PONE-D-22-21988Health professionals and scientists’ views on genome-wide NIPT in the French public health system:

Critical analysis of the ethical issues raised by prenatal genomicsPLOS ONE

Dear Dr. Perrot,

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PLOS ONE

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Additional Editor Comments:

The topic of the manuscript is interesting. Nevertheless, the reviewers raised several concerns: considering this point, I invite authors to perform the required major revisions.

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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

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: N/A

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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: No

Reviewer #3: No

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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: Dear authors,

congratulations for your paper. NIPT is the future of prenatal diagnosis, but Is crucial to understand that information about is pivotal

I think you paper is interesting, I would suggest to try to ameliorate the presentation of the result in a more schematic way, moreover to add a table with a summary of findings

I would recommend to go even more thought the crucial role of women awareness of the meaning of this test, is has been demonstrated worldwide that women understanding of this test is still quite confusing, the words diagnostic and screening are still often confused this pose enormous risk for health care professional, for this point I suggest to read and cite:PMID: 33111167

best regards

Reviewer #2: This is an interesting article reporting health professionals’ views on genome-wide NIPT in the French public system. While the results are interesting, major flaws should be addressed especially when it comes to the methodology, quotes translation, and English academic writing.

For the methodology, the authors state that they analyse the views of French HPs around GW-NIPT, based on semi-structured interviews and a comprehensive literature review that includes clinical consent forms, guidelines, regulatory texts, institutional reports, laboratory information leaflets. While they report their findings from the qualitative data, the comprehensive review part is missing. So, it is not clear if the authors conducted two separated studies (empirical and conceptual analysis based on comprehensive review) and that they are trying to combine in one study and in such case, they should describe how the comprehensive review was performed, the inclusion and exclusion criteria, what kind of studies were included, etc. or if they are referring to the literature from diverse sources to better interpret their findings.

The translation of the quotes needs to be revised as some sections seem to reflect a literal translation and the written English should conform with the academic English writing throughout the manuscript. Many sentences are structurally unclear, rendering therefore the meaning and the understanding very complex and unachievable. Here are few examples:

Line 360: “…by the private sector to make diagnostic returns that they do not know. What does diagnostic returns mean? The results?

Lines 370-371: “…It is absolutely necessary that we arrive in France at a situation that is, in fact, very consensual”. The translation is unclear.

Lines 551-552: “Questioning the rationality of women-couples in making choices about their personal circumstances and projects is not new”. What does rationality mean in this context?

Line 437: we can say to ourselves. This is a sentence that should be reviewed.

Lines 446-447: “anxiety that could be generated in women by GW-NIPT”. Please review.

Line 483: “How to decide what information is relevant or not to feedback to pregnant women”. Please review.

Lines 525-526: “Is the test likely to lead to an increase in the number of TOPs whether?” Please review.

Line 530: “not always admissible for a TOP”.

Line 534: “questions that will be posed to professionals”…please review. And the list goes on…

Introduction

p.4 line 73: The authors state “despite clinical benefits of GW-NIPT” without mentioning what are these. Please nuance.

Line 74: this screening test is largely driven by industry. So what does this mean and how it does impact its use and implementation?

Context

Why not give context about TOP in France? Is it legal? Prohibited at some point in time during the pregnancy? The authors only briefly discuss TOP as a theme that was developed in their interviews. It would be of benefit to the reader to have a glance about the situation of pregnancy termination in France.

Methodology

Lines 201-204: Many details are missing from the methodology used to collect the data. For instance, how the themes were developed and how were they validated? In what language were the interviews conducted? How the translation into English was done and validated (is it through translation and back-translation?) How HP were recruited? Based on what criteria?

Line 205: “…were conducted online” how? Via Zoom? Via another software, etc.?

Line 211: “During the qualitative study, we discovered how the subject of extending the screening offer if currently at the centre of debates in France”. At what point of time during the qualitative study? During the tata analysis? Data collection?

Also please replace discovered with noted.

