Dear Dr. Thordardottir,

Thank you very much for submitting your manuscript "Mortality and major disease risk among migrants of the 1991-2001 Balkan wars to Sweden" (PMEDICINE-D-19-03629) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

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We expect to receive your revised manuscript by May 11 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

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Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon). eg, "Mortality and major disease risk among migrants of the 1991-2001 Balkan wars to Sweden: register-based cohort study".

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. When completing the checklist, please use section and paragraph numbers, rather than page numbers. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

*As the study is observational, it isn't straight forward to infer causality; in most of the manuscript text, this is appropriately presented but there are a few places where the authors mention "elevated/increased risk" or "reduced risk" which does seem to imply the association is causal and the language could be fine-tuned in such instances (ie "associated with increased risk").

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Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper.

One big issue is the use of linear regression. Since there are a lot of people from each of a bunch of countries, the assumption of independent errors that linear regression makes will be violated. One method of dealing with this is a multilevel model. In addition, this allows clearer use of both individual and country-level variables.

In addition,

Line 106-7 Do not categorize independent variables. In *Regression Modeling Strategies* Frank Harrell lists 11 problems with doing this and sums up "Nothing could be more disastrous". I wrote a blog post illustrating some of the problems : https://medium.com/@peterflom/what-happens-when-we-categorize-an-independent-variable-in-regression-77d4c5862b6c

Peter Flom

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Reviewer #2: The paper addresses a relevant health problem and the data used together with the analytic strategy adds to the literature. The topic as well as the data-set itself is very complex and this is a good attempt to attack the issues at hand. To this reviewer's mind, there are some points that could be sharpened in the paper. Comments:

The background and the conclusion in the abstract should - as the methods part does - make clear that this is a comparison between different groups of immigrants.

The authors present complex models first and then later return to stratified analyses (but also there we see only adjusted models). I would much have preferred to from the beginning see more presentation of the crude data, e.g. starting with something like table 4 displaying incidence rates, HR:s in unadjusted and then adjusted models in strata as in table 4. Then proceed to the multivariate models.

Likewise, it would be easier to understand the data and follow the line of interpretation if we in the modeling could see what happens in different steps of the adjustment. This need not be covariate by covariate, but could be in "chunks" of co-variates. The present results-section does not convince the reader that the models presented are the adequate ones and does not permit assessment of effect-modification and alike phenomena.

Persons with missing data on education is an extreme group judging from table 4. It is not clear in the methods part how the missing category was handled and if the choice of method here influence the results in a major way. Have the authors considered an imputation here or some more advanced strategy to find out what is happening?

The tables are very unclear about what a "rate" is. E.g. table 4 shows hazard ratios, not rates, the other tables show both incidence rates and hazard ratios. It is very difficult to find out the enumeration of the denominators for the rates.

It is very good that we for many tables see both incidence rates and the hazard ratio. This in turn could lead to a part in the discussion to show what the absolute health impact is likely to be in say 1000 individuals during five years of observation.

The discussion could be better structured. The study, say the authors, "offers a unique opportunity to examine the health consequences of additional stressors brought on by war exposure". The critical question is then if the design, data, analysis and results reflect a causal pathway for this, or if the findings are a result of other things such as data handling, selection of who migrates, or exposures in the home-country. Some of the hazard ratios are quite low and could be the result of bias rather than causal. The discussion enters this discussion but only partly and fragmented. Mostly, the authors use a rather strong "causal language" - which admittedly could be used around psychiatric disorders but is more questionable for e.g. cancer. A clearer structure could probably also lead to a shortening, which would put the message across clearer.

In the conclusion, line 315-321 is a repetition of the main findings and unnecessary. What comes after are consequences of the findings and the interpretation, which is a good final note. Could more of this be "transplanted" to the abstract?

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Reviewer #3: Comments to author

This is an important and well-performed register-based investigation on the risk of mortality and major disease risk among migrants of the 1991-2001 Balkan wars to Sweden compare to migrants from other European counties to Sweden during the same period. The strengths of the study includes the use of comprehensive registers and careful statistical analyses. The manuscript is well written and easy to read.

I have only minor comments:

METHODS

1. They authors should describe any work/effort validating the information source. How accurate is the information in this database, how complete are the data; are they equally complete throughout the study period?

2. Line 85, ICD-10 for CVD diagnosis is I00-I99, not 100-199

3. Line 94 and Line 97, ICD-7 code of 150 is "esophagus"

4. Line 95, ICD-7 code for lung cancer 162-163, code 161 is a diagnosis of larynx, the author has defined it as a separate subtype (Line 98).

