PONE-D-21-11149

Health economic evaluation of noninvasive prenatal testing and serum screening for Down syndrome

PLOS ONE

Dear Dr. Xiao,

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.

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Sherif A. Shazly, M.B.B.Ch

Academic Editor

PLOS ONE

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2. Thank you for including your ethics statement:  "All examinations were approved by the ethics committee of Zhuhai Center for Maternal and Child Healthcare and informed consent was obtained from pregnant women.The authors of the manuscript declare no conflicts of interest.".   

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3. Please amend the manuscript submission data (via Edit Submission) to include authors Guoqing Wang, Huayu Luo.

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Reviewers' comments:

Reviewer #1: Dear authors,

Thanks for your submission. I just have some minor comments;

1- Please mention the full name of hormone uE3 before using the abbreviation at first mention in the document (line 106).

2- Titles of tables 1 and 2 need to be more informative.

3- In the discussion you mention that the DS risks calculated with or without the NT were significantly different in the first trimester (line 238), but i couldn't find such comparison in results section.

4- In the discussion you mention in line 253 that cfDNA is undetectable in maternal blood until 2 h after delivery. What is the significance of this information in relation to you discussion argument?

Finally the manuscript is generally acceptable and worth publishing after these minor rivisions

Thanks,

Reviewer #2: General Comments

The paper is interesting. The message is straight forward, and the results presented support the conclusion. The authors successfully demonstrate how NIPT can be used as a non-invasive primary step for the diagnosis Down Syndrome. They also provide evidence showing that it may be more cost effective and accurate than serum screening. However, the results are not discussed in depth and I see several other problems with the manuscript.

Firstly, there seems to be a lack of detail in the methods. While many of the details are ratified within the results, the Methods and Materials section at times is somewhat ambiguous, especially regarding the number of study participants and the included tests.

Secondly, the first page of the discussion, while interesting in context of the history of down syndrome screening, would probably fit better within the introduction. This first portion of the discussion makes the section very long and while it provides some context, it does not provide information that supports the presented results.

Thirdly, the paper would be well served by including graphical representation of the results, rather than including all results within tables. The one figure that was included was illegible.

Thirdly, while it is stated at line 72 “We also performed a health economic evaluation of four screening strategies from a public health perspective.” very little discussion is given to the possible economic impact or outcomes of the different screening strategies. In table 4 it is demonstrated that strategy 4 (where NIPT is the only screening method) is approximately 25,000,000 CNY cheaper than the next cheapest strategy and over 50,000,000 CNY cheaper than strategy 1, a factor of over 4 times cheaper. At line 260 it is stated “In the public health service program, cost is the most important factor preventing NIPT from replacing SS as a first-line prenatal DS screening strategy. Additionally, the cost-effectiveness ratio of the screening strategy is the most important consideration for local health administrations.” If this is the case, and strategy 4 is considerably cheaper with promising outcomes why is this not being considered or implemented? There is no critical discussion present on this. Furthermore, there seems to be no discussion over the advantages or disadvantages of using NIPT over SS as the primary screening method, apart from NIPT being less susceptible to subjective factors (which are not outlined).

Finally, at line 312 “Therefore, secondary prevention and control of birth defects using NIPT instead of SS as a first-line test for prenatal DS screening can greatly reduce the frequency of IPD and IPD-related miscarriages”. While I agree that this conclusion is correct based on the presented results, can this conclusion be made in regards to IPD-related miscarriage when a single miscarriage was recorded?

Specific Points

INTRODUCTION

1. Line 53: “200-300 genes” is there no better precise estimate?

2. Line 65: Is there any trimester separation for NIPT or is it as applicable through pregnancy?

METHODS AND MATERIALS

3. Line 81: Did all women undergo both SS and NIPT or was it a mixture? Not clear.

4. No where in the methods do the authors specify the number of women that were tested. I assume it was 17363 as mentioned in the introduction.

5. Line 83: Are there breakpoints which categorise high risk in the NIPT test like described for SS?

6. Line 84: Is there a reason why only amniocentesis was recommended for SS while amniocentesis or cordocentesis was recommended for NIPT?

7. Again, were both SS and NIPT performed on all the women or SS on one proportion and NIPT on another? Based on the results I assume SS and NIPT were both performed on all patients. Needs to be outlined better within the Methods.

8. Line 85: How many patients underwent IPD?

9. Line 157: Figure 1 is essentially unreadable. Needs to be remade.

RESULTS

NIPT

10. Line 190: Table 2: “FPV” not consistent with “FPR, False Positive Rate”

11. Line 192: “*Z ≥ 3 indicates high risk in NIPT” Z is not outlined in NIPT methods section as risk assessment is in the SS methods section (Line 106 - 108).

DISCUSSION

12. Line 285: Is this true? There is no reference for this statement. The NIH priced NIPT in the USA as $700-1000 per test in 2014. One would expect this to be cheaper 7 years later.

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PONE-D-21-11149R1Health economic evaluation of noninvasive prenatal testing and serum screening for Down syndromePLOS ONE

Dear Dr. Xiao,

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 address reviewer 1's reiterated question about your statistical analysis.

Please submit your revised manuscript by Dec 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: 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,

Yann Benetreau, PhD

Senior 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: (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

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

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

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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: 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. 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: Dear authors,

Thanks for your response. I just have some minor comments.

1- the first mentioning of uE3 is now moved to line 81 (this part was not included in your original submission), hence you should the full name of this abbreviation accordingly.

2- Your response to my 3rd comment is inadequate : (It has been mentioned in line 206.“For the 10 cases missed in first-trimester screening, calculation without NT and with the serum indicators PAPP-A and F β-hCG identified 4 cases, and the detection rate was increased to 62.5% (10/16) (Table 1).”). This doesn't necessarily imply significance. There has to be a p-value of at least <0.05 based on a suitable statistical test to conclude significant difference.

Reviewer #2: The authors have taken time to address each of my comments to a degree which I believe to be satisfactory.

**********

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.

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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-21-11149R2

Health economic evaluation of noninvasive prenatal testing and serum screening for Down syndrome

PLOS ONE

Dear Dr. Xiao,

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.

Both reviewers are now happy with the technical aspects of the paper. I am not the original editor responsible for this paper, so I apologize, but I am going to request two small additional considerations. First, this is a topic where there are ethical issues involved, concerning the rights of those living with disabilities. I request the authors to refer briefly to this literature in the Introduction (a couple of sentences plus references would suffice).

Second, it would be helpful in the Discussion section to note that the results for China may not transfer readily to other countries. In some other countries, late detection of Down's syndrome may be too late for termination of the pregnancy to be legally permitted. Even where it is legally permitted, not all parents may exercise the choice to terminate the pregnancy. I don't know if this is an option in China (would Zhuhai Municipality permit the parents to continue on with the pregnancy?). In these circumstances the parents still benefit from screening in being able to prepare for the birth of a differently-abled child, but it would affect the economic costs and benefits of the outcome. Again, a couple of sentences qualifying the findings would suffice.

Please submit your revised manuscript by Apr 07 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,

Susan Horton

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.

[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: 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: I Don't Know

********** 

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

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

Reviewer #1: No

********** 

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

[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.]

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Health economic evaluation of noninvasive prenatal testing and serum screening for Down syndrome

PONE-D-21-11149R3

Dear Dr. Xiao,

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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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,

Susan Horton

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

please accept 2 small edits to the text (for English-language speakers): in line 337, delete the word "born" (it is ok to say "have the baby") and instead of "disability child" in line 338 please say "child with disabilities": in the literature on disability, the convention now is to put the person first, followed by the term describing their abilities.

Reviewers' comments: