PONE-D-19-17740

Rare disease in Malaysia: Challenges and solution

PLOS ONE

Dear Dr. SHAFIE,

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.

Reviewer 1 recommended rejection, so please pay special attention to the requirements for publication that this reviewer requests. Please conduct a literature search to determine if the results of this paper are 'outdated' as Reviewer 1 suggests. I believe that Reviewer 1's requests that some of the source material, particularly the questionnaire, and the literature supporting the triangulation process are reasonable requirements for publication. I will not of course automatically defer to Reviewer 1's opinion that the interviews be redone, since that would amount to redoing the research and would require a new submission of a new manuscript.

We would appreciate receiving your revised manuscript by Sep 20 2019 11:59PM. When you are 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.

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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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
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• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

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We look forward to receiving your revised manuscript.

Kind regards,

James M. Lightwood

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include copies of the interview guide(s) used in the study, in both the original language and English, as Supporting Information, or include a citation if they have been published previously.

3. Please describe in more detail the literature search strategy used in your study (including search terms and dates of the searches), and describe more clearly the results obtained from the literature search. Specifically, please name the sources of information for the data in Table 3.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

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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: N/A

Reviewer #2: 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: No

Reviewer #2: 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: 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: 1. The information is outdated. It needs to be updated by revisiting the literature and redoing the interviews.

2. The checklist for qualitative research studies has not been filled.

3. It is difficult to assess how much data this paper has captured. It appears quite thin. The questionnaire needs to be included as a supplementary file. Also, provide detailed supplementary files of the interviews, as in the recent paper “The role of patient organizations in the rare disease ecosystem in India: An interview-based study.” Orphanet J Rare Dis. 14:117 (2019). Make a list of the literature which was consulted in the triangulation process, and include this as a supplementary file.

4. The English needs improvement. There are many awkward phrases, such as in Line 112, Line 108. Some lines are confusing such as Line 121 -Line 122. Even quotes should be edited for correct English.

Reviewer #2: In the manuscript, Shafie et al. report the current situation of and the recent advances in rare disease realm in Malaysia via cross-sectional study, document-survey and interviews. Authors gathered the information from the multiple points of view, including healthcare system and governance, clinical expertise and patient management, newborn screening, funding and rare disease awareness and patient advocacy, which has high importance in terms of strategic development of new healthcare policies and R&D programs in developing countries, however, the manuscript still holds major and minor issues of concern.

Major Comments:

- The limitation of this cross-sectional study/analysis is its lack of estimation of the numbers of rare diseases/patients expanding toward the entire country, which lead to their underestimation. Rare disease patients could be seen and treated in the other general private and public hospitals than the Ministry of Health Malaysia’s facilities or university hospitals. In order to claim that “they (funding in Malaysia) are not sufficient to cover the high number of rare disease patients”, the estimation would be indispensable.

- The WHO definition of rare diseases has to be referenced. In Europe, some diseases are excluded from the rare disease definition, such as infection and drug hypersensitivities, which handling should be described in the manuscript. And also, authors should mention the diseases which prevalence is less than 0.65% of the population.

- The demographics of the respondents should be shown as well. Especially, the department which the respondents belong to could bias the number of diseases/patients in rare disease realms.

Minor comments:

If space permits, the paper would benefit from the following points of view;

- Comparison of newborn screening tests covered by UHC between Malaysia and the other country which has implemented UHC.

- Research budget in rare diseases research in Malaysia and potential collaboration with International Rare Diseases Research Consortium (IRDiRC).

- Additional description of the potential undiagnosed diseases patients. Authors could refer the undiagnosed disease programs in the other Asian Pacific countries (Western Australia, Japan, etc.).

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Reviewer #1: Yes: Dr. Gayatri Saberwal, Dr. Mohua Chakraborty Choudhury

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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-17740R1

Rare disease in Malaysia: Challenges and solutions

PLOS ONE

Dear Dr. SHAFIE,

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.

We would appreciate receiving your revised manuscript by Dec 08 2019 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

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 look forward to receiving your revised manuscript.

Kind regards,

James M. Lightwood

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Reviewer 2 requests a minor revision, which concerns more clarity on the definition used for rare disease in the manuscript, and how that related to the WHO criteria, and some discussion of how the problem of measuring and setting standards for the study of rare disease in Malaysia should be handled, given the problems with reporting. I think this is a valid point and important to address, especially because the authors state in their response to reviewers that the motivation for the study is to initiate adequate research on, and surveillance for, rare diseases in Malaysia.

I do think the revision does display lack of clarity on the issue of the definition of rare diseases in Malaysia. For example, in the Abstract, under Results section, you state in lines 54 to 56:

' Malaysia uses the World Health Organisation’s (WHO) definition of a rare disease as "any disease that is prevalent in 0.65% to 1% of the population and for which and the diagnosis and treatment are complicated”. '

But in the Results section, under Malaysian Healthcare System and Governance, lines 185 to 188, you state:

" To date, there is no official definition of rare disease in Malaysia. Although the Malaysian Rare Disorders Society (MRDS), a voluntary organisation, defines rare disease as a disease that affects less than 1 in 4,000 people in a community [20], feedback from the MOH has informally used the WHO definition of rare disease, which is any disease that is prevalent in 0.65% to 1% of the population, and the diagnosis and treatment are complicated. "

So, even though, apparently, the only effective definition of rare disease in Malaysia is the WHO definition, but this is adopted by a voluntary organization, MRDS. The statement that 'Malaysia uses' in the Abstract could be criticized as being vague or misleading. Is there evidence that the MRDS definition is widely used in Malaysia in the absence of an official definition? In any case, I think the statement in the Abstract needs to be clarified or qualified. I think the issue of the definition of rare disease in Malaysia needs to be more precisely described and Reviewer 2's concerns be addressed.

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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: (No Response)

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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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: 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 #1: (No Response)

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 #1: (No Response)

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: (No Response)

Reviewer #2: I have had a chance to review the revisions made to the manuscript by Shafie et al. entitled “Rare disease in Malaysia: Challenges and solutions”. Overall, the manuscript has improved but I wish to make the following point:

As commented by Ed2, authors must review the “original” source (≠ref #11) of the WHO definition of rare diseases (White paper? Website?). From the original WHO source(s), authors would find the reason why WHO set “0.65-1.00%” for the prevalence of rare disease definition, and should provide considerable explanation about the reason why authors excluded the diseases which prevalence is less than 0.65% of the population from this survey. In order to promote creation of a clear rare disease national plan in Malaysia, solution(s) should be considered not only for the “relatively common” rare disease patients but also for people living with rarer diseases.

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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 #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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-17740R2

Rare disease in Malaysia: Challenges and solutions

PLOS ONE

Dear Dr. SHAFIE,

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.

Reviewer 2 recommends acceptance of the revised manuscript, and I agree that you have adequately addressed Reviewer 2's comments. 

Reviewer 1 has one remaining concern that I think should be addressed, which concerns the World Health Organization's definition of 'rare disease' that seems to implicitly asserted, or perhaps implied, in lines 187 to 192 of the revised manuscript, starting with "feedback from the MOH has informally used the WHO definition of rare disease, which is any disease that is prevalent in 0.65% to 1% of the population, and the diagnosis and treatment are complicated [11]."

Reviewer 1 requests a direct reference to the WHO definition, and an explanation of why diseases with less that 0.65% prevalence are omitted from your analysis. I think this issue needs to be addressed before the manuscript is accepted for publication. 

I read your reference 11, and  it's references that can reasonably be supposed to support the WHO definition stated in your manuscript, but could not find a reference to any WHO document. I searched the WHO site and did not find a section or document on their website that gave any definition. I did find a document that gave a definition adopted by the  Europe Union, which defines a rare disease as one that affects less than 0.1% 'of the population', which presumably refers to its prevalence.  See 'COMMUNICATION FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT, THE COUNCIL, THE EUROPEAN ECONOMIC AND SOCIAL

COMMITTEE AND THE COMMITTEE OF THE REGIONS on Rare Diseases: Europe's challenges'

https://op.europa.eu/en/publication-detail/-/publication/c8a042d8-ffb9-4b01-9c91-c1497a2b3fd7/language-en

I wonder whether this WHO definition is really a 'folklore' definition, that is, one that is not official (perhaps it is given in a WHO working paper, or conference), but taken as such in the rare disease community. 

I suggest that the authors conduct a search to back up the assertion in reference 11, that seems to have no clear backing. If they can find a reference, they should give it instead of, or in addition, to reference 11, and discuss why disease below the lower bound of that definition are omitted from consideration in the manuscript.

However, if the authors cannot find a clear reference to an official WHO source, I think Reviewer 1's concern can be addressed by a discussion of the problem posed by the use of such a 'folklore' definition by the rare disease community, and problems this situation (in my view, rather obviously) poses for planning for rare disease treatment in Malaysia and other countries. I think that finding would also be an interesting result that deserves to be discussed in the Results section.

We would appreciate receiving your revised manuscript by Jan 25 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

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 look forward to receiving your revised manuscript.

Kind regards,

James M. Lightwood

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Rare disease in Malaysia: Challenges and solutions

PONE-D-19-17740R3

Dear Dr. Shafie,

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,

Kwasi Torpey, MD PhD MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: