Why does it take so long for rare disease patients to get an accurate diagnosis?—A qualitative investigation of patient experiences of hereditary angioedema

Moeko Isono; Minori Kokado; Kazuto Kato

doi:10.1371/journal.pone.0265847

Peer Review History

Original SubmissionSeptember 3, 2021
13 Dec 2021 Decision Letter - Girijesh Kumar Patel, Editor PONE-D-21-28571Why does it take so long for rare disease patients to get an accurate diagnosis? - A qualitative investigation of patient experiences of hereditary angioedemaPLOS ONE Dear Dr. Kato, 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. Based on the reviewer's comments and careful evaluation, this manuscript need minor revision. Please submit your revised manuscript by Jan 27 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: N/A ****** 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 ****** 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 ****** 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, First of all, I would like to congratulate and thank you for addressing the problem of such a complex and heterogeneous subject. The language of the manuscript is scientific, unambiguous, and explicit. The whole manuscript is highly engaging for me as a reviewer and an ordinary person from the masses. I am sure this information would add some new knowledge to the scientific field as well as this manuscript may guide some readers who may have HAE. Here, there are some suggestions from my side: 1-Authors may add a table of the rare diseases which are hard to diagnose and and have no specific symptoms. 2-It would be great if the authors put a little bit of emphasis on diagnosing rare diseases in low and middle-income countries, too, as they face different challenges like socio-economic, limited resources, lack of data services, and competing for health priorities. 3-In this manuscript, a paragraph describes the recent and current projects and policies in different developed countries (from lines 66 to 77) to address this issue. Some developing countries where rare diseases are mishandled because of the diagnostic issues have started taking the initiative to address this problem. Ministry of Health and Family Welfare, Government of India formulated a National Policy for Treatment of Rare Diseases (NPTRD) in July 2017. A group of volunteers created a not-for-profit organization named Organization for Rare Diseases India (ORDI; www.ordindia.org). The North-West University's Centre for Human Metabolomics (CHM) establishes the first rare disease (RD) biobank in South Africa and Africa. The author may add information about some of these policies. Specific suggestions about HAE: 1-There should be a little more description about the HAE, mainly different types of HAE (type I, II, and III), the possible genetic and molecular alteration and damage mechanism, and symptoms of each type. 2-Authors may add the information about the difference between acquired angioedema and HAE to clear the confusion between the two. 5-Authors may add some information if HAE is specific to any ethnicity or race. 6-The methodologies are excellent, but I found the sample size very small; I know it is a rare disease, so collecting many samples is challenging. My suggestion for the authors (for the future) is to collaborate with other countries like India, Iran, and South Africa, where many patients are diagnosed with HAE and information is available. I am not sure if it is possible or not. 6-Authors may add some of the clinical reports of the interviewees 7-Authors may add the information about specific blood tests to confirm Hereditary Angioedema Type I, II, or III. General minor concerns: 1-There are some space issues, which may be formatted very quickly, for example, line 627. 2-The heading in line 542 needs to be corrected. Reviewer #2: Working in the field of rare diseases is a challenge due to low sample number and delayed diagnosis. In this aspect, authors have made good and repeated effort in collecting/enrolling the hereditary angioedema rare disease patients in the survey. The overall findings of this qualitative study are interesting, especially the possible reasons for delay in the diagnosis of rare diseases. The approaches reported by patients in this study could be followed by other rare disease patients with challenges of diagnosis. That being said, I would have been more favorable for this article if the authors included similar studies on at least another one rare disease to see the generality of findings of this study. I believe, even though this is only a qualitative study, the interpretations from patient survey in this study will provide important directions to other patients with rare diseases. ****** 6. 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: Yes: sabiha khatoon Reviewer #2: Yes:** Subash Kairamkonda [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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0265847.r001
Revision 1
