PONE-D-20-00773

Participation in interventions and recommended follow-up for non-attendees in cervical cancer screening -taking the women’s own preferred test method into account - a Swedish randomised controlled trial

PLOS ONE

Dear Dr Lilliecreutz,

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Joakim Dillner, M.D.

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Additional Editor Comments (if provided):

Dear Dr. Lilliecreutz,

The reviews are now completed and I would like to invite you to resubmit a revised version of the paper that takes the reviewers´commenst into account.

In addition:

The paper describes that the participants were enrolled before an IRB approval was obtained. This could have been a cause for a rejection without reviews, but I decided to give you the opportunity to explain. Please include this both in the accompanying letter when you resubmit the paper and in the revised manuscript itself.

From the comments, I am concerned about that it is not clear if the outcome is measured by cytology or histopathology, that it is not clear what the difference is between per protocol and intention to treat and how these 2 analyses could even have different conclusions. Please give exact counts (not only percentages) already in the abstract. Finally, please have a native English speaker revsie the paper before you resubmit.

I look forward to receive the revised manuscript,

Best Regards Joakim Dillner, Editor

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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: Partly

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: No

Reviewer #2: Yes

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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: No

Reviewer #2: 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: Long-term non-attenders to cervical screening have a higher risk of cervical cancer; therefore, determining effective ways to reach women who do not respond to routine invitations is important for the effectiveness of the screening program. This paper examines the effect on participation, follow-up, and disease detection of two active interventions involving self-sampling with the routine practice of sending a reminder invitation. The authors have also compared to a population that routinely attends cervical screening. While the premise is important, there are several aspects of the paper that need clarification and structuring to better highlight the study protocol and the results.

1) The materials and methods section needs to be reorganized for clarity – statements regarding registration of the trial can be moved to the end; information on the extraction of the comparison group can be included under the “attended group” heading along with further details on this population and reasoning on the selection criteria; a description of the ITT and per protocol population definitions should be included in the analysis section.

2) In the second paragraph of the methods, the authors state that all three groups received the yearly invitations. Is it possible to separate the effects of the intervention and the routine yearly invitations? Did they occur simultaneously or sequentially?

3) More details on the interventions would be helpful for reproducibility and understanding effects. What information did women receive about the intervention procedure? More details on the HPV self-sampling are needed – what test was used, were instructions included?

4) The authors have explored a series of outcomes related to the screening process but what is most interesting is the comparison between the interventions at each stage. That said, it would be helpful for the reader if the results were organized by outcome rather than a mix of intervention arm and outcome. As it stands, the results are somewhat hard to follow. The first stage in the results are framed as “obtaining an index sample”, would it be fair to say that this reflects “participation” and that the interventions are differently effective in increasing participation as compared to the control group? This interpretation might be more understandable to the reader and corresponds better to the screening process reflected in the choice of the other outcomes.

5) Perhaps it should be noted again that Table 5 reflects cytological results, and therefore *suspected* cancer, correct? If I’ve understood it correctly, these are not histopathologically confirmed cancer whereas Table 6 reflects results that are histopathologically confirmed. Furthermore, the description of Table 6 needs to be edited. The OR mentioned in line 295 is from Table 5 not Table 6 (this matters for the results summarized in the abstract as well). This needs to be clarified in the final paragraph of the Discussion (starting at Line 382).

6) While the authors have detected more underlying disease (and suspected cases of cancer) in the intervention arms as compared to the general population that attends screening regularly, the authors have made this conclusion based on cytology results which precludes information on staging. Therefore, statements on the downstaging effect of the interventions should be made with more caution at the end of the Discussion.

Smaller edits

1) Ref 4 - HPV16/18 cause 70% of all cervical cancer, not just SCC.

2) Please read through the text again – there are several typos that make the text less readable.

3) I may have missed something, but the dates for the interventions described in the second paragraph of the materials and methods section don’t line up with the dates described for each intervention separately.

4) I suggest using “abnormality” or “positive screening result” to describe the index tests that needed further follow-up rather than “pathology”. Also, I suggest replacing “PAD” in Table 6 with “histopathological results”. Furthermore, it can be noted that HSIL/LSIL terminology is used for both cytology and histology in this context to clarify for the reader.

Reviewer #2: Lilliecreutz et al., studied outcome of two intervention arms and one control group among non-attendees in cervical cancer screening.

They randomized 10.500 women to three groups among those that had not participated in > 6 years. Among the group of women who were randomized to get a HPV self-sample kit, 34.1% sent in an index sample (either HPV-sample or a pap-smear). Corresponding figures were 25.5% and 7.0% (cytology) for women that was invited by telephone and by routine reminder by post, respectively. The majority of the women 63.4% who answered the telephone wanted to have a pap smear (38.5%) or to be sent a HPV self- sampling kit (24.9%) (p<0.001). Women who chose an HPV self-test were older and gave anxiety/ fear as a reason to decline participation, and they were also less likely to participate in the follow-up if HPV-positive compared to the women who chose a Pap smear. In the by protocol analysis the telephone group (among those who answered) was the most effective regarding collection of an index sample compared to the HPV self-sampling test and control group with 31,7% vs 26,1% and 7,0% ( p<0.001) respectively in each group. The attendance to the recommended follow-up in total was 87%. Non-attendees had a three respectively eight times higher risk of having a HSIL or SCC compared to women screen as recommended (OR 3.3 CI 95% 1.9-5.2, OR 8.6 CI 1.6-30). A total of ten SCC and one adenocarcinoma were found in the non-attendee group with a study intervention compare to one SCC in the non attendee group without any study intervention ( p=0.02, OR 8.1 CI 95% 1.2-350).

They concluded that the best strategy to get more non-attendees to participate is to send a HPV-self sample kit.

The study is interesting due to its size of invited population based women and the engagement of 24 midwifes in order to perform the telephone arm.

Comments

The manuscript will benefit from improvements as mentioned below.

1. Abstract. Please clarify which result that was used to conclude that the best intervention method to get as many non-attendees as possible to leave a sample is to send a HPV self sampling test together with an invitation letter? In contrast (line 344) in the discussion you favour personal contact with a midwife with an option for the woman to choose sampling method.

2. Please describe that “intention to treat statistical analysis” was performed in both abstract and materials and methods.

3. Please clarify “by protocol” in the Material and Method section.

4. Line 179 ASC-H? Please change to ” that cannot exclude a high-grade squamous intraepithelial lesion”

5. Line 368. Please clarify the term “majority”?

6. Line 337. Please consider a recent study which also observed increased return rates of self-samples by increasing age (PMID: 32082413).

7. Table 1. Please give explanations (footnotes) of “Intention to treat”, “Index sample”, “By protocol” and add headings in the two left bottom squares.

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Reviewer #1: No

Reviewer #2: No

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Participation in interventions and recommended follow-up for non-attendees in cervical cancer screening -taking the women´s own preferred test method into account

- a Swedish randomised controlled trial

PONE-D-20-00773R1

Dear Dr. Lilliecreutz,

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.

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Kind regards,

Joakim Dillner, M.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 #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: Yes

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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: 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 #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: The revision of the paper addressed most of the raised comments. Also the methods section improved.

Data were analysed with descriptive statistics. -> The authors use hypothesis testing. However, hypothesis testing is no descriptive statistics (it is inferential statistics, see

https://www.mdpi.com/2504-4990/1/3/54

The rejection of the null- hypothesis was set to 0.05 -> The significance level alpha was set to 0.05

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #3: No