5. Line 97, ICD-7 code for liver cancer are 155 and 156

6. Line 107-108, please indicate first degree relatives in the methods; as the authors have mentioned in Table 4, siblings, parents, and children.

7. Please clarify how the rate of morbidities and mortalities was calculated, it was for per 100 000 inhabitants or per 100 000 person years.

RESULTS

8. Please add a footnote to indicate incidence rates (IR) in Table 1, 2 and Supplementary Table 5, for per 100 000 inhabitants, or per 100 000 person years.

DISCUSSIONS AND CONCLUSION

9. It should be noted that cancer survival in Sweden overall is internationally favorable. The findings that some groups with low cancer incidence may have even a more favorable survival. Even the study has controlled by the variable of residence time and country-level cancer and related rates, the possibility of immigrants diagnosed with a cancer in the earlier stage may move back to their home country, while severely ill patients stay in host country, causing bias in Hazard rates.

10. Suggest how your findings are useful for health care workers (or policy makers)? What might they do with this information?

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachments

Attachment

Submitted filename: Comments to author.docx

Dear Dr. Thordardottir,

Thank you very much for re-submitting your manuscript "Mortality and major disease risk among migrants of the 1991-2001 Balkan wars to Sweden: A register-based cohort study" (PMEDICINE-D-19-03629R1) for consideration at PLOS Medicine.

I have discussed the paper with editorial colleagues and it was also seen again by two reviewers. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions. Otherwise, we look forward to receiving the revised manuscript shortly.

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

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Requests from Editors:

Noting the comments from our academic editor (below), we ask you to give some thought to how study participants are described in the text (including the title and abstract). In particular, the term "war migrants" seems unusual, and "displaced persons" or "persons displaced by war" would be preferred. We suggest explaining the legal status of study participants in Sweden early in your article, and then using a standard term throughout the text - one possibility would be to use an abbreviation (e.g., "asylum seekers/refugees", "AS/R").

To your data statement, please non-author contact details to the two sources mentioned for readers interested in inquiring about access to study data.

Please add a sentence, say, to your abstract quoting aggregate demographic details for study participants.

At line 26, please begin the sentence "Our findings indicate that ..." or similar.

Early in the methods section of your main text, please state whether or not the study had a protocol or prespecified analysis plan, and if so attach the relevant document as a supplementary file, referred to in the text. Please highlight analyses that were not prespecified.

Noting "p<0.0001" at line 203 and elsewhere, please quote exact p values or "p<0.001" throughout the article.

Please remove the information on funding and competing interests from the end of the main text. In the event of publication, this information will appear in the article metadata, via information provided in the submission form.

Throughout the paper, please add p values alongside 95% CI, where available.

Are you able to add a URL, and accessed date, to reference 9?

Please move the STROBE checklist to a separate attached file and refer to this in the methods section of your main text (i.e., "See S1_STROBE_Checklist" or similar).

Comments from academic editor:

a. Definitions: I would suggest using the terms asylum seekers, refugees and (economic) migrants.

i. I believe all displaced persons from the Balkan war would be considered asylum seekers while some may have received refugee status during their time in Sweden. However, the authors need to clarify whether Sweden gave the Balkan ‘refugees’ a special status until the war was done and then they had to return (I am not sure if this is the case, but Germany did).

ii. Displaced persons from other countries (they may be asylum seekers, refugees or migrants).

b. I also agree with the referee who said “I would much have preferred to from the beginning see more presentation of the crude data, e.g. starting with something like table 4 displaying incidence rates, HR:s in unadjusted and then adjusted models in strata as in table 4. Then proceed to the multivariate models.”

Comments from Reviewers:

***Reviewer #1:

The authors have addressed my concerns and I now recommend publication.

*** Reviewer #3:

Comments:

The authors have satisfactorily responded to all my questions and made the necessary changes to the manuscript. I have no additional comments.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachments

Attachment

Submitted filename: Comments to authorXL2.docx

Dear Dr. Thordardottir,

On behalf of my colleagues and the academic editor, Dr. Paul Spiegel, I am delighted to inform you that your manuscript entitled "Mortality and major disease risk among migrants of the 1991-2001 Balkan wars to Sweden: A register-based cohort study" (PMEDICINE-D-19-03629R2) has been accepted for publication in PLOS Medicine.

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Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Richard Turner, PhD

Senior Editor

PLOS Medicine

plosmedicine.org