6 Feb 2022 Author Response Dear Dr. Patel: Thank you for inviting us to submit a revised draft of our manuscript. We also appreciate the time and effort you and the reviewers have dedicated to providing insightful feedback on ways to strengthen our paper. We have responded to all the individual comments by the reviewers in a point-by-point fashion. Responses are indicated with blue colored font. In addition, we found two errors in the expressions in Table 4 and have corrected them. The article has undergone a round of proof-reading by a professional language editing service to improve the language, grammar, and overall tone of the manuscript. We apologize for the inconvenience caused as a result of us making corrections after the peer review. We hope that the manuscript is positively received by the reviewers and editors. Thank you very much for your consideration. Sincerely, Kazuto Kato (Please note that the page and line numbers in our response correspond to those shown in the manuscript in our computer. They may slightly change depending on the computer environment.) Reviewer #1 1. Authors may add a table of the rare diseases which are hard to diagnose and have no specific symptoms. Thank you for your suggestion. It would have been interesting to explore this aspect, but, unfortunately, after considering the possibility of preparing a table of rare diseases that are hard to diagnose and have no specific symptoms, we reached a conclusion that it would not be possible to tabulate this information, due to two reasons. First, it is difficult to define ‘rare diseases which are hard to diagnose’. It is known that most rare diseases are difficult to diagnose. Even if we understand it as ‘rare diseases with long reported periods of not being diagnosed’, we are faced with the problem that there is no uniform definition of the undiagnosed days (i.e.,. the definition of start and end points, whether the time period is calculated using the mean or median). Second, we also think that it is difficult to select rare diseases that have no specific, identifying symptoms. Many rare diseases are said to share symptoms with ‘common’ diseases. In addition, each patient suffering from the same rare disease can have a multitude of different signs and symptoms. We believe it is important to clarify which diseases are difficult to diagnose so that more attention is given to them. Consequently, we hope we will be able to tackle these issues in the future work. 2. It would be great if the authors put a little bit of emphasis on diagnosing rare diseases in low and middle-income countries, too, as they face different challenges like socio-economic, limited resources, lack of data services, and competing for health priorities. Thank you for highlighting this important point. We have added this information about developing countries and regions in the revised manuscript (lines 57–59). 3. In this manuscript, a paragraph describes the recent and current projects and policies in different developed countries (from lines 66 to 77) to address this issue. Some developing countries where rare diseases are mishandled because of the diagnostic issues have started taking the initiative to address this problem. Ministry of Health and Family Welfare, Government of India formulated a National Policy for Treatment of Rare Diseases (NPTRD) in July 2017. A group of volunteers created a not-for-profit organization named Organization for Rare Diseases India (ORDI; www.ordindia.org). The North-West University's Centre for Human Metabolomics (CHM) establishes the first rare disease (RD) biobank in South Africa and Africa. The author may add information about some of these policies. We appreciate your comment on this point. We have accordingly added the description to the revised manuscript (lines 68–75). Specific suggestions about HAE 1. There should be a little more description about the HAE, mainly different types of HAE (type I, II, and III), the possible genetic and molecular alteration and damage mechanism, and symptoms of each type. We thank you for this comment. We agree that this point requires additional clarification and have consequently added the information to the revised manuscript (lines 102–112, 115–116). However, we have kept the description of type 3 (i.e., HAE with normal C1-INH function) to a minimum. Type 3 is a very rare form of hereditary angioedema and is not diagnosed by C1-INH activity, so our study does not cover it. 2. Authors may add the information about the difference between acquired angioedema and HAE to clear the confusion between the two. We appreciate your comment. We have accordingly added an explanation about acquired angioedema in the section describing HAE. (lines 110–112). 3. Authors may add some information if HAE is specific to any ethnicity or race. Thank you for the valid query. We have added the relevant information to the revised manuscript (108–109). 4. The methodologies are excellent, but I found the sample size very small; I know it is a rare disease, so collecting many samples is challenging. My suggestion for the authors (for the future) is to collaborate with other countries like India, Iran, and South Africa, where many patients are diagnosed with HAE and information is available. I am not sure if it is possible or not. We agree that gathering additional information, as you suggested, would be valuable. It would be a very good idea to carry out collaborations with medical professionals and patients in those countries. For our present work, however, we do not think that it is possible to carry out these collaborations in a short time, particularly, because we do not have any connections with HAE specialists and patients with HAE in other countries. We would definitely like to consider this as a direction for future research. 