Healthcare costs and outcomes associated with laboratory-confirmed Lyme disease in Ontario, Canada: A population-based cohort study

Stephen Mac; Gerald Evans; Eleanor Pullenayegum; Samir N. Patel; Beate Sander

doi:10.1371/journal.pone.0286552

Peer Review History

Original SubmissionFebruary 26, 2023
6 Apr 2023 Decision Letter - Shuo-Yan Gau, Editor PONE-D-23-05674Healthcare Costs and Outcomes Associated with Laboratory-confirmed Lyme disease in Ontario, Canada: A Population-based Cohort Study PLOS ONE Dear Dr. Stephen Mac, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, the reviewers feel that certain specific issues must be addressed before the manuscript can be accepted. Please see the comments below. 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 May 06, 2023. 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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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I appreciate that this study has provided the associations between the health burden of LD and its utilization of healthcare resources in Ontario. This manuscript is well organized, and the topic has good merit to discuss. However, I am curious why the study period is from 2006 to 2018. Additionally, Figure 3 appears a bit cluttered and visually confusing. Reviewer #2: The manuscript provided rigorous and extensive analyses on the direct medical costs of Lyme disease. However, I would like to suggest the authors to provide some clarifications - Page 6 line 108-109: Please provide more details about how the unexposed participants were idenified and deemed as uninfected (ie. laboratory-confirmed uninfected participants). - The costs should be accounted for the staging of Lyme disease, namely erythema migrans and disseminated lyme disease. - I strongly recommend the authors include non-medical costs of Lyme disease, such as absenteeism and presenteeism. Examples of recent studies including non-medical costs of Lyme disease are as follows; BMC Public Health. 2022 Nov 28;22(1):2194. doi: 10.1186/s12889-022-14380-6. and Emerg Infect Dis. 2022 Jun;28(6):1170-1179. doi: 10.3201/eid2806.211335. However, I completely leave the decision whether to perform non-medical cost analyses to the authors. - There were several "Error! Reference source not found" in the manuscript. Please correct them. ****** 6. 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Revision 1
21 Apr 2023 Author Response Stephen Mac Institute of Health Policy, Management, and Evaluation University of Toronto 155 College St., 4th floor Toronto, ON M5T 3M6 Email: sm.mac@mail.utoronto.ca To: Dr. Shuo-Yan Gau Academic Editor PLOS ONE April 21, 2023 RE: PONE-D-23-05674 “Healthcare Costs and Outcomes Associated with Laboratory-confirmed Lyme disease in Ontario, Canada: A Population-based Cohort Study” Dear Dr. Gau, Thank you for taking the time to review and move forward with our manuscript. We have addressed all comments and suggestions in this resubmission to PLOS ONE. Please find enclosed our revised manuscript. We have addressed the additional requirements per your request and ensured that our manuscript meets PLOS ONE’s style requirements. Regarding data availability, we outline this in the Footnotes under Data Availability Statement that is standard for all studies conducted at ICES: “The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.” Following this letter, we included our detailed response (with page numbers corresponding to the tracked manuscript) to all comments for your review. Thank you for your time and consideration. We look forward to the final decision. Sincerely, Stephen Mac On behalf of all authors below Stephen Mac PhD Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network, Toronto, Canada Gerald A. Evans MD FRCPC Department of Medicine, Queen’s University, Kingston, Canada Samir N. Patel PhD FCCM Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada Public Health Ontario, Toronto, Canada Eleanor M. Pullenayegum PhD Dalla Lana School of Public Health, University of Toronto, Toronto, Canada The Hospital for Sick Children, Toronto, Canada Beate Sander PhD Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network, Toronto, Canada ICES, Toronto, Canada Public Health Ontario, Toronto, Canada REVIEWER #1 COMMENTS Comment: I appreciate that this study has provided the associations between the health burden of LD and its utilization of healthcare resources in Ontario. This manuscript is well organized, and the topic has good merit to discuss. However, I am curious why the study period is from 2006 to 2018. Response: Thank you for this comment. The study period is limited from 2006 to 2018 as this was the duration of data that was available at the time this study was initiated in 2020. Since the laboratory data comes from Public Health Ontario, there are various timely processes required to de-identify, clean, and transfer the data to ICES in Ontario for linkage to administrative data and for subsequent analysis. Unfortunately, this data cut cannot be updated for this study at this point due to lack of resources. However, we are