PONE-D-19-26797

Administration of Lower Doses of Radium-224 Ankylosing Spondylitis Patients Results in No Evidence of Significant Overall Determent

PLOS ONE

Dear Dr. Hoel,

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Suminori Akiba, M.D., Ph.D.

Academic Editor

PLOS ONE

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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: No

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

Reviewer #1: No

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?

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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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: This is a study using the raw data of previous work by Wick RR et. ( Incidence of leukaemia and other malignant diseases following injections of the short-lived alpha-emitter 224Ra into man. Radiat Environ Biophys. 2009 Aug;48(3):287-94) and the authors analysed all mortality within the studied 224Ra-treated and untreated ankylosing spondylitis patient populations. They concluded that 224Ra treatment at typical levels of 5.6 to 11.1MBq in total administered dose had no negative impact on the survival of the ankylosing spondylitis patients compared to the control patients. The results showed that the treatments resulted in a significant reduction in the relative risk of death from all causes because of the reduced incidence of non-cancer deaths – most notably in the percentage reduction in deaths from CNS lesions, cardiovascular disease and ill-defined /unknown causes.

There are some issues requiring further statement.

1. Manuscript style

The manuscript style does not fit the journal's instruction for authors, including the text citation and references writing style. The authors need to revise it.

2. Methods

The authors wrote " As a first step in the analysis, data for the smaller number of female patients was removed from the study. This is because males and females exhibit different disease and survival profiles.

However, some questions remain that what kinds of effect " females” have on Radium-224 exposure?

3. Since cancer and non-cancer are competing causes of death.

Can the authors do a Competing risk model in Statistical analysis?

Or cause-specific hazard function?

4. Can the authors address some limitation of this study at the section of Discussion.

Reviewer #2: [General comments]

This manuscript focuses on mortality from non-cancer diseases and all causes rather than specific types of cancer which may or may not be associated with therapeutic exposures to ionizing radiation among ankylosing spondylitis patients. The authors demonstrate no significant increase of overall mortality in relation to the Ra-224 treatment based on the analyses of the archived follow-up data. However, a caution should be paid in interpreting the results because the quality of follow-up were likely to be different for different populations (patients with or without Ra-224 treatment). In addition, baseline characteristics were likely to be different between patients with and without Ra-224 treatment. In these points, the authors should describe a little bit detail about how to follow the study subjects (with reference to the relevant previous study), and the reason why some of the patients were not treated with Ra-224. Without relevant explanations, the authors cannot come to the conclusion. The following are specific comments.

[Specific comments]

#1, 1st paragraph, page 4, METHODS

How to follow-up for mortality should be described at least briefly. In addition, the reviewer wonder if the authors used information on date of exit (date of last observation) for each study subject, but there was no description in the text.

#2, 2nd paragraph, page 5, METHODS

The authors described “The Cox model allowed for the different ages of the patients entering the study”, but it is unclear if they used attained age of study subjects as time scale in the Cox model, or they used age at entry as a stratified variable or a covariate in the Cox model. Please make it clear.

#3, line 1-2, page 6, RESULTS

The proportions of the deceased subjects were different for three populations. The possible reason for it and its potential impact should be carefully discussed in DISCUSSION section.

#4, line 4 and 11, page 6, RESULTS,

Table 1 was referred but it was missing in the paper.

#5, line 8, page 6, RESULTS,

Confidence interval was shown, but either 90% or 95% CI was unclear. Please specify it here and later on where appropriate.

#6, line 12, page 6, RESULTS,

“The odds ratio” was shown here, but it should be “hazard ratio.” In addition, RRs should be revised to HRs through the text.

#7, line 14, page 6, RESULTS,

There was a typo; RR of “098.” It should be revised.

#8, line 1, page 7, RESULTS,

Figure 2 was referred here, but Figures 3-6 were already referred earlier. Please reorder the figures.

#9, 1st sentence of 2nd paragraph, page 8, DISCUSSION,

The authors discussed about their assumption that radium-treated and control populations were identical in all respects except for dose from administered Ra. They should carefully explain the justification of their assumption.

#10, Fig. 2,

The proportions of selected causes of death were shown for three population, but a table which shows numbers of deaths and crude rates is more informative than this kind of figure.

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Reviewer #1: No

Reviewer #2: No

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Administration of Lower Doses of Radium-224 to Ankylosing Spondylitis Patients Results in No Evidence of Significant Overall Determent

PONE-D-19-26797R1

Dear Dr. Hoel,

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,

Suminori Akiba, M.D., 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 #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 #2: Yes

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

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 #2: 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 #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 #2: All the comments from reviewers have been addressed and the manusccript seems to be revised satisfactory. However, there are several typographic errors including the followings, and I would like to suggest the authors to check English throuout the manuscript.

line 212 "RR" should be read as "HR"

line 220: "older then" should be read as "older than"

line 240: "The results this study" should be read as "The results of this study"

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Reviewer #2: No