PONE-D-21-01326

Digestive tolerability and acceptability of Fibersol-2 in healthy and diarrheal children 1-3 years old at a rural facility, Bangladesh: results from a four arm exploratory study

PLOS ONE

Dear Dr. Shahid,

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.

Your manuscript has been reviewed by two experts, and they have found some points that need to be addressed before this manuscript is considered for publication. Please go through the reviewers' comments and consider addressing these points, and prepare a revised version.

Please submit your revised manuscript by Apr 30 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,

Ivan D. Florez, MD, MSc, 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. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses.

For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

3. Please provide a sample size and power calculation in the Methods, or discuss the reasons for not performing one before study initiation.

4. Please provide additional details about your study design in your Methods, including randomisation methods and outcomes measured.

5. n your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as:

a) the recruitment date range (month and year),

b) a table of relevant demographic details,

c) a statement as to whether your sample can be considered representative of a larger population,

d) a description of how participants were recruited.

6. 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.

7. Thank you for stating the following in the Financial Disclosure section:

'This research study was funded by Matsutani Chemical Industry Company Limited, Japan on behalf of ADM/Matsutani LLC, USA. The International Centre for Diarrhoeal Disease Research, Bangladesh, receives unrestricted support from the Government of the People's Republic of Bangladesh, Global Affairs Canada, the Swedish International Development Cooperation Agency and the UK Department for International Development.'

We note that one or more of the authors have an affiliation to the commercial funders of this research study, Matsutani Chemical Industry Co. Ltd

a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement.

“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.  

Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and  there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

c. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

8. Please include a separate caption for each figure in your manuscript.

9. Please ensure that you refer to Figure 1 in your text as, if accepted, production will need this reference to link the reader to the figure.

10. Please include your tables 1-6 as part of your main manuscript and remove the individual files. Please note that supplementary tables should remain as separate "supporting information" files.

11. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information

[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: No

Reviewer #2: Yes

**********

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

Reviewer #1: No

Reviewer #2: Yes

**********

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

**********

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: No

Reviewer #2: 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: This exploratory Phase 1/2 study examined the digestive tolerability and acceptability of two different doses of Fibersol-2 (a fermentable, non-viscous dextrin) to relieve abdominal symptoms and improve stool consistency in both healthy children and children with diarrhea, 1-3 years old, in Bangladesh. 2.5g and 5 g of Fibersol-2 were administered twice daily to 55 children each in both groups, and there was no placebo group. This study is part of a registered efficacy trial.

Comments:

Abstract:

ll. 40-41 “No adverse events…were observed in healthy children, except for one…” Probably more accurate to state “Only one of the healthy children experienced any adverse events…”

ll. 46-47 “…devoid of any adverse events” should more correctly stated as “minimal adverse events,” since the authors report one child who experienced an adverse event. One does not equal none.

Statistical analysis

l.187 Medians should be reported with their interquartile ranges, either in place of, or in addition to the range. Because the range is sensitive to outliers, the IQR gives a better summary of where the bulk of the data lie.

ll.189-89 Please specify which non-parametric tests were used.

This is a four-arm study, but the authors have not taken advantage of this fact in the descriptive statistics or in the analyses. Rather than do two separate sets of analyses, comparing low vs. high dose within the groups of children with and without diarrhea separately, a more appropriate analysis would summarize data and perform comparisons across all four groups(Healthy/high dose, healthy/low dose, diarrheal high dose/diarrheal low dose) simultaneously. This could be done with two-way ANOVA for continuous variables (with dose as one factor and diarrheal group as the other factor) and chi square/Fisher’s exact test for categorical variables. This would allow for comparison across both the dosage and the health status of the children, which is not possible if children with and without diarrhea are examined separately. This would also eliminate the confusion that runs throughout the paper as to which groups are being compared at a given time; sometimes “groups” refers to dosage groups, at other times, to health status groups.

The authors should note that with such a small study, a finding of “no difference” could be due to a lack of power to detect a difference of a given size.

Results

See above for a suggested re-working of the analyses.

