use Permuted Blocks”, Headache 46, 7, 1210-1212.

Berger, VW (2015). “Failure To Look Beyond Blocks Is a Mistake”, Methods of Information in Medicine 54, 3, 290.

Berger, VW (2015). “Concealing the Block Sizes Is Not Sufficient”, Clinics in Orthopedic Surgery 7, 422-423.

Berger, VW Agnor, RC, Bejleri, K (2016). “Comparing MTI Randomization Procedures to Blocked Randomization”, Statistics in Medicine 35, 5, 685-694.

Zhao, WL and Berger, VW (2017). “Better Alternatives to Permuted Block Randomization for Clinical Trials with Unequal Allocation”, Hematology 22, 1, 61-63.

Zhao, WL, Berger, VW, Yu, Z (2017). "The Asymptotic Maximal Procedure for Subject Randomization in Clinical Trials", Statistical Methods in Medical Research 27, 7, 2142-2153.

Especially in an unmasked trial, this is inexcusable.  It is stated that:

"Allocation concealment was ensured using sequentially numbered opaque, sealed envelopes".

How would sealed envelopes in any way, shape, or form ensure allocation concealment?  Short answer:  They don't.  The reality is that allocation concealment is rendered impossible by the combination of the lack of masking and the fatally flawed randomization method used.  See:

Berger, VW (2005). “Is Allocation Concealment a Binary Phenomenon?”, Medical Journal of Australia 183, 3, 165.

Berger, VW Do, AC (2010). “Allocation Concealment Continues To Be Misunderstood”, Journal of Clinical Epidemiology 63, 4, 468-470.

What is the plan for dealing with missing data?

How will the data be analyzed?

Why are there no p-values in Table 1?  See:

Berger, VW (2009). “Do Not Test for Baseline Imbalances Unless They Are Known To Be Present?”, Quality of Life Research 18, 399.

Berger, VW (2010). “Testing for Baseline Balance: Can We Finally Get It Right?”, Journal of Clinical Epidemiology 63, 8, 939-940.

Please submit your revised manuscript by Jan 03 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Vance Berger

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: Partly

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

Reviewer #1: No

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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

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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

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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 manuscript entitled ‘Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): a pilot randomised controlled trial’ with the aim to examine the feasibility of humidified O2 (heated humidified or cold humidified ) to standard O2 in children with severe acute asthma and to obtain data on recruitment, tolerability and outcome measure stability.

The manuscript can be further improved based on the comments below and requires thorough proofreading.

Abstract

Page 3 Line 39-40, the sentence ‘ (shortest for standard O2, 37.9(29.1) hours) and 14.6 (14.2) hours (shortest for cold humidified O2, 13.1(14.9) hours) respectively’ to be revised and to state for all groups with their respective Median ±IQR.

Page 3 Line 41, for ‘inhaled treatment was 31.4 (22.2) hours, the group name to be stated. Likewise to include other groups readings.

Introduction

Page 5, Introduction was too short. More information to be provided.

Methods

Recruitment

Page 6, more information to be provided on how the subjects were recruited (as illustrated in Figure 1) in the method section.

Randomization

Page 7 Line 95-96, more description to be provided for this sentence ‘Stratified block randomisation (age (2-5 years and 6-16 years) and centre, block sizes of 3 and 6)’

Outcome measures

Page 8 Line 129, full name for abbreviation ASS (Asthma Severity Score) to be stated.

Data analysis

Page 9 Line 141, statistical software including version and publisher name which was used to perform the descriptive statistics to be stated.

More information on missing data to be provided in terms of percentage, pattern etc.

Results

Page 10 Line 157, incomplete sentence.

Page 10 Line 158-162 and 164-168, content were similar and repeated.

Page 11-12, Line 180-181, sentence missing.

Page 13 Line 194-199, separate groups findings to be provided.

Page 10 & 14 Line 158, Line 164, Line 216, there were many ‘Error! Reference source not found:’

There were many missing data/not assessed and this needs to be discussed.

Table 1, the title can be expanded. At least 1 decimal point for the percentage figures. In the table footnote, it was stated ‘***=3 values missing’ but was not found in the table. Range to be replaced with IQR.

Table 2, the readings at baseline, 2-hour, 4-hour, 6-hour, 8-hour and 12-hour to be provided before deriving the mean difference. Intent to treat and n to be stated.

Figure 1, the assessment period to be incorporated in and intention to treat to be stated.

Figure 2, n to be stated. There were two titles. Title in the graph to be removed.