5. Authors may add some of the clinical reports of the interviewees. We appreciate your suggestion. We would like to point out is that in this study the interviewees were patients who self-reported their HAE, and we did not collect detailed clinical information. However, we have added some additional information about the severity of the symptoms experienced by each patient (Table 1). 6. Authors may add the information about specific blood tests to confirm Hereditary Angioedema Type I, II, or III. Thank you for the comment. We agree with you and recognize the importance of describing the information about the diagnostic tests for HAE. However, we believe it is important to point out that some of the diagnostic criteria set out in Japan do not necessarily correspond to those set out by the World Allergy Organization (WAO) in collaboration with the European Academy of Allergy and Clinical Immunology (EAACI). In other words, it is our humble opinion and belief that incorporating the precise and detailed information on this aspect is not feasible because it is not directly relevant to the main purpose and scope of this study. Therefore, we decided not to include the information about blood tests. We hope that you can understand our viewpoint. General minor concerns 1. There are some space issues, which may be formatted very quickly, for example, line 627. Thank you for pointing it out. We have made the necessary change. 2. The heading in line 542 needs to be corrected. This error has been corrected in accordance with your comment (line 565). Reviewer #2 Working in the field of rare diseases is a challenge due to low sample number and delayed diagnosis. In this aspect, authors have made good and repeated effort in collecting/enrolling the hereditary angioedema rare disease patients in the survey. The overall findings of this qualitative study are interesting, especially the possible reasons for delay in the diagnosis of rare diseases. The approaches reported by patients in this study could be followed by other rare disease patients with challenges of diagnosis. That being said, I would have been more favorable for this article if the authors included similar studies on at least another one rare disease to see the generality of findings of this study. I believe, even though this is only a qualitative study, the interpretations from patient survey in this study will provide important directions to other patients with rare diseases. You have raised a crucial point. We agree that there is a need to demonstrate whether the results can be generalized to other diseases. As one of our future research works, we think that we should plan a research project on this issue, but unfortunately, for our current work, it would be difficult to conduct an additional research in a short time. We therefore reviewed the previous literature based on the results of our study. As a result, we found patient narratives from qualitative reports of Fabry's disease and epidermolysis bullosa that described similar experiences. Based on this, the description in the Discussion section has been modified (lines 453–457 of the revised manuscript). In a future study, we would like to investigate the generalizability of our findings to other diseases. Thank you for your valuable comment. There has been substantial modification to the paper in line with the reviewers’ suggestions, and I hope that the paper will benefit from these revisions. Once again, we thank you for the time you put in reviewing our paper and look forward to meeting your expectations. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0265847.r002
9 Mar 2022 Decision Letter - Girijesh Kumar Patel, Editor Why does it take so long for rare disease patients to get an accurate diagnosis? - A qualitative investigation of patient experiences of hereditary angioedema PONE-D-21-28571R1 Dear Dr. Kato, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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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: All comments have been addressed Reviewer #2: All comments have been addressed ******** 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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 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: Yes Reviewer #2: Yes ****** 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: Yes 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 #1: Dear Authors. Thank you all for addressing all suggestions and concerns specified by me. I want to congratulate and thank you all for writing such an informative report after reading the current version of the manuscript. According to my view your manuscript is of very highly importance and ready to publish. Reviewer #2: The authors have addressed all the comments and concerns of reviewers to satisfaction. The language edits have improved the manuscript's readability and made it easy to understand for the readers. ****** 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: Yes: Sabiha Khatoon Reviewer #2: Yes:** Subash Kairamkonda https://doi.org/10.1371/journal.pone.0265847.r003
Formally Accepted
11 Mar 2022 Acceptance Letter - Girijesh Kumar Patel, Editor PONE-D-21-28571R1 Why does it take so long for rare disease patients to get an accurate diagnosis? - A qualitative investigation of patient experiences of hereditary angioedema Dear Dr. Kato: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Girijesh Kumar Patel Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0265847.r004

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