Also note that in Table S1, the comparison of wealth status between the two groups is incorrect; this calls for a Fisher’s exact test of the counts in each quintile by the groups being compared. In the table as currently reported, this represents a 5x2 table, and the test has a p-value of 0.13, indicating that there is no difference in wealth distribution between the two groups. In addition, neither family size nor number of sleeping rooms appear to be normally distributed. When this is the case, data should be summarized with medians and IQRs and compared with Wilcoxon rank sum tests.

Tables S2 and S3.

I am not sure why the authors present data on the characteristics of the children at baseline and at Day 21. This is not an efficacy study; if the authors wish to report on adverse events involving, e.g., weight loss over the one-week intervention period, they should look at changes and not aggregate before and after measurements. I would not expect that many of these measurements would change as a result of a one-week intervention, however, and the stated intention of the study is not efficacy, but tolerability and acceptability.

Tables 3 and 4. The data in these tables is primary to the goal of the study and could be presented in a more informative manner. E.g., it is probably not necessary to present results by day; summarizing by study period across the four groups would provide more easily digestible information (and even with this level of detail, it is not possible to tell whether the same or a different child suffered from given symptoms in the different periods). I’m not sure why pre-intervention symptoms are presented if the goal is to assess tolerability of the treatment during the treatment period. If the authors are not going to do an analysis in which they adjust for pre-intervention characteristics of individual children, and eligibility characteristics of the children have eliminated any serious conditions, these data are not, I think, necessary.

Conclusions

The authors purport to have shown the safety and tolerability of Fibrosol-2; it would seem that a large sample of children is not needed to confirm this, but to have sufficient power to examine efficacy outcomes.

The paper would also benefit from editing to correct grammatical and sentence structure errors.

Reviewer #2: Interesting study about dextrin compound - fibersol2 use in healthy children and children with diarrhea (1-3 years of age). Study is executed well with a control and study population and with an N of 60 however not a randomized trial. Well written manuscript.

**********

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.]

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-21-01326R1Digestive tolerability and acceptability of Fibersol-2 in healthy and diarrheal children 1-3 years old at a rural facility, Bangladesh: results from a four arm exploratory studyPLOS ONE

Dear Dr. Shahid,

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.

==============================

ACADEMIC EDITOR: The reviewer has raised key elements that need to be addressed. Particularly, they state that  the concept of efficacy is not clear. Please address their comments and provide a point by point response .

==============================

Please submit your revised manuscript by Dec 19 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: 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,

Ivan D. Florez, MD, MSc, PhD

Academic Editor

PLOS ONE

[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)

**********

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

**********

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

Reviewer #1: No

**********

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

**********

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

**********

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 think that the authors, while purporting to have tolerability and feasibility as their primary outcomes, have confused these concepts with efficacy. For tolerability and feasibility, the important question is whether or not children had an unacceptable reaction to the Fibersol, and whether this was associated with health state or dosage. Therefore, the period that is of most importance is the period during which the children are taking the Fibersol (not before, or after, when it is no longer being given to them). Looking at changes in/alleviation of symptoms as a result of taking Fibersol is actually a different question, and would require comparing pre-intervention symptoms to end of intervention symptoms.

I would suggest a rehaul of the paper. The authors stand a better chance of making conclusions about tolerability than they do about efficacy. This is not an efficacy analysis, nor was it powered to be. So what about the responses to the Fibersol during the time it was taken? Is it actually feasible and tolerable as the authors conclude? Looking at Table 2, the authors observed the following:

Abdominal pain during intervention: 20% of D/L kids; 7% of D/H kids

Abdominal distention: 27% of D/L kids; 20% of D/H kids

Abdominal rumbling: 27% of D/L kids; 27% of D/H kids

Abdominal bloating: 40% of D/L kids; 47% of D/H kids

Vomiting: 33% of H/H, D/L, D/H kids

Fever: 7% of H/L and H/H kids, 27% of D/L and D/H kids

I would argue that these are some alarming side effects in children so young, and most of them (except for vomiting) occur much more frequently in the diarrheal group. I am not sure how the authors conclude that “Regarding the digestive tolerability, there were some symptoms observed for both [diarrheal] groups during the study period.” Isn’t that the crux of the paper?

I would suggest the following steps:

1. Look at each outcome (as listed above), comparing WITHIN groups across dosages. For no one does the dosage appear to come into play.

2. Because of the fact that dosage doesn’t matter, compare healthy to diarrheal kids, who have a much lower tolerance for Fibersol.

3. Conclude that it doesn’t appear, from your evidence, that Fibersol is tolerable for children with diarrhea.

If you compare the different dosages in healthy kids, there are no differences in symptoms while taking Fibersol. If you compare the different dosages in diarrheal kids, there are no differences in symptoms while taking Fibersol. If you lump dosages together, then you get the following, comparing healthy to diarrheal children (at any dose):

Abdominal pain: p=0.09

Abdominal distension: p=0.01

Abdominal rumbling: p=0.005

Abdominal bloating: p<0.001

Vomiting: p=0.37 (no difference, but bad in both groups!)

Fever: p=0.08.

This strongly suggests that healthy children tolerate the Fibersol much better than the diarrheal children. The fact that symptoms lessen after the treatment has been stopped doesn’t prove the treatment is efficacious, if the treatment caused the symptoms in the first place.

I believe that the authors should re-think their analysis in terms of what question they are trying to answer, and re-evaluate their conclusions.

Minor comments: summarize diarrhea duration with medians and IQRs, not means and sds. These do not appear to be normally distributed.

**********

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

[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-21-01326R2Digestive tolerability and acceptability of Fibersol-2 in healthy and diarrheal children 1-3 years old at a rural facility, Bangladesh: results from a four arm exploratory studyPLOS ONE

Dear Dr. Shahid,

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.

Your paper was reviewed for one of our reviewers, and it still needs some work before considering it for publication. Please pay special attention to the comments provided by the reviewer and consider a revision and resubmission.

The paper also requires a grammar edition. It would benefit the paper, a reading by a native English speaker before resubmission. Please submit your revised manuscript by Apr 03 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,

Ivan D. Florez, MD, MSc, 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):

Your paper was reviewed for one of our reviewers, and it still needs some work before considering it for publication. Please pay special attention to the comments provided by the reviewer and consider a revision and resubmission.

The paper also requires a grammar edition. It would benefit the paper, a reading by a native English speaker before resubmission.

[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)

**********

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: Partly

**********

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

Reviewer #1: 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

**********

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

**********

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: Thank you for addressing most of my concerns; however, I still find the paper a bit confusing in part and suggest the following:

When summarizing with the median and IQR, please indicate in text, e.g.: the median (IQR) duration of resolution… (l. 43).

l. 62. Did children in the diarrheal group have more bloating after the intervention than before? If so, I would question the conclusion of “well-tolerated.” I see that this is addressed in the Discussion but the lack of pre-intervention data should be mentioned here if you are going to talk about it with respect to the other symptoms.

ll. 102-03. I believe that the authors are confusing tolerability with efficacy. Tolerability=any side effects of use? Efficacy=reduces symptoms. This should be clarified.

l. 114. Should add …Fibersol-2 at two different doses…

l. 145. Reduction of symptoms is different from tolerability. This should be clarified. See above.

ll. 162-164. Here the outcome is stated in terms of symptoms, not efficacy. This needs to be cleaned up throughout the paper.

ll. 220. I think it would be more clear to call the groups: healthy children/high dose, healthy children/low dose, children with diarrhea/high dose, children with diarrhea/low dose

Discussion, ll. 268-273. This information is in the Results and should not be repeated here. The authors should state as a limitation the fact that no data on bloating or rumbling were available for the pre-intervention period, but that these were increased in the group of children with diarrhea after the intervention. Then the authors can discuss why they think this was not related to the intervention, if that is what they believe.

Overall, the paper should be edited for grammar and coherence.

**********

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

[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.

Digestive tolerability and acceptability of Fibersol-2 in healthy and diarrheal children 1-3 years old at a rural facility, Bangladesh: results from a four arm exploratory study

PONE-D-21-01326R3

Dear Dr. Shahid,

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,

Miquel Vall-llosera Camps

Senior Editor

PLOS ONE

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

**********

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

**********

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

Reviewer #1: 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

**********

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

**********

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: (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

**********