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Reviewer #1: No

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PONE-D-20-30805R1Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): a pilot randomised controlled trialPLOS ONE

Dear Dr. Jones,

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 Jan 20 2022 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 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,

Andres Azuero, Ph.D., MBA

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dr. Jones - I have read the revision of your manuscript as well as feedback from two pulmonologists who reviewed it. I have also read the reviews from your initial submission. In my opinion, the presentation of the research is in line with what can be expected of a pilot project: the focus is on feasibility and acceptability, not inference. The goal is to try out the procedures and logistics and see what works and what doesn’t so that problems in a large confirmatory trial are avoided. The outcome data themselves are secondary, and whatever conclusion of benefit or not, apply to the sample only; no statement should be made about generalizability of results and no formal testing should be conducted, although uncertainty can be expressed in the form of confidence intervals or credible intervals.

Regardless, looking at the reviews from the original submission and the revision, a common theme is that reviewers had a difficult time seeing this study as a pilot and tried to interpret it, at least partially, as if it was a confirmatory study, which is clearly not, and therefore the concerns about baseline imbalances, inferential testing, and statistical power. In addition to that, the prior academic editor, who has studied in-depth the nuances of randomization procedures, expressed concern about the randomization procedure and how it was implemented.

Therefore, to avoid confusion and over-interpretation of results, the following is needed:

1) A statement in the abstract along the lines of:

“Because of the small sample size of this pilot, conclusions cannot be extrapolated beyond the study sample.” So that from the beginning readers are not looking for inferential conclusions.

2) A paragraph in the methods section explaining to readers the purpose of a pilot study such as yours. In addition to your reference 9 (Lancaster et al, 2004), consider using the following:

https://www.nccih.nih.gov/grants/pilot-studies-common-uses-and-misuses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081994/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917389/

3) A paragraph in the discussion about what you will do to improve the randomization in a future confirmatory trial. For instance, increase the number of random block sizes to 3, 6, 9, 12, and 15, or use a different randomization method altogether, and implement a computerized system (as opposed to the envelopes).

Minor fix: typo in abstract results: “[…]time (hours) taken to step down nebulised to inhaled treatment was 5.6 (14.3),” should be 35.6 (14.3).

Finally, please respond to the reviewer comments.

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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)

Reviewer #3: (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: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

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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 #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 #2: Yes

Reviewer #3: Yes

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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 #2: The manuscript, "Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): a pilot randomized controlled trial" by Jones and colleagues examines the feasibility of comparing types supplemental oxygen in asthmatic children experiencing acute exacerbations. The authors identify several potential barriers to a full-scale investigation, including difficulties in recruiting volunteers to complete some of the desired outcome measures, and difficulties in achieving adequate overnight data collection. As such, this manuscript provides insights that will be useful to clinical investigators studying other clinically relevant questions. Therefore, this manuscript will be of interest to a fairly general audience. The manuscript has been significantly improved by the revisions. However, there are still some areas that are not clear in the current manuscript. These minor issues include the following:

1. The Procedures section specifies the duration of assessment to be "as long as they required O2 (and until discharge)". Do the authors mean that all the patients were followed until their discharge? Alternatively, this sentence could mean the patients were followed until they were either off O2 or had been discharged. This sentence should be rewritten to be more clear.

2. The Procedures mention that the parents or guardians provided recommendations regarding potential meaningful patient outcomes and post-A&E Department therapy. The details regarding these findings are provided in the Supplemental Material. However, no reference to this is made within the Procedures section. The authors should state that these findings are provided in the Supplemental Material appendix to make it easier for the interested reader to locate them.

3. The authors state that the outcomes were not designated as primary or secondary, but do not provide a rationale for doing that. The authors should provide a rationale as to why they chose to not designate outcomes as primary or secondary.

4. The authors should provide more details regarding how they arrived at 30 per group as their sample size. Did they conduct a power analysis? Was this based on the average number of children seen in the A&E Department for acute asthma exacerbations?

5. The Discussion outlines some of the barriers experienced by the authors in obtaining their data. While they report some of the approaches that were not successful, it would be helpful if they would include potential ways that they might be successful in collecting a more complete data set in a subsequent study. This is particularly important since the difficulties with missing data precluded the use of a clinically relevant assessment, the PRAM score.

Reviewer #3: In the table !, when you compare the three groups with parametric method do you use to write they are similar?

Can you explain why did not carried out hypothesis testing?

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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

Reviewer #3: 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.

Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): a pilot randomised controlled trial

PONE-D-20-30805R2

Dear Dr. Jones,

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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Kind regards,

Andres Azuero, Ph.D., MBA

Academic Editor

PLOS ONE