Role of serum uric acid in ischemic stroke: A case-control study in Bangladesh

Mohammad Ibrahim Khalil; Marium Salwa; Sarmin Sultana; Mohammad Abdullah Al Mamun; Nilima Barman; M. Atiqul Haque

doi:10.1371/journal.pone.0236747

Peer Review History

Original SubmissionFebruary 3, 2020
6 May 2020 Decision Letter - Marietta Zille, Editor PONE-D-20-03190 Role of serum uric acid in ischemic stroke: A case-control study in Bangladesh PLOS ONE Dear Dr. Salwa, 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 Jun 20 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. 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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, Marietta Zille, PhD Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Comments to the Author Reviewer #1: The proposed paper is interesting and well-written. However some revision are needed before it could be accepted for pubblication: - Although the use of categorical variables permit to obtain OR the use of continuous variables seems to be more usefull for multivariate model. Please also add a model (logistic regressione) with stroke has the dependent variables and with age, systolic BP, glucose, total cholesterol and uric acid as covariates and provide the relative beta for the association. Since authors describe in the methods section that they calculated the relative categorical variable (hypertension, dyslipidemia and so on) from the relative continue variables those are surely presents and usable for the analysis. Furthermore continue values need to be added to table 1. - Why Atrial Fibrillation falls under the definition of CHD? if it is a mistake please correct. - When discussing on gender role in relatioship between uric acid and stroke or even with CV events in general please also cite two recent pubblication on this issue (i.e. Association between uric acid and pulse wave velocity in hypertensive patients and in the general population: a systematic review and meta-analysis. Blood Press. 2020 [Epub ahead of print] and Pulse wave velocity progression over a medium-term follow-up in hypertensives: Focus on uric acid. J Clin Hypertens (Greenwich). 2019 Jul;21(7):975-983). - One minor comments: please don't use the word "attack" through the Whole text since it doesn0t sound very scientific. Reviewer #2: Interesting paper Sme issues should be added Abstract, It should be written again dividing into introduction/methods/results/conclusion Methods. N of patients should not written in the methods but in the results. Methods. Due to reduced sample size normal distribution should be checked for Methods. Level of significance for choosing variables in the multivariate analysis should be added. Reviewer #3: The authors of the present manuscript aim to evaluate the role of serum uric acid (SUA) in patients with ischemic stroke, assessing sex-based differences and try to differentiate it from other cardiovascular risk factors. They carried out a case control study, being the cases patients with a diagnosis of ischemic stroke and the controls, outpatients attended to the neurology department without history of previous stroke. The final conclusion is that elevated SUA level is a significant risk factor for ischemic stroke with an association exclusively in males. The purpose of the study is interesting. However, it does not add any new relevant information related to the topic. Additionally some questions should be elucidated according to STROBE statement. - Title and abstract provide an informative and balanced summary of what was done and what was found. -Introduction is good. However, a prespecified hypotheses is lacking. -Methods: – - The authors compare a group (cases) whose have been admitted into hospital because of ischemic stroke with other group (controls) whose were outpatients with different neurologic disorders. Probably, the different setting (in-patients vs outpatients) in the groups introduces a bias in selection because of the fact that it has been described higher SUA levels in the acute phase of stroke. On the other hand, it has been also reported higher SUA levels in other neurologic disorders such as Parkinson disease or multiple sclerosis what make more difficult to interpret the results. – - In this regard, the authors shoud explain how matching of cases and controls was addressed. – - Some important variables which could influence the results are lacking. The authors should add information about body mass index (the presence of obesity and metabolic syndrome are strongly related to SUA levels), renal disease or glomerular filtration rate, and they should add information regarding the treatment of the both samples. We do not know if there were patients under uricosuric drugs for instance. It is known that some drugs apart from loop diuretics or thiazides are able to modify the levels of SUA (ACEi, ARB.) – - The authors should explain how the study size was arrived at. - Results: The main results are well described and reported. - Discussion: The main finding of the present study is that the cases of ischemic stroke had higher levels of SUA than those of the controls. From that point on, the authors assume a predictive positive role of the uric acid in the incidence of ischemic stroke what has not been able to infere from the design of the present study, therefore the discussion and the conclussion are confusing and they must be changed in order to explain accurately the real interpretation of the results. 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.0236747.r001
Revision 1
19 Jun 2020 Author Response Reviewer #1 1. Although the use of categorical variables permits to obtain OR the use of continuous variables seems to be more useful for multivariate model. Please also add a model (logistic regression) with stroke has the dependent variables and with age, systolic BP, glucose, total cholesterol, and uric acid as covariates and provide the relative beta for the association. Since authors describe in the methods section that they calculated the relative categorical variable (hypertension, dyslipidemia and so on) from the relative continue variables those are surely presents and usable for the analysis. Response: Regression model has been re-constructed according to the suggestion. Page 12 (Table 3). As many of our participants were on antihypertensive and anti-diabetic medication, their blood pressure and OGTT measurement during data collection did not accurately reflect their hypertensive or diabetic status. Thus, including systolic BP and blood glucose level in regression analysis might not exactly represent their association with ischemic stroke. So, we have included total cholesterol level and triglyceride level to represent the lipid profile of the participants while excluding categorical variable of dyslipidemia from the regression model as per your suggestion. Result of the study has been changed due to the change in nature of variables. A regression model is attached below constructed according to the reviewer’s instruction. 2. Furthermore, continue values need to be added to table 1 Response: Added Page 9 (Table 1) 3. Why Atrial Fibrillation falls under the definition of CHD? if it is a mistake please correct Response: Corrected Page 8, Line 148 4. When discussing on gender role in relationship between uric acid and stroke or even with CV events in general please also cite two recent publication on this issue (i.e. Association between uric acid and pulse wave velocity in hypertensive patients and in the general population: a systematic review and meta-analysis. Blood Press. 2020 [Epub ahead of print] and Pulse wave velocity progression over a medium-term follow-up in hypertensives: Focus on uric acid. J Clin Hypertens (Greenwich). 2019 Jul;21(7):975-983). Response: Addressed Page 14, Line 224 5. - One minor comments: please don't use the word "attack" through the Whole text since it doesn0t sound very scientific. Response: Edited All over the text Table. Logistic regression result showing association of different biochemical and physical measurement with acute ischemic stroke (Requested by the reviewer #1) Variables Male a Female b Both c OR (95% CI) OR (95% CI) OR (95% CI) Age 1.027 (0.99-1.06) 1.05 (0.99- 1.09) 1.03 (1.01-1.05) Sex - - TC 1.021 (1.01-1.03)* 1.03 (1.02- 1.05)* 1.025 (1.02-1.03) Fasting blood glucose 1.13 (1.02-1.27)* 1.25 (0.99-1.58) 1.129 (1.03-1.24) Systolic BP 1.04 (1.03-1.05)* 1.03 (1.01- 1.05)* 1.036 (1.03-1.05) SUA level 1.25 (0.98-1.60) 1.69 (1.15-2.50)* 1.318 (1.09-1.60) P-value < 0.05 Reviewer’s comment Response Reviewer #2 1. Abstract, it should be written again dividing into introduction/methods/results/conclusion Response: Modified Page 2, Line 24-44 2. Methods. N of patients should not write in the methods but in the results. Response: Corrected Page 7, line 114 and Page 9, line 166 3. Methods. Due to reduced sample size normal distribution should be checked for Response: Continuous variables were normally distributed. 4. Methods. Level of significance for choosing variables in the multivariate analysis should be added. Response: Corrected Page 9, line 158 Reviewer’s comment Response Reviewer #3 1. Introduction is good. However, a prespecified hypotheses is lacking. Response: Research questions are added Page 5 2. Methods: – - The authors compare a group (cases) whose have been admitted into hospital because of ischemic stroke with other group (controls) whose were outpatients with different neurologic disorders. Probably, the different setting (in-patients vs outpatients) in the groups introduces a bias in selection because of the fact that it has been described higher SUA levels in the acute phase of stroke. On the other hand, it has been also reported higher SUA levels in other neurologic disorders such as Parkinson disease or multiple sclerosis what make more difficult to interpret the results. – - In this regard, the authors should explain how matching of cases and controls was addressed. Response: Selection and matching procedures have been elaborated under a separate heading “Cases and controls” Page 5 2. – - Some important variables which could influence the results are lacking. The authors should add information about body mass index (the presence of obesity and metabolic syndrome are strongly related to SUA levels), renal disease or glomerular filtration rate, and they should add information regarding the treatment of the both samples. We do not know if there were patients under uricosuric drugs for instance. It is known that some drugs apart from loop diuretics or thiazides are able to modify the levels of SUA (ACEi, ARB.) Response: - The list of drugs used during data collection has been provided. Page 6, line 97-99 - We were not able to measure height and weight for all the participants as many of them were bed-ridden, thus lacking BMI in the study outcome. It has been addressed in the limitation. Page 16, line 267-270 - Participants with glomerular filtration rate less than 60 ml/sec were excluded initially from the study. Page 6, line 95 3. The authors should explain how the study size was arrived at. Response: We employed consecutive sampling to enroll the patients for both case and control groups within our data collection period of six months. Therefore, we did not go for formal sample size calculation. Page 5, Line 81-85 4. Discussion: The main finding of the present study is that the cases of ischemic stroke had higher levels of SUA than those of the controls. From that point on, the authors assume a predictive positive role of the uric acid in the incidence of ischemic stroke what has not been able to infer from the design of the present study, therefore the discussion and the conclusion are confusing and they must be changed in order to explain accurately the real interpretation of the results. Response: Corrected accordingly. Throughout the whole text Attachments Attachment Submitted filename: Response to reviewers.docx* https://doi.org/10.1371/journal.pone.0236747.r002
14 Jul 2020 Decision Letter - Marietta Zille, Editor Role of serum uric acid in ischemic stroke: A case-control study in Bangladesh PONE-D-20-03190R1 Dear Dr. Salwa, 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, Marietta Zille, PhD Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0236747.r003
Formally Accepted
23 Jul 2020 Acceptance Letter - Marietta Zille, Editor PONE-D-20-03190R1 Role of serum uric acid in ischemic stroke: A case-control study in Bangladesh Dear Dr. Salwa: 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. Marietta Zille Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0236747.r004

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