PONE-D-20-30996

Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis)

PLOS ONE

Dear Dr. Winkvist,

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 Jul 26 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. 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,

Yuanyuan Wang, PhD

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 you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Additional Editor Comments:

The reviewers have raised some methodological issues that the authors will need to consider and address, such as sample size, confounding, and adherence to intervention.

[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: Yes

Reviewer #2: Partly

Reviewer #3: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

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: No

Reviewer #2: Yes

Reviewer #3: No

**********

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: Yes

**********

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: Abstract

- line 5: "... pharmacological treatment does not always resolve these factors."

- line 18: there's nothing in the reported result that suggests a trend towards better physical functioning; this should be removed.

- line 20 to 23: are the results presented mean scores at a particular time or changes in mean scores? If so, the results should explain this more clearly.

- what is the reason for excluding participants with medication changes - is this a per-protocol analysis? If so this should be stated more explicitly.

- line 25: the difference and its confidence interval (and p-value if desired) should be reported.

Methods

- please re-consider whether it is really necessary to go through the procedure described for identifying confounders to adjust for. If the sequence allocation was randomised, then this procedure is not necessary, and adjustment for age and sex only is probably sufficient. Furthermore most of what is described in lines 222 to 230 are actually results.

Results

- Table 1 could be more informative if you had separate columns for those randomised to receive control diet first and those randomised to receive intervention diet first (do not conduct statistical tests comparing the groups if you do this)

- please indicate the differences (including units) and 95% confidence intervals for the intakes described in lines 288 to 290

- please avoid phrases such as "a trend towards /negligible/significant..." e.g. in line 18, line 292, unless you have actually explored the statistical evidence for the trend you describe. Also avoid phrases such as "close to significant" e.g. line 303 - a result is either statistically significant (more appropriately, there is evidence for a difference) or not.

- line 300: this sentence should be describing a difference in some outcome, not a difference in analysis as it seems to imply; please re-word this appropriately, e.g. "There was no evidence of a difference in HAQ between the intervention diet period and control diet period."

- Table 3 should report the mean changes and the standard errors, not confidence intervals, of the mean changes in the second and third columns (titled 'intervention' and 'control')

- The structure of Table 4 should match that of Table 3, i.e. the same information should be provided.

Discussion

- line 365 and 366 and elsewhere: avoid phrases such as "did not reach significance", "reached significance" (line 362/3) for the reasons explained above, and statements suggesting a trend towards some outcome, as this has not been formally tested.

Reviewer #2: This is an interesting paper, however, some change should be made:

I am concerned about the energy prescription (1100 kcal/day) because it should be a personalized one, the same for protein prescription this should be mentioned in the discussion.

The authors did not mention if they evaluated physical activity and, diet consumed the 2 days a week that patients did not receive the anti-inflammatory diet.

In table 1 include the weight and comorbidities of studied patients

The authors should include the following references in the discussion:

Ideal food pyramid for patients with rheumatoid arthritis: a narrative review. Clinical Nutrition 2021;40:661-689.

Effect of a Dynamic Exercise Program in Combination With Mediterranean Diet on Quality of Life in Women With Rheumatoid Arthritis. J Clin Rheumatol 2020;26(7S Suppl 2):S116-S122. doi: 10.1097/RHU.0000000000001064.

In the discussion HrQoL and statistical significance are mentioned could be abbreviated

Reviewer #3: Thank you to the authors for this interesting study. I appreciate that studies investigating dietary interventions can be particularly challenging and often with unavoidable limitations. I include some thoughts below:

Major

-There are clearly multiple confounders and I am not clear as to how the authors took account of these in their analyses. Aside from sociodemographic factors and other patient and disease characteristics, how about the fact that pharmacological treatment was allowed to vary – how could this have affected the results?

-The sample size was small and potentially subject to selection bias. Could these be reasons for the results seen and the lack of significance in at least some of the findings?

