PONE-D-22-06021New multimodal intervention to reduce Irritable Bowel Syndrome (IBS) severity symptoms - pilot study with a 12 month’s follow upPLOS ONE

Dear Dr. Hinse,

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 23 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:

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We look forward to receiving your revised manuscript.

Kind regards,

Wan-Long Chuang, M.D., Ph.D.

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 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

3. The in-house editorial staff feels that your study meets the World Health Organization definition of a clinical trial because it is a prospective study in which participants received 12 session of AMT to investigate the effects on IBS.

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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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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: No

Reviewer #3: 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: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance].

COMMENTS: Please note that, your ABSTRACT is well drafted but assay type. It is preferable [refer to item 1b of CONSORT checklist 2010: Structured summary of trial design, methods, results, and conclusions] to divide the ABSTRACT with small sections like ‘Objective(s)’, ‘Methods’, ‘Results’, ‘Conclusions’, etc. which is an accepted practice of most of the good/standard journals [including this one, though ‘The PLoS One Guidelines to Authors’ did not specify an Abstract format, it is desirable]. It will definitely (generally) be more informative then, I guess, whatever the article type may be.

This study being ‘pilot’ in nature, sample size is not a big issue. However, [though many things are ignored (loosely looked at / evaluated)] methodological issues need to be very rigorous followed {in case of clinical trial, CONSORT guidelines are to be strictly observed/followed}. I am sure that the authors are aware of the well-known drawbacks of a single-arm design [a type of Quasi-experimental research], and it is often said that ‘alright to have ‘single-arm design’ (before-after study) when that is the only possibility’, however, it is very essential to keep the limitations in mind while interpreting results. Considering ‘pilot’ (a feasibility study) nature of the study although it is acceptable/alright, as you know, a classical/ideal clinical trial/study needs/requires a concurrently {but similarly} handled/treated appropriately selected/chosen control/comparison parallel group/arm. In this context, please read the following which is pasted from one standard textbook on ‘Research Methodology’:

“Inferential statistics (i.e., hypothesis testing + estimation of CI) is built on the population model [which means the underlying assumption is that there is/are population(s) and we are dealing with random sample(s) drawn from that/those population(s)]. Although in clinical trial (involving at least two groups) we do not really deal with random samples (generally a non-probabilistic convenience sampling), ‘allocation’ to treatment groups is ‘randomly’ done which enable us to evoke the population model and we can use inferential statistics safely. But when there is only one group (so that there is no question of random allocation), with ‘non-random’ selection, it may be questionable to use inferential statistics even if you have two measurement sets as ‘pre-post’ or use ‘internal grouping for comparison.”

Therefore, I guess, it would have been nice to adhered to original plan [lines 89-90] of ‘a waiting group design’.

Although all statistical analyses are performed correctly, few table values [example: q-values (false discovery rate correction for multiple testing) in table-2]] are not explained adequately, in my opinion. How to read [and interpret] these table values may be very briefly explained. Same with table-3.

Please note that the measures/tools used are definitely appropriate, but most of them yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure. Then application of suitable non-parametric test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (i.e. normal)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s) [suitable / most desired/applicable], but should be used whenever/wherever they are available [for example, instead of paired ‘t’ test use Wilcoxon’s Signed Ranked test].

Moreover, limitations (if any) of the study are not mentioned/listed anywhere. Does that mean {according to authors} there are none? As pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently [one should carefully consider/look at the clinical implications of the study].

There is no problem in accepting this article after minor revision, in my opinion.

Reviewer #2: 1. The study population should be more specifically characterized so that we could know what the target population of AMT would be. What are the predominant symptoms? How about the subgroups (IBS-C, IBS-D, mixed…)? Did these bowel symptoms improve after AMT?

2. In this study, female patients were predominant (92% in abstract and 89% in main text, please clarify) so the generalizability of this study should be discussed in more depth. Traditionally, male IBS patients tend to have diarrhea (IBS-D) and female patients are more likely to have constipation.

3. The novelty of this study is AMT. However, several of the modules and sessions of AMT were conducted by psychology students. Did these students receive related medical training regarding IBS? Did they conduct the AMT under surveillance? What were their experiences and background? It would be better to clarify these points before AMT is put into clinical practice.

