The epidemiology, treatment patterns, healthcare utilizations and costs of Acute Myeloid Leukaemia (AML) in Taiwan

Huai-Hsuan Huang; Chieh-Min Chen; Chen-Yu Wang; William Wei-Yuan Hsu; Ho-Min Chen; Bor-Sheng Ko; Fei-Yuan Hsiao

doi:10.1371/journal.pone.0261871

Peer Review History

Original SubmissionSeptember 1, 2021
19 Oct 2021 Decision Letter - Mohamed A Yassin, Editor PONE-D-21-28087The Epidemiology, Treatment Patterns, Healthcare Utilizations and Costs of Acute Myeloid Leukaemia (AML) in Taiwan, 2006-2015PLOS ONE Dear Dr. Hsiao 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. Please submit your revised manuscript by Dec 03 2021 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. When you're 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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Reviewer #1: Partly Reviewer #2: Yes Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 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 Reviewer #3: No ****** 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 Reviewer #3: 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: Overall, the study is nicely written but has a limited novelty and limited detailed analysis. Specific comments: - In the title, unless the period 2006-2015 is different from the usual, I suggest removing the period from the title. - 36,250 is it repeated twice in the abstract - the incidence rates reported in the introduction are old. - In the study population section (methods), the year 2001 should be 2011. - The sentence "We only analyze baseline characteristics of patients diagnosed with AML from 2011 to 2015 and received induction therapy within one year before the date of newly diagnosed AML" is confusing. Please, revise - Receiving ara-c with anthracycline is a standard therapy while the definition used in the paper classifies this as non-standard. Please, clarify. - Put the baseline characteristics as the first part of your results. - replace Q1-Q3 with IQR - Did the pattern of treatment change with age? Reviewer #2: This is an interesting study and the authors have collected a unique dataset. The paper is generally well written and structured. Only some minor comments: - The authors need to check each plot in detail, they have to replace “Supplementary Table 4” with “Supplementary Table 3”. - They have to remove commas (,) before “and”. For example, “healthcare utilization, and costs” (from Abstract: methods). - In the Results section of the abstract there is a parenthesis (n=1744; ), where something is missing. - Also in the same section syntactical error concerning the stated value of $36,250, it is repeated twice without making grammatical sense. - In the same paragraph correct “remaing” with “remaining”, replace “costs was $78,876” with “costs were $78,876” and “For those received” with “For those who received”. - In the Introduction part replace “100,000 persons” with “100,000 individuals”. Reviewer #3: Treatment costs need to be itemized. Chemotherapy costs are elaborated upon. However it is not clear if supportive care expenses were also included or not. I think these should be included. Also hospital bed occupancy estimated cost and outpatient visit cost should also be computed. The sentence "We only analyze baseline characteristics of patients diagnosed with AML from 2011 to 2015 and received induction therapy within one year before the date of newly diagnosed AML" is unclear. NCCN abbreviation is mentioned in the abstract without adding its definition as : National Comprehensive Cancer Network ****** 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: No Reviewer #2: No Reviewer #3: 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.] 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.0261871.r001
Revision 1
25 Nov 2021 Author Response November 26, 2021 Dr. Mohamed A Yassin Academic Editor, PLOS ONE Manuscript ID: PONE-D-21-28087 Title: The Epidemiology, Treatment Patterns, Healthcare Utilizations and Costs of Acute Myeloid Leukaemia (AML) in Taiwan. Dear Dr. Yassin: Thank you for the opportunity to respond to the reviewer’s comments regarding our manuscript. We extend our gratitude to the reviewers who provided constructive comments. More importantly, we appreciate the opportunity to respond to their reviews. Responding to the comments has allowed us to improve the overall quality of the work, which we hope has now addressed the issues raised. Below, you will find a point-by-point response to each of their concerns. We