PONE-D-19-30828

Improved Health Care Utilization and Costs in Transplanted versus Non-transplanted Adults with Sickle Cell Disease

PLOS ONE

Dear Dr.Saraf,

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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: Yes

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

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Thank you for the opportunity to review this work from Dr. Saraf and his colleagues. The authors in this manuscript are trying to provide an evidence on the improvement of health care utilization (HCU) and the associated costs in patients who were diagnosed with sickle cell disease (SCD) and underwent stem cell transplant compared to patients who received standard of care. Overall, the used methods are appropriate and the manuscript is well written. The following are my comments:

1- For the conclusion, I recommend to adjust the language the conclusion to be as following: “In conclusion, allogeneic HSCT may leads to improvements in health care utilization and costs compared to standard-of-care therapy in high risk SCD adults.” Given the relative small size and the need of multicenter study to replicate these findings before providing a such strong recommendation.

2- In abstract, “HSCT” needs to be defined for one time in the beginning.

3- This article published in JAMA recently which underscores the need for disease-modifying therapies to improve the underlying morbidity and mortality associated with SCD. You might use it to justify the importance of transplant as a disease modifying therapy and how could improve the lifetime income of individuals with SCD on top of the suggested improvement in HCU in the current presented evidence (economic benefits on multiple levels). https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2755485?utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamanetworkopen&utm_content=mthlyforyou&utm_term=120819&term=120819

4- In the introduction, hydroxyurea is mentioned as the only FDA approved therapy available to treat patients with SCD. Now, since voxelotor has been recently approved by FDA in November 22, 2019 (which I understand that happened after submitting this manuscript), I highly recommend to comment on this medication and the related benefits as another option for patients with SCD.

5- I recommend to define more in the inclusion criteria the exact meaning of “match related HSCT”. Does that mean matched sibling or matched parents or other related family members or combination of all of them? And I recommend to report the percentage of each category in case we have a combination.

6- It is unclear the age range that included in this study. The authors reported median and interquartile range (IQR). The IQR for HSCT group is 16-51. I assume this means there are some children who aged less than 16 and included in this study. I recommend to clarify this point to know what kind of population we are dealing with in this study and to report the percentages of children (less than or equals 16) and adults (more than 16).

7- The current literature suggests that myeloablative conditioning has good outcomes on survival, GVHD and engraftment with even possible superiority of myeloablative over nonmyeloablative/reduced intensity conditioning (RIC) in children population and subsequently possible less burden on health care system, whereas nonmyeloablative has better outcomes in adults. I suggest to put a rationale for limiting the data on RIC since we are talking about possible combined population in this evidence.

8- Proceeded not proceed in page 11, line 8.

9- In the legend of figure 1, I suggest to clarify the population and the time frame you are trying to investigate. I believe these outcomes reported on all patients in the year prior to HSCT based on the results section.

Reviewer #2: 1. The authors have done a fair job in presenting the data. Authors have described the statistical analyses used on the data, but did not indicate the level of significance when comparing different groups on the data. Although the P values are mentioned absence of indication of level of significance leads to undermining and confusion of the data presented. In a study that focuses on comparison of clinical data over a period of time, analyses and representation needs to be precise and clearly stated.

2. Clinical level of significance should be mentioned in all the data that is presented.

3. Is there a reason why there were greater costs observed in female group of patients versus male group of patients? Did the authors compare HSCT Vs non HSCT patients based on gender?

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Reviewer #1: Yes: Jehad Almasri

Reviewer #2: No

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Improved Health Care Utilization and Costs in Transplanted versus Non-transplanted Adults with Sickle Cell Disease

PONE-D-19-30828R1

Dear Dr. Saraf,

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

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With kind regards,

Senthilnathan Palaniyandi, 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: (No Response)

Reviewer #2: 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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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

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. 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: Two minor points:

1- The conclusion language need to be modified in the abstract as well.

2- I would still highly recommend to add the actual age range in the manuscript. I understand your range is 16-51 but I do not see this has been mentioned any where in the manuscript.

Reviewer #2: (No Response)

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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: Jehad Almasri

Reviewer #2: No