4. Similarly, the nutritional counselling and education for food tolerances were conducted by “experienced therapist”. Who were they? Background of nutrition?

5. Did these patients receive medical treatment during the AMT period? One patient received treatment for psychosis on enrolment? Should this patient be excluded?

6. Since only 21 of the 36 patients had the 12-month follow-up, it may not be very confident to say the AMT effect to be profound and lasting.

6. English editing by a native speaker is suggested.

Reviewer #3: Irritable bowel syndrome treatment is various and broad. It means that efficacy of single irritable bowel syndrome treatment is inadequate. Multimodal therapy to improve the severity of IBS in patients without psychological comorbidities with a sustained effect at 12 months’ follow-up in this study.

However there are some biases. First, apart from small sample size, the gender composition is not equilibrium and up to 92% female. Second, AMT was evaluated as a therapy package including physician-patient consultations, the question of specific therapy effects versus non-specific effects (placebo effects, context effects, patient expectations etc.) was not an issue of the present analysis. Third, 51 patients were included in the study but the dropout rate was 29.4%(15/51).

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Attachments

Attachment

Submitted filename: renamed_04f37.docx

PONE-D-22-06021R1New multimodal intervention to reduce Irritable Bowel Syndrome (IBS) severity symptoms - pilot study with a 12 month’s follow upPLOS ONE

Dear Dr. Hinse,

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 Oct 06 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 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: 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,

Wan-Long Chuang, M.D., Ph.D.

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.

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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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #4: Partly

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

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #4: 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: (No Response)

Reviewer #2: (No Response)

Reviewer #4: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #4: 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 #1: COMMENTS: Since all of the comments made on earlier draft are considered positively, I recommend the acceptance because the manuscript now has achieved acceptable level, in my opinion.

Reviewer #2: (No Response)

Reviewer #4: The manuscript demonstrated an 8-week AMT therapy would improve the IBS and maintain its effect at after 12 months’ follow-up, which is limited in the IBS patients without psychological comorbidities. The manuscript has been received one round review by 3 reviewers. And I found the manuscript is interesting and the authors have adequately responded to the 3 reviewers. Nevertheless, I still have some other comments which need to be clarified before final publication.

1. The manuscript should be edited by a native English speaker before publication.

2. For most readers, even among IBS specialists, are unfamiliar with anthroposophic therapy. More detailed introduction regarding the background, rationale and efficacy in treating other disorders by using such therpay should be described in the INTRODUCTION.

3. As described in the Method, the AMT included psychoeducation, psychotherapy, art therapy, external application, and nutritional counselling. What is the rationale for including external application for IBS? What kind of nutrition suggestion was applied in the AMT? A more detailed description is required.

4. Since psychotherapy and nutritional suggestions have already been shown to be effective in reduction IBS severity, the current results suggested that the AMT by adding anthroposophic components may reverse the proven efficacy of psychotherapy/nutrition suggestions. The authors should comment the limitation on this.

5. Since multimodalities were included in AMT, did all the modalities were required to use by the IBS patients during the 8-week treatment period and follow-up? Was it possible that some IBS patients would prefer some modalities without using other modules, which would lead to the unfavorable outcome in the IBS patients with psychological co-morbidity?

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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: Dr. Sanjeev Sarmukaddam

Reviewer #2: No

Reviewer #4: No

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[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.

New multimodal intervention to reduce Irritable Bowel Syndrome (IBS) severity symptoms - pilot study with a 12 month follow up

PONE-D-22-06021R2

Dear Dr. Hinse,

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,

Wan-Long Chuang, M.D., 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: All comments have been addressed

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #4: Yes

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #4: 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: (No Response)

Reviewer #2: Yes

Reviewer #4: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #4: 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 #1: COMMENTS: Since all of the comments made on earlier draft are considered positively, I recommend the acceptance because the manuscript now has achieved acceptable level, in my opinion. In fact, the earlier version was already accepted on 22.07.2022.

Reviewer #2: The authors have adequately responded to the reviewers' comments and suggestions. I think this manuscript is ready for publication.

Reviewer #4: The authors have addressed all my concerns I raised. And I am quite satisfied with the authors' answers.

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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: Dr. Sanjeev Sarmukaddam

Reviewer #2: No

Reviewer #4: No

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