While authors divided their sample into health professionals and scientists, they later noted that 16 out of 17 are HPs and researchers at the same time and 1 is a medical biologist. So why is this dichotomy necessary and how it plays when interpreting data, if any? Also, what is the difference between scientist and researcher and why not stick to one term scientist or researcher?

p.11 line 233: this theme is not only about additional training of prescribers but also about the limited number when it comes to human resources (genetic counselors, medical geneticist, etc.) available to counsel pregnant people about the test.

p.12 lines 272-273: the lack. Of harmonisation in antenatal care includes a variety of factor. Is it the consent form? The information offered? The technology used? Please explain further.

p.14 line 318: please nuance how this previous approach considered a medical negligence and whose responsibility is it in this analysis of the interview? And in what way it harms pregnant women? It it because the consent is not informed anymore i.e the pregnant woman is somehow forced to consent? Etc….

p.17 lines 377-378: “…has agreed on a list of incidental finding classified as valid” please explain. What does valid imply?

p.25 lines 570-571: How the terms standard vs. expanded are defined? Based on what criteria?

Please explain.

p.25 line 587-589: what is a generic consent form and how is it different from other consent forms?

p.25-26 lines 589-593: “While it is important to provide detailed information, an overload of information should be avoided as this could undermine rather than facilitate the ability of pregnant women to make autonomous choices….decision-making process”: how can this be done? How should a HP provide detailed information while avoiding an overload of information? The sentence structure and meaning are confusing.

What are the limitations and strengths of your study? Did you notice any difference in between for example the perceptions of medical geneticists and those of obgyns?

A reference that could be of interest to interpret and discuss your data:

Haidar, H., Birko, S., Laberge, AM. et al. Views of Canadian healthcare professionals on the future uses of non-invasive prenatal testing: a mixed method study. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01151-5

Reviewer #3: I read with great interest the Manuscript titled “Health professionals and scientists’ views on genome-wide NIPT in the French public health system: Critical analysis of the ethical issues raised by prenatal genomics” (PONE-D-22-21988), which falls within the aim of this Journal.

In my honest opinion, the topic is interesting enough to attract the readers’ attention. Nevertheless, authors should clarify some point and improve the discussion citing relevant and novel key articles about the topic.

Authors should consider the following recommendations:

- Inclusion/exclusion criteria should be better clarified.

- The authors have not adequately highlighted the strengths and limitations of their study. I suggest clarifying these points.What are the actual clinical implications of this study? it is important to report the results obtained by the authors in the context of clinical practice and to adequately highlight what contribution this study adds to the literature already existing on the topic and to future study perspectives.

- Recent and novel evidence suggested that epigenetic changes, in particular altered expression of selective miRNA, may play a key role in both placental-induced diseases such intrauterine growth restriction. It would be mandatory to discuss (at least briefly) this topic, referring to: PMID: 28466013; PMID: 20104830.

- The real challenge in the era of molecular medicine is to find a biomarker, or even better a panel of biomarkers, for early diagnosis of pre-eclampsia, intrauterine growth restriction and stillbirth. I would stress this point, referring to: PMID: 28243732; PMID: 35245721.

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Reviewer #1: No

Reviewer #2: Yes: Hazar Haidar

Reviewer #3: Yes: Pietro Serra

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Health professionals and scientists’ views on genome-wide NIPT in the French public health system:

Critical analysis of the ethical issues raised by prenatal genomics.

PONE-D-22-21988R1

Dear Dr. Perrot,

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,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Authors performed the required corrections, which were positively evaluated by the reviewers. I am pleased to accept this paper for publication.

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 #3: 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 #3: Yes

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

Reviewer #3: N/A

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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 #3: 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 #3: 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 #3: I read with great interest the Manuscript titled Health professionals and scientists’ views on genome-wide NIPT in the French public health system: Critical analysis of the ethical issues raised by prenatal genomics." (PONE-D-22-21988R1), which falls within the aim of this Journal. In my honest opinion, the topic is interesting enough to attract the readers’ attention.

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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 #3: Yes: Pietro Serra

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