hope that you agree that the revised manuscript provides a novel contribution and is publishable in PLOS ONE. Sincerely, Fei-Yuan Hsiao, PhD Reviewers' comments: Reviewer #1: Overall, the study is nicely written but has a limited novelty and limited detailed analysis. Comment 1: In the title, unless the period 2006-2015 is different from the usual, I suggest removing the period from the title. [REPLY: Thank you for the comment. The title is revised as suggested.] Comment 2: 36,250 is it repeated twice in the abstract [REPLY: Thank you for the comment. The correction is revised as suggested.] Comment 3: The incidence rates reported in the introduction are old. [REPLY: Thank you for the comment. We have added some new data in the incidence rates reported in the Introduction section. “In Europe, the incidence of AML has increased in years and the highest incidence was found in the UK, with an incidence rate of 4.05 cases per 100,000 individuals in 2017”. To the best of our knowledge, these are the most updated incidence data we could retrieved from the literature.] Comment 4: In the study population section (methods), the year 2001 should be 2011. [REPLY: Thank you for the comment. The correction is revised as suggested.] Comment 5: The sentence "We only analyze baseline characteristics of patients diagnosed with AML from 2011 to 2015 and received induction therapy within one year before the date of newly diagnosed AML" is confusing. Please, revise [REPLY: Thank you for the comment. For better clarity, the sentence is rephrased as “As the detailed information of induction treatment status was only available from 2011 in the NHIRD, we only analyze baseline characteristic of patients with newly diagnosed AML and received induction therapy from 2011 to 2015.” Comment 6: Receiving ara-c with anthracycline is a standard therapy while the definition used in the paper classifies this as non-standard. Please, clarify. [REPLY: Thank you for the comment. We agree that receiving cytarabine with anthracycline is a standard therapy; therefore, the definition of standard-dose cytarabine regimen in our study is patients who received an intravenous antineoplastic, immunomodulating agent (including anthracycline) and the accumulated dose of cytarabine is less than 3000 milligrams within 21 days from the diagnosis date of AML. The definition of a non-standard dose cytarabine regimen in our study is that patients who received an intravenous antineoplastic, immunomodulating agent and medications other than cytarabine, idarubicin and daunorubicin or received idarubicin or daunorubicin only within 21 days from the diagnosis date AML. To make the sentence clear, the sentence is rephrased as “All other patients who received medications apart from cytarabine, idarubicin and daunorubicin or received only idarubicin or daunorubicin within 21 days from the diagnosis date AML was defined as receiving a non-standard-dose cytarabine (N-SDAC) regimen.” Comment 7: Put the baseline characteristics as the first part of your results. [REPLY: Thank you for the comment. As we reported epidemiology from 2006 to 2015 and then limited our study cohort as patients with newly diagnosed AML and received induction therapy from 2011 to 2015 for further analyses. We decided to kept the epidemiology as the first part of our results. However, we have modified the subtitles in the revised manuscript for better clarity.] Comment 8: Replace Q1-Q3 with IQR [REPLY: Thank you for the comment. The modification is revised as suggested. In order to provide informative data, the value of IQR was presented as a range. Comment 9: Did the pattern of treatment change with age? [REPLY: Thank you for the comment. Indeed, we found that age at treatment was different across different induction regimen received from our AML patients. The median age at treatment was the youngest for those received high-dose cytarabine (HDAC) regimens [52 years old] but was highest for those received non-standard-dose cytarabine (N-SDAC) regimen [60 years old]. (Table 1)] Reviewer #2: This is an interesting study and the authors have collected a unique dataset. The paper is generally well written and structured. Only some minor comments: Comment 1: The authors need to check each plot in detail, they have to replace “Supplementary Table 4” with “Supplementary Table 3”. [REPLY: Thank you for the comment. The correction is revised as suggested.] Comment 2: They have to remove commas (,) before “and”. For example, “healthcare utilization, and costs” (from Abstract: methods). [REPLY: Thank you for the comment. The correction is revised as suggested.] Comment 3: In the Results section of the abstract there is a parenthesis (n=1744; ), where something is missing. [REPLY: Thank you for pointing this out. The missing value is written as (n=1744; 80.04%) in the results section of the abstract.] Comment 4: Also, in the same section syntactical error concerning the stated value of $36,250, it is repeated twice without making grammatical sense. [REPLY: Thank you for the comment. As mentioned in our reply to reviewer#1’s comment #2, the repeated value of $36,250 is deleted in the results section of the abstract.] Comment 5: In the same paragraph correct “remaing” with “remaining”, replace “costs was $78,876” with “costs were $78,876” and “For those received” with “For those who received”. [REPLY: Thank you for the comment. The correction is revised as suggested. Comment 6: In the Introduction part replace “100,000 persons” with “100,000 individuals”. [REPLY: Thank you for the comment. The modification is revised as suggested.] Reviewer #3: Comment 1: Treatment costs need to be itemized. Chemotherapy costs are elaborated upon. [REPLY: Thank you very much for the comment. We understand the reviewer’s comment. Indeed, the chemotherapy costs are elaborated upon. However, we have adopted another approach, by categorizing AML patients into 6 groups according to their treatment regimens (high-dose cytarabine (HDAC), standard-dose cytarabine (SDAC) or non-standard-dose cytarabine (N-SDAC)) and status of HSCT. This approach allows us to capture the interaction between treatment regimens and HSCT on treatment costs of AML. It is obvious that for patient who treated with chemotherapy alone, the treatment costs were highest for HDAC ($42,271) but comparable for SDAC and N-SDAC ($36,199, and $36,250). However, for those who received hematopoietic stem cell transplantation (HSCT) after induction therapy, their median medical costs were comparable to each other regardless which induction therapy they received ($78,876 for HDAC, $78,593 for SDAC, and $79,776 for N-SDAC). By adopting this approach, we also believe that chemotherapy costs were well characterized.] Comment 2: However, it is not clear if supportive care expenses were also included or not. I think these should be included. [REPLY: Thank you very much for the comment. We would like to clarify with the reviewer that as the Taiwan’s National Health Insurance provide comprehensive coverage for healthcare services during hospitalization, supportive care expense are included in the calculation of the hospitalization cost. We have provided this information in the revised manuscript.] Comment 3: Also, hospital bed occupancy estimated cost and outpatient visit cost should also be computed. [REPLY: Thank you for the comment. As mentioned in the reply to reviewer#3’s comment #2, we had computed the costs of hospitalization and the costs of OPD in Supplementary Table 2. Comment 4: The sentence "We only analyze baseline characteristics of patients diagnosed with AML from 2011 to 2015 and received induction therapy within one year before the date of newly diagnosed AML" is unclear. [REPLY: Thank you for the comment. As mentioned in the reply to reviewer#1’s comment #5. The sentence is rephrased.] Comment 5: NCCN abbreviation is mentioned in the abstract without adding its definition as: National Comprehensive Cancer Network [REPLY: Thank you for the comment. The definition of NCCN is revised as suggested in the abstract.] https://doi.org/10.1371/journal.pone.0261871.r002
13 Dec 2021 Decision Letter - Mohamed A Yassin, Editor The Epidemiology, Treatment Patterns, Healthcare Utilizations and Costs of Acute Myeloid Leukaemia (AML) in Taiwan PONE-D-21-28087R1 Dear Dr.Fei 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. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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. Kind regards, Mohamed A Yassin, MD Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0261871.r003
Formally Accepted
19 Dec 2021 Acceptance Letter - Mohamed A Yassin, Editor PONE-D-21-28087R1 The Epidemiology, Treatment Patterns, Healthcare Utilizations and Costs of Acute Myeloid Leukaemia (AML) in Taiwan Dear Dr. Hsiao: 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. Mohamed A Yassin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0261871.r004

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