Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer

Yixuan Zou; Fei Tang; Jeffery C. Talbert; Chee M. Ng

doi:10.1371/journal.pone.0230571

Peer Review History

Original SubmissionOctober 6, 2019
4 Dec 2019 Decision Letter - Chih-Pin Chuu, Editor PONE-D-19-27455 Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer PLOS ONE Dear Dr. Ng, 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 follow the suggestions of the two reviewers who are experts in prostate cancer field and revise the manuscript to answer their questions. ============================== We would appreciate receiving your revised manuscript by Jan 18 2020 11:59PM. 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Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [Note: HTML markup is below. Please do not edit.] 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: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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: No 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: This study well demonstrated pharmacokinetic in leuprorelin treatment of prostate cancer from insurance population data. The authors are trying to mechanistically explain leuprorelin's effect on prostate cancer cell proliferation by PSA kinetics, which may be quite ambitious But the article did find itself a role in explaining tumor resistant patterns, which can be of great value in selected patients to early modify prostate cancer treatment Advantages 1. Proposed a good model of drug resistance development by demonstrating individual leuprorelin sensitive and resistant cancer cell growth rate using PSA findings. 2. Reconfirmed important covariates in prostate cancer development including baseline PSA and hemoglobin, clarify important factors associated with leuprorelin treatment 3. Specify the portion of leuprorelin-resistant cancer cell population and its growth rate can improve patient’s follow-up and the early detection of most at risk patients. 4. The data source is unique and stands for the real-world population. No pharmacokinetics of leuprorelin researches with Humana database to date yet. 5. Provide population mean prostate growth rate and resistance portion for future reference. Shortcomings 1. Large between-patient variability may indicate that few models may not best estimate leuprorelin on drug resistance of prostate cancer, 2. Need to exclude majority of patients (2035/2354 =86.4%) under leuprorelin treatment in order to build up a explanable model, indicated that the model may not be universally applicable. 3. Figure legends can be refined for better understanding eg. Fig.3A legends should add HGB and Fig.3B BAS on the figure. 4. This research did not take into account the incomplete testosterone suppression and its effect on PSA kinetics. Reviewer #2: This manuscript is a study which looks at disease progression model for patients with hormone sensitive prostate cancer on leuprorelin. The conclusion is that the proportion of the original prostate cancer cells inherently resistant to treatment was estimated to be 1.94%. This is an interesting study and it can be published after some revision. Strengths of this study: 1 Large sample size. 2 Well data analyzed. This paper is easy to follow and well structured. But the characters of the prostate cancer patients should be clarified. The prostate cancer staging, Gleason score of prostate cancer and comorbility data are not available in the paper. This is a major limitation of the study. The authors should tell us the distribution of prostate cancer risk factors in these patients. ****** 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 [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. https://doi.org/10.1371/journal.pone.0230571.r001
Revision 1
17 Feb 2020 Author Response Response to Reviewers Reviewer #1 Comments This study well demonstrated pharmacokinetic in leuprorelin treatment of prostate cancer from insurance population data The authors are trying to mechanistically explain leuprorelin's effect on prostate cancer cell proliferation by PSA kinetics, which may be quite ambitious But the article did find itself a role in explaining tumor resistant patterns, which can be of great value in selected patients to early modify prostate cancer treatment We would like to thank the reviewer’s comments, and we have made some changes to our manuscript accordingly. Advantages 1. Proposed a good model of drug resistance development by demonstrating individual leuprorelin sensitive and resistant cancer cell growth rate using PSA findings. 2. Reconfirmed important covariates in prostate cancer development including baseline PSA and hemoglobin, clarify important factors associated with leuprorelin treatment 3. Specify the portion of leuprorelin-resistant cancer cell population and its growth rate can improve patient’s follow-up and the early detection of most at risk patients. 4. The data source is unique and stands for the real-world population. No pharmacokinetics of leuprorelin researches with Humana database to date yet. 5. Provide population mean prostate growth rate and resistance portion for future reference. Shortcomings 1. Large between-patient variability may indicate that few models may not best estimate leuprorelin on drug resistance of prostate cancer We acknowledge that the presence of large between-patient variability is a limitation of our study, and we have included this in our discussion section L621-625. 2. Need to exclude majority of patients (2035/2354 =86.4%) under leuprorelin treatment in order to build up a explanable model, indicated that the model may not be universally applicable. We acknowledge that the need to exclude the majority of patients is a limitation of our study, and we have included this our discussion section L621-625, which reads, “Additionally, exclusion of a large proportion of patients (86.4%) diagnosed with malignant PCa and treated by leuprorelin in an effort to build an explainable model, as well as the presence of large between-patient variability observed in some model parameter estimates, may pose a limitation to interpretation of our findings.” 3. Figure legends can be refined for better understanding eg. Fig.3A legends should add HGB and Fig.3B BAS on the figure. Figures 3A and 3B have been corrected to include HGB and BAS on the figures. 4. This research did not take into account the incomplete testosterone suppression and its effect on PSA kinetics. Testosterone levels are not available in our dataset, as it was not routinely monitored during the period covered by our database (2007-2011). We have acknowledged this limitation in our discussion section L631-634, which reads, “Similarly, though LHRH agonists have been assumed to cause testosterone suppression [63], testosterone levels were not available in our patient database for us to investigate the possibility of incomplete testosterone suppression and its relationship with PSA kinetics.” Reviewer #2: This manuscript is a study which looks at disease progression model for patients with hormone sensitive prostate cancer on leuprorelin. The conclusion is that the proportion of the original prostate cancer cells inherently resistant to treatment was estimated to be 1.94%. This is an interesting study and it can be published after some revision. We would like to thank the reviewer’s comments, and please see our response below. Strengths of this study: 1 Large sample size. 2 Well data analyzed. This paper is easy to follow and well structured. But the characters of the prostate cancer patients should be clarified. The prostate cancer staging, Gleason score of prostate cancer and comorbility data are not available in the paper. This is a major limitation of the study. The authors should tell us the distribution of prostate cancer risk factors in these patients. The prostate cancer staging and Gleason score of the patients are, unfortunately, not available in our dataset, as they were not associated with any diagnostic/procedural/laboratory codes and therefore were not captured by de-identified data extraction from the electronic health records. These limitations were acknowledged in the discussion section L626-631. Though comorbidities influence survival in patients with metastatic prostate cancer because they are associated with non-cancer associated deaths, to our knowledge, the effect of comorbidities is on biomedical progression (i.e., progression to castration resistance) has not been reported in the literature. As we focused on biomedical progression in castration-sensitive prostate cancer patients instead of survival in patients with castration-resistant disease, we think that comorbidities are likely not as important than the other factors mentioned and studied in our manuscript, including demographics and laboratory values. Additionally, electronic health record (EHR) problem lists have been shown to have poor sensitivity for detecting major comorbidities compared to free-text notes in the EHR (Daskivich TJ et al, Am J Manag Care. 2018 Jan 1;24(1):e24-e29); however, the latter was not accessible to the authors due to the de-identified nature of the data source. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0230571.r002
4 Mar 2020 Decision Letter - Chih-Pin Chuu, Editor Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer PONE-D-19-27455R1 Dear Dr. Ng, 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. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, Chih-Pin Chuu, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0230571.r003
Formally Accepted
9 Mar 2020 Acceptance Letter - Chih-Pin Chuu, Editor PONE-D-19-27455R1 Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer Dear Dr. Ng: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Chih-Pin Chuu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0230571.r004

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