-The study duration was less than 3 months, which is an important limitation. Have the authors continued with the study, do they plan to present longer-term results and is there any plan for more objective outcomes to be studied?

-How certain can we be about patients adhering to the specific dietary interventions? Do the authors think that a phone call and the patients’ ‘word’ was enough, could this have been an issue?

-Baseline BMI in these patients was 26.6? What do the authors think about this, importantly in relation to the outcomes study, which are all subjective?

-Could the authors elaborate in the discussion regarding the observations after exclusion of pharmacological treatments from the analyses?

Minor

-The text throughout could be more concise to my opinion. The introduction for example and discussion are long and could be tightened up, also for messages to be more clearly relayed to the reader.

-The EULAR acronym should be updated to the correct full name (European Alliance of Associations for Rheumatology).

**********

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

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.

PONE-D-20-30996R1

Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis)

PLOS ONE

Dear Dr. Winkvist,

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 24 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. 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,

Yuanyuan Wang, PhD

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 (if provided):

One reviewer has made additional comments about the standard practice for analysing and reporting randomised controlled trials. I would suggest the authors revise the manuscript accordingly.

[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 #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

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

Reviewer #3: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

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

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #3: 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: I thank the authors for their response to reviewers' comments which has vastly improved the manuscript.

There are a few remaining issues which the authors have not revised but have instead offered explanations or refutations to justify their original position. I would like to comment on these with a view to coming to an agreement that is consistent with the standard practice for analysing and reporting randomised trials.

In the results table for a continuous outcome in a randomised trial, it is standard practice to report the means and standard errors of the continuous outcome in each group - not confidence intervals - followed by the between-group differences, confidence intervals for the between-group difference, and p-values for the hypothesis tests comparing outcomes in the groups. Please amend Table 3 and Table 4 to be consistent with this standard practice.

It is also not standard practice to perform hypothesis tests/report p-values for differences in baseline characteristics between arms in a randomised trial, as you have done in Table 2. Between-group differences at baseline are not expected to occur in this study design due to randomisation, and any occurrence thereof is purely by chance and therefore there's nothing you could meaningfully make of it. It would therefore be best to remove the p-value column and note (c) from Table 2. For the same reason, it is not standard practice in randomised trials to explore confounding by baseline covariates, because randomisation 'designs away' any known/unknown/potential confounding. Arguments have been made for exploring confounding in 'small' trials to deal with chance imbalance which is more likely when you have fewer observations; however, if a study is prospectively designed to answer a research question - including a sample size calculation which justifies the number of participants required - then it cannot be deemed 'small' and susceptible to chance imbalances to justify exploring for confounding.

I had previously commented that phrases such as "a trend towards significance" or "close to significant" should be avoided, and the authors responded by saying that such small p-values, in light of the small sample size, should not lead to a conclusion of no change. The authors chose to keep these statements and to indicate that something may be going on that could be evaluated with a larger sample size/stronger study design in the future. While I agree that a conclusion of no change would not be appropriate, the correct inference to be drawn from those p-values (given the parameters of the design of the study) is "no evidence of a difference". This is not the same as concluding no change or saying that there is no difference; rather, this is simply an interpretation of the statistical evidence for/against the hypothesis being tested. After presenting the whole discussion including issues around the small size of the study, a conclusion can be drawn that bears this evidence in mind when determining what it means or does not mean. Phrases such as "a trend towards significance" or "close to significant" when interpreting hypothesis tests are poor (and non-standard) practice that should be avoided entirely.

Reviewer #2: The authors have adequately addressed all my comments and statistical analysis was appropriately performed

Reviewer #3: (No Response)

**********

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: Yes: Lilia Castillo Martínez

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.

Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis)

PONE-D-20-30996R2

Dear Dr. Winkvist,

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,

Yuanyuan Wang, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have addressed the reviewer's comments properly.

Reviewers' comments: