PONE-D-22-23111Partial Heart Transplantation for Severe Pediatric Semilunar Valve Dysfunction: A Clinical Trial ProtocolPLOS ONE

Dear Dr. Zilinskas,

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"BG and JK are funded by NIH-NHLBI Institutional Postdoctoral Training Grants (T32 HL-007260). TKR is funded by the American Association for Thoracic Surgery, the Children's Excellence Fund held by the Department of Pediatrics at the Medical University of South Carolina, the Brett Boyer Foundation, and the Emerson Heart Foundation."

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Additional Editor Comments (if provided):

The manuscript has been reviewed by independent reviewers including a statistical reviewer. They have raised some important points including certain ethical considerations and statistical/study design suggestions. Please carefully consider their comments and suggestions.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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: No

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Ochoa and colleagues describe a protocol for a prospective nonrandomized, single-center, single arm pilot trial where a “partial heart transplant” will be performed in infants and young children with semilunar valve disease. The hypothesis is that the transplant semilunar valves will grow with the patient and avoid known complications associated with current valve options for these children. This a reasonable protocol, however, I have following specific comments for the authors

“Inability for the parent(s) or legal guardian(s) to understand English or Spanish”, this seems like an inappropriate exclusion criterion, especially when all study procedures are standard clinical care, and one would expect that inability to understand these languages does not preclude clinical care.

There is another ethical issue/potential risk with this procedure that is not discussed. A potential organ for life-saving heart transplant is diverted for a treatment that has other surgical options. This should be discussed and potentially be part of the informed consent. Furthermore, donor selection is not discussed in detail, could these donors have suboptimal cardiac function and not suitable for conventional heart transplant?

It may be after this submission, but there has been a clinical case described as “first partial heart transplant” from Duke University in the news lately. Citation of that would be important for complete reference of prior work.

Lower levels of immunosuppression are proposed as a possibility after first year, a description of such protocol is important for completeness.

Reviewer #2: This study addresses an interesting topic. It is well detailed and may lead to interesting results. Some comments follow.

1. The sample size is rather small. It is necessary to specify the power of the study. Similarly, the fact that it is a nonrandomized single-center study may strongly limit its practical usefulness. Indeed, my main concern is about how general the obtained results would be. It is difficult to understand why such a small sample size is aimed to be collected.

2. Missing data management needs a better discussion. Missing data could be completely-at-random, at-random, not-at-random. Sensitivity analysis should be planned to avoid misleading inference whenever complete-case analysis is performed.

3. The data analysis is based on descriptive statistics only. This strongly limits the project. If research questions cannot be tested, if inference cannot be performed, the study simply describes a specific sample, that may not be representative of a larger population. Which general info do you expect to get from a simple descriptive analysis? Cause-effect relationships cannot be investigated, nor any characterization of the outcomes could be discussed. The data analysis is not sufficient to provide informative results. I strongly suggest to plan a more detailed and extensive statistical analysis, based on a larger sample. Statistical inference must be guranteed.

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Reviewer #1: No

Reviewer #2: No

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Partial Heart Transplantation for Severe Pediatric Semilunar Valve Dysfunction: A Clinical Trial Protocol

PONE-D-22-23111R1

Dear Dr. Rajab,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Jaimin R. Trivedi, MBBS, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Authors have responded to the comments adequately and made appropriate changes. This manuscript is well written.

Reviewer #2: All my comments are properly addressed. I believe this work is ready to be published. It will be a starting point for further analyses on the topic.

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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: No

Reviewer #2: No

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