confident that this cohort, which includes 13 years of patients, provides an appropriate sample size to provide an estimate of the health outcomes and economic burden associated with lab-confirmed Lyme disease in Ontario, Canada. Comment: Additionally, Figure 3 appears a bit cluttered and visually confusing. Response: We agree that this figure may feel clustered and so we have focused on the four phases: pre-diagnosis, acute, post-acute and continuing care. We have also included a description of Figure 3 in the manuscript and how it can be interpreted on page 15 (lines 220-222). The Figure 3 caption has been updated to “Figure 3. Mean 10-day standardized costs for Lyme disease phase-of-care between pre-diagnosis to continuing care” on page 15 (lines 226-227). REVIEWER #2 COMMENTS Comment: Page 6 line 108-109: Please provide more details about how the unexposed participants were identified and deemed as uninfected (i.e., laboratory-confirmed uninfected participants). Response: We described in detail how unexposed individuals were identified in the manuscript on page 5 (lines 93-95): “Individuals neither infected with LD nor had a PHO serologic test record were selected from the Registered Persons Database (RPDB) for matching. We excluded individuals with negative PHO test results to avoid potential confounding healthcare seeking behaviours.” This description in the original manuscript seems out of place and we have taken your suggestion and moved the details to page 6 (lines 118-120) to describe the unexposed individual selection before describing the matching technique. Comment: The costs should be accounted for the staging of Lyme disease, namely erythema migrans and disseminated Lyme disease. Response: This is a very good comment. We would have also preferred to present the analysis based on the staging of Lyme disease (i.e., early localized, early disseminated, late disseminated). However, the variables collected within the laboratory (Public Health Ontario) and reportable disease dataset (iPHIS) do not identify the LD stage, symptoms experienced, or time from symptom onset. Therefore, we elected to present these findings as costs within standardized phases post-diagnosis. We have acknowledged this limitation in the Discussion section on page 20 (lines 308-310). Comment: I strongly recommend the authors include non-medical costs of Lyme disease, such as absenteeism and presenteeism. Examples of recent studies including non-medical costs of Lyme disease are as follows; BMC Public Health. 2022 Nov 28;22(1):2194. doi: 10.1186/s12889-022-14380-6. and Emerg Infect Dis. 2022 Jun;28(6):1170-1179. doi: 10.3201/eid2806.211335. However, I completely leave the decision whether to perform non-medical cost analyses to the authors. Response: Thanks for the comment. The societal costs of Lyme disease are important to understand and indeed missing due to the objective of this study, which was to understand the real-world economic burden of Lyme disease to the healthcare system using administrative data. Unfortunately, societal costs are unable to be estimated with health administrative data that we have access to in Canada, as the data collected is solely from the Minister of Health’s perspective and does not capture time off, indirect costs, caregiver burden, transportation used, etc. These costs would need to be estimated via other data sources or more appropriate study designs such as a cross-sectional survey or prospective cohort study, along with applying a human capital or friction cost method. We have highlighted this in our Discussion and further expanded on the recent studies you shared that were completed in Belgium and the United States on page 21 (lines 322-323). Comment: There were several "Error! Reference source not found" in the manuscript. Please correct them. Response: Apologies for these formatting errors in the manuscript. We have identified all the cross-reference errors and have corrected them all. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0286552.r002
18 May 2023 Decision Letter - Shuo-Yan Gau, Editor Healthcare Costs and Outcomes Associated with Laboratory-confirmed Lyme disease in Ontario, Canada: A Population-based Cohort Study PONE-D-23-05674R1 Dear Dr. Mac, 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, Shuo-Yan Gau 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 #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: 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 #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: (No Response) Reviewer #2: (No Response) ****** 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 ******** https://doi.org/10.1371/journal.pone.0286552.r003
Formally Accepted
13 Jun 2023 Acceptance Letter - Shuo-Yan Gau, Editor PONE-D-23-05674R1 Healthcare Costs and Outcomes Associated with Laboratory-confirmed Lyme disease in Ontario, Canada: A Population-based Cohort Study Dear Dr. Mac: 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 Mr. Shuo-Yan Gau Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0286552.r004

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