Serum albumin is independently associated with higher mortality in adult sickle cell patients: Results of three independent cohorts

Mehdi Nouraie; Allison E. Ashley-Koch; Melanie E. Garrett; Nithya Sritharan; Yingze Zhang; Jane Little; Victor R. Gordeuk; Mark T. Gladwin; Marilyn J. Telen; Gregory J. Kato

doi:10.1371/journal.pone.0237543

Peer Review History

Original SubmissionMay 12, 2020
27 May 2020 Decision Letter - Mary Hamer Hodges, Editor PONE-D-20-14109 Serum albumin independently predicts higher mortality in adult sickle cell patients: Results of three independent cohorts. PLOS ONE Dear Dr. Mehdi Nouraie, 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. The conclusion could have been bolstered by more references to the literature on albumin synthesis rates in children with acute-phase protein responses to infection in edematous and non-edematous protein-energy malnutrition. The speculation that hepatic synthetic rates may be affected because of the the association of low albumin with liver enzyme elevation raised concern in the concluding paragraph which should be re-phrased. Please submit your revised manuscript by June 15th. 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Mary Hamer Hodges 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 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 3. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments (if provided): We recommend addressing the comments made by Reviewer #1 and resubmitting. [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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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 paper reports on the outcome of analysis on 3 large retrospective cohort of subjects with Sickle Cell Disease. The hypotheses, and justification were clear. The results were clear. Albumin as a negative acute phase protein is a biomarker for worse outcome and this is consistent across a range of clinical models. The conclusion could have been bolstered by reference to the literature where albumin synthesis rates were measured in vivo. So in a model of severe malnutrition in children albumin concentration were modulated by catabolic rates rather than synthesis rates. In fact children with severe malnutrition were able to synthesize a range of positive acute phase proteins at fast enough rate in response to infections. So Sickle cell as an example of inflammatory state may behave similarly. (Morlese JF, Forrester T, Badaloo A, Del Rosario M, Frazer M, Jahoor F. Albumin kinetics in edematous and nonedematous protein-energy malnourished children. Am J Clin Nutr. 1996 Dec;64(6):952-9. doi: 10.1093/ajcn/64.6.952. PMID: 8942422 & Reid, M., Badaloo, A., Forrester, T., Morlese, J.F., Heird, W.C. & Jahoor, F. (2002) The acute-phase protein response to infection in edematous and nonedematous protein-energy malnutrition. Am J Clin Nutr, 76, 1409-1415.). While the authors speculated in the manuscript that hepatic synthetic rates may be affected because of the the association of low albumin with liver enzyme elevation this may not be the case. Within that context I am little concerned about the wording of the concluding paragraph which at a casual glance may seem to be advocating supplemental albumin treatment in SCD and perhaps a clear definite statement that this is not their recommendation should be made ****** 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: Marvin E Reid [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.0237543.r001
Revision 1
4 Jun 2020 Author Response PONE-D-20-14109 Dear Dr. Hodges; We appreciate your and review comments on our manuscript. Hereby, we are responding to comments and addressing changes in the manuscript: Comment: The conclusion could have been bolstered by more references to the literature on albumin synthesis rates in children with acute-phase protein responses to infection in edematous and non-edematous protein-energy malnutrition. The speculation that hepatic synthetic rates may be affected because of the association of low albumin with liver enzyme elevation raised concern in the concluding paragraph which should be re-phrased. Response: We modified the discussion and conclusion to reflect the reviewer’s comments. Comment: In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. Response: The current manuscript is using three different databases. Data from one of these cohort (CSSCD) was received through an agreement with NHLBI/BioLincc. This agreement prohibits investigator form any further data sharing. However, other investigators can apply directly to BioLincc for their own access to the data. The remaining two cohorts are governed by academic institutional IRBs which have their own restrictions on sharing. However, both of the other cohorts are available for access via dbGaP. So, regretfully we are unable to comply within the legal terms of our data use agreement. Comment: We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. Response: This sentence was changed to: “We did not measure these proteins in all cohorts but an analysis in the Walk-PHaSST cohort showed that serum albumin and haptoglobin are not correlated (r = 0.06, P = 0.17).” Reviewer #1 comment: This paper reports on the outcome of analysis on 3 large retrospective cohort of subjects with Sickle Cell Disease. The hypotheses, and justification were clear. The results were clear. Albumin as a negative acute phase protein is a biomarker for worse outcome and this is consistent across a range of clinical models. The conclusion could have been bolstered by reference to the literature where albumin synthesis rates were measured in vivo. So in a model of severe malnutrition in children albumin concentration were modulated by catabolic rates rather than synthesis rates. In fact children with severe malnutrition were able to synthesize a range of positive acute phase proteins at fast enough rate in response to infections. So Sickle cell as an example of inflammatory state may behave similarly. (Morlese JF, Forrester T, Badaloo A, Del Rosario M, Frazer M, Jahoor F. Albumin kinetics in edematous and nonedematous protein-energy malnourished children. Am J Clin Nutr. 1996 Dec;64(6):952-9. doi: 10.1093/ajcn/64.6.952. PMID: 8942422 & Reid, M., Badaloo, A., Forrester, T., Morlese, J.F., Heird, W.C. & Jahoor, F. (2002) The acute-phase protein response to infection in edematous and nonedematous protein-energy malnutrition. Am J Clin Nutr, 76, 1409-1415.). While the authors speculated in the manuscript that hepatic synthetic rates may be affected because of the association of low albumin with liver enzyme elevation this may not be the case. Within that context I am little concerned about the wording of the concluding paragraph which at a casual glance may seem to be advocating supplemental albumin treatment in SCD and perhaps a clear definite statement that this is not their recommendation should be made Response: We cited these references in discussion as: “Studies in children with severe malnutrition have shown that plasma albumin concentration was modulated by catabolic rates rather than synthesis rates[19, 20]. SCD patient are in a state of hyper-inflammation which could lead to faster catabolic rates.” Also, we changed the conclusion to: “There are existing controversies to consider albumin as a supplementary treatment for liver and renal failure as well as volume resuscitation in sepsis [37]. Our findings support the importance of plasma albumin measure and potential benefit of boosting plasma levels of albumin in SCD, especially in SCD endemic countries with high frequency of protein-calorie malnutrition.” Sincerely yours, Mehdi Nouraie, MD, PhD Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0237543.r002
9 Jul 2020 Decision Letter - Mary Hamer Hodges, Editor PONE-D-20-14109R1 Serum albumin independently predicts higher mortality in adult sickle cell patients: Results of three independent cohorts . PLOS ONE Dear Mehdi Nouraie, 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 address the inter-study variability, possible causes and study limitations Please submit your revised manuscript by 18th July. 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Mary Hamer Hodges Academic Editor PLOS ONE Additional Editor Comments (if provided): Please address the comments from reviewer #3 regarding the inter-study variability. If no potential cause for this variability can be identified it should be discussed as a weakness of their results. [Note: HTML markup is below. Please do not edit.] 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 Reviewer #3: (No Response) ******** 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 Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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 Reviewer #3: 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 Reviewer #3: 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: The authors have addressed my concerns appropriately. The limitations of post-hoc secondary data analyses were addressed satisfactorily. Reviewer #2: Serum albumin independently predicts higher mortality in adult sickle cell patients: Results of three independent cohorts is an interesting article all modifications were done as per reviewers recommendations the manuscript looks much better Reviewer #3: This paper presents the results for 3 different SSD studies. It was found that low serum albumin was associated with higher mortality across all 3 studies. However, the paper also looks at predictors of low serum albumin in Tables 1 and 2 of the manuscript. There is a large amount of inter-study variability which is not well accounted for. It seems possible that there are significant differences in the enrolled populations of the 3 studies and that these differences may impact the predictors relationship with serum albumin. Please see the attached PDF for my specific comments. ****** 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: MARVIN REID Reviewer #2: Yes:** Mohamed A Yassin 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.0237543.r003
Revision 2
12 Jul 2020 Author Response Dear Dr. Hodges Authors appreciate your and reviewers’ invaluable new comments on our manuscript. Hereby, we are addressing the comments and changes in the new version. Editor Review Please address the inter-study variability, possible causes and study limitations Response: We added this statement to study limitation: “Serum albumin was comparable between all three cohorts whereas inter-study variation exists in some other clinical variables. This variability could be due to random variation or different patient characteristics including age, disease severity, genetic structure, disease modifying treatments (including hydroxyurea and chronic transfusion) and comorbidities (as well as their treatment). Other factors that can cause inter-study variability are different birth cohorts and time period between CSSCD and the two other studies, differences in the study protocol and laboratory measurements. These differences could limit the generalizability of our findings to any new sickle cell cohort.” Reviewer #3 comments: This paper presents the results for 3 different SSD studies. It was found that low serum albumin was associated with higher mortality across all 3 studies. However, the paper also looks at predictors of low serum albumin in Tables 1 and 2 of the manuscript. There is a large amount of inter-study variability which is not well accounted for. It seems possible that there are significant differences in the enrolled populations of the 3 studies and that these differences may impact the predictors relationship with serum albumin. See below for specific comments. 1.1 Specific Comments 1. The term “predicts” in the title is misleading. Many people will interpret the claim that “Serum albumin independently predicts higher mortality” as a statement of that serum albumin has a high predictive value (sensitivity, specificity, AUC, etc) with respect to mortality. However, what is shown is that low serum corresponds to a high hazard ratio. I think “Serum albumin is independently associated with higher mortality” is a more appropriate phrase. Response: We changed the title to: “Serum albumin is independently associated with higher mortality in adult sickle cell patients: Results of three independent cohorts” 2. You mentioned you tested serum albumin for normality. Do you mean the residuals from the individual fitted linear models are normal? Serum albumin should not be normal on its own, unless the predictor variables are all insignificant. The residuals are what we expect to be normal. In point of fact, when the sample size is large the ordinary least squares estimates are asymptotically normal even if the residuals are non-normal. The sample sizes in this study are large enough that I think the results are valid even if the residuals are not normal. Response: We removed this statement from the statistical analysis as it did not impact our analysis. 3. The false discovery rate adjustment method and procedure should be stated. Response: We added this statement in statistical method: “We adjusted for multiple hypotheses testing using Simes method [17]”. 4. The results of table 1 and 2 make drawing conclusions about associations between serum albumin and sickle cell clinical variables challenging. Many of the variables change signs, even significantly, from study to study. For example ARC beta is significant in the WALK study at 0.03. For CCSSD it is significant at -0.02. Then it is insignificant at 0.001 for OMG. There are many examples of this behavior. Inter-study variability of beta and even significance is to expected; however, when a variable is significant and changes signs from study to study represents a failure in validation. A disclaimer or a summary across all 3 studies of which variables of interest exhibited consistent behavior would help a reader understand how to better interpret Tables 1 and 2. Response: We added this statement at the end of first result section: “In both Walk-PHaSST and OMG cohorts, higher eGFR was consistently associated with higher serum albumin whereas in CSSCD and Walk-PHaSST cohorts, higher LDH and lower alkaline phosphatase were associated with higher serum albumin.” 5. Is there any insight into why there is such a significant amount of inter-study variability. Certainly CCSSCD, which ended in 1988, might be difficult to compare to patients collected after the year 2000. Are there differences in Age, hemoglobin, or other variables appearing in tables 1 and 2 between the 3 studies? Perhaps the populations at enrollment are significantly different. If so multivariate models that include the variables in table 1 and 2 might be more consistent. Response: We added some statements to describe inter-study variability (please see the response to editor comment). In addition, tables 1 and 2 are presenting age and hemoglobin adjusted correlations to partially adjust for baseline differences between three cohorts. 6. In Tables 1 and 2 it is stated that p<0.015 and <0.001 are significant after FDR. However, there are rows in bold with p-values greater than these amounts. Response: We removed the bold marks to prevent any confusion in these tables. 7. In the discussion it is stated that “ Finally, we also did 203 not correct for multiple testing.” However, in each table the FDR rate is listed. FDR is a multiplicity adjustment method. This is confusing was and FDR used or not? Response: It was removed from discussion Sincerely, Mehdi Nouraie, MD, PhD Associate Professor of Medicine University of Pittsburgh Attachments Attachment Submitted filename: Response to Reviewers_3.docx https://doi.org/10.1371/journal.pone.0237543.r004
29 Jul 2020 Decision Letter - Mary Hamer Hodges, Editor Serum albumin is independently associated with higher mortality in adult sickle cell patients: Results of three independent cohorts PONE-D-20-14109R2 Dear Dr. Mehdi Nouraie, 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, Mary Hamer Hodges 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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: 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 #3: 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 #3: 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 #3: (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 #3: Yes:** Adam Lane https://doi.org/10.1371/journal.pone.0237543.r005
Formally Accepted
30 Jul 2020 Acceptance Letter - Mary Hamer Hodges, Editor PONE-D-20-14109R2 Serum albumin is independently associated with higher mortality in adult sickle cell patients: Results of three independent cohorts Dear Dr. Nouraie: 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. Mary Hamer Hodges Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0237543.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .