Serum albumin and gamma gap levels, and combined effect for risk of mortality in a Japanese population from the J-MICC study

Kenichi Shibuya; Rie Ibusuki; Daisaku Nishimoto; Shiroh Tanoue; Chihaya Koriyama; Shuhei Niiyama; Yasuyuki Kakihana; Toshiro Takezaki; Megumi Hara; Yuichiro Nishida; Sadao Suzuki; Takeshi Nishiyama; Mako Nagayoshi; Takashi Tamura; Yudai Tamada; Rieko Okada; Teruhide Koyama; Satomi Tomida; Kiyonori Kuriki; Jun Otonari; Hiroaki Ikezaki; Asahi Hishida; Masashi Ishizu; Sakurako Katsuura-Kamano; Kenji Wakai; Keitaro Matsuo; for the J-MICC Study group

doi:10.1371/journal.pone.0336926

Peer Review History

Original SubmissionMay 22, 2024
25 Aug 2025 Decision Letter - Nayan Chandra Mohanto, Editor Dear Dr. Takezaki, 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 Oct 09 2025 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. 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'. 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Thank you for stating the following financial disclosure: “This study was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer [grant number 17015018], Innovative Areas [grant number 221S0001], and the Japan Society for the Promotion of Science (JSPS) KAKENHI [grant numbers. 16H06277 and 22H04923; CoBiA] from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. 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For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. 5. In the online submission form, you indicated that your data is available only on request from a third party. Please note that your Data Availability Statement is currently missing the contact details for the third party, such as an email address or a link to where data requests can be made. Please update your statement with the missing information. 6. One of the noted authors is a group or consortium: J-MICC Study group In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. 7. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Additional Editor Comments: Dear author (s), Thank you for submitting your manuscript in PLOS one. We are regret informing you that the present version of your manuscript is not suitable for publications. Please go through the reviewers comments and try to address all the suggestions. Please ensure that language in the manuscript is grammatically correct. Explain the methodology more clearly. Improve the scientific flaw of writing highlighting the novelty of the study. Discussion part should be more specific based on your findings. Please resubmit your revised manuscript once it will be ready. With thanks Academic editor [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? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: I Don't Know Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: No Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: This cohort study explored the associations between serum albumin and gamma gap levels as well as their combined effect on mortality risk in a Japanese population. There are so many variables in this study to compare among low to high albumin levels, protein intake, total protein level, and gamma gap levels with all-causes and specific causes of death. Initially readers may feel a bit uncomfortable to understand the whole process and analysis. However the authors involved in this study have been written the manuscript in a very clear and understandable manner. They also very clearly identified their limitations. I truly appropriate their efforts and honesty. Anyway there are some minor correction to improve this article. The comments are listed below: 1.My first impression about the co-authorship of this parer. I found, there are 26 co-authors in this paper. Although this study includes huge number of participants around 36,000, I can understand the contributions of each authors. However, I would suggest you to reduce the number of co-authors in this paper. Previously published one cohort study in PLOS One journal that analyzed more than 80,000 samples were just 10 co-authors. By considering this study, I would suggest to keep maximum 15-18 co-authors. 2.In Table 1, Table 3, and Table 5, please correct the unit of serum high gamma gap levels. 3.In Table 3, please correct the spelling mistake Medel 1, Medel 2 and Medel 3 on the top of the table. Reviewer #2: The following list of issues needs to be addressed: 1. Throughout the manuscript some statements lack of reference. You should add more updated reference. 2. Discuss further details about the function of albumin how it maintains the oncotic pressure as well as how it contributes to transport, solubilization and stabilization. 3. The manuscript would be more understandable after the inclusion of a flow diagram of study design that outlines participant recruitment, inclusion and exclusion criteria, and the ultimate sample size. 4. The measurement technique and kits used for the quantification of total serum protein and albumin are not described. Clarify the information in the materials and methods section. 5. What criteria did you use to separate the age groups of 35–49, 50–59, and 60–69 years? In the statistical part, explain it. 6. Mean or median of serum total protein, albumin, and gamma gap level for male and female is necessary for a better understanding. 7. What type of information you are providing or recommending to the general population through this study. 8. Please briefly discuss the physiological and clinical significance of low albumin and high levels of gamma gap level in respect to the diseases. 9. There have repetitions of some information and typos error. You should revise the manuscript properly. 10. Show the relationship among serum total protein, albumin, and gamma gap levels, if there have. ****** 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.] 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. Attachments Attachment Submitted filename: Recommendation and Comments for PONE-D-24-16646.docx https://doi.org/10.1371/journal.pone.0336926.r001
Revision 1
2 Oct 2025 Author Response Dear Reviewer 1: On behalf of my co-authors, we would like to express our great appreciation to the reviewers. We have carefully taken the reviewers’ comments into consideration in the preparation of our revision. All changes to the reviewer 1 and reviewer 2 are combined and are highlighted in yellow maker in the manuscript. We have included point-to-point response to the reviewer’ comments as follows. 1. My first impression about the co-authorship of this paper. I found, there are 26 co-authors in this paper. Although this study includes huge number of participants around 36,000, I can understand the contributions of each authors. However, I would suggest you to reduce the number of co-authors in this paper. Previously published one cohort study in PLOS One journal that analyzed more than 80,000 samples were just 10 co-authors. By considering this study, I would suggest to keep maximum 15-18 co-authors. We can understand reviewer’s suggestion. However, our J-MICC study group has our authorship rule including number of authors according to each contribution by institute and university. Our group has previously published manuscripts to the PLoS One according to our rule: PLoS One. 2023;18(2):e0279169. doi: 10.1371/journal.pone.0279169 with 32 authors; and PLoS One. 2022;17(1):e0262252. doi: 10.1371/journal.pone.0262252 with 29 authors.　We would appreciate it if you could let us keep 26 authors. 2. In Table 1, Table 3, and Table 5, please correct the unit of serum high gamma gap levels. We correct the unit of serum high gamma gap levels in Table 1, Table 3, and Table 5, and Fig 2, too. 3. In Table 3, please correct the spelling mistake Medel 1, Medel 2 and Medel 3 on the top of the table. We correct the spelling mistake to Model 1, Model 2 and Model 3 in Table 3. Dear Reviewer 2: On behalf of my co-authors, we would like to express our great appreciation to the reviewers. We have carefully taken the reviewers’ comments into consideration in the preparation of our revision. All changes to the reviewer 1 and reviewer 2 are combined and are highlighted in yellow maker in the manuscript. We have included point-to-point response to the reviewer’ comments as follows. 1. Throughout the manuscript some statements lack of reference. You should add more updated reference. We added and updated references. We also deleted the sentences without reference in Discussion. [update] 1. Henry's Clinical Diagnosis and Management by Laboratory Methods. 24 ed. Philadelphia, PA: Elsevier; 2021. 2. Serum Albumin: Structure, Functions and Health Impact (Protein Biochemistry, Synthesis, Structure and Cellular Functions). New York: Nova Science Pub Inc; 2012. [add] 4. Moramarco S, Morciano L, Morucci L, Messinese M, Gualtieri P, Carestia M. Epidemiology of Hypoalbuminemia in Hospitalized Patients: A Clinical Matter or an Emerging Public Health Problem? Nutrients. 2020 Nov 27;12(12):3656. doi: 10.3390/nu12123656. PubMed: PMC7760225. 5. Oster HS, Dolev Y, Kehat O, Weis-Meilik A, Mittelman M. Serum Hypoalbuminemia Is a Long-Term Prognostic Marker in Medical Hospitalized Patients, Irrespective of the Underlying Disease. J Clin Med. 2022;11(5):1207. doi: 10.3390/jcm11051207. PubMed: PMC8911288. 2. Discuss further details about the function of albumin how it maintains the oncotic pressure as well as how it contributes to transport, solubilization and stabilization. We added further details about the function of albumin in Introduction. � Introduction, line 59-77; “Albumin is a negatively charged protein with a high concentration and relatively large molecular weight, accounting for approximately 75–80% of plasma colloid osmotic pressure [2]. The negative charge of the albumin molecule also attracts cations and water, contributing to water retention within capillaries and playing a crucial role in stabilizing blood volume [2]. Furthermore, albumin molecules possess various ligand-binding sites, enabling them to bind and transport substances such as fatty acids, hormones, bilirubin, and calcium [2]. Approximately 40% of the calcium in whole blood exists in a bound state with albumin, which buffers and stabilizes blood calcium levels [1]. Highly hydrophobic molecules also become soluble in blood by binding to albumin, allowing them to be transported to target tissues [2]. Furthermore, albumin binds to drugs and toxins, suppressing the concentration of free active forms and mitigating rapid onset of action or toxicity [2]. Physiologically, low albumin levels impair the maintenance of adequate plasma colloidal osmolarity. This makes it easier for fluid to leak from blood vessels into tissues, potentially causing edema, pleural effusion, and ascites. Furthermore, as albumin transports various substances, its reduction serves as an indicator of conditions such as malnutrition, liver dysfunction, and chronic inflammation. Clinically, hypoalbuminemia is a poor prognostic indicator, with numerous studies showing a strong association with increased mortality in hospitalized patients and those with chronic diseases [4, 5].” 3. The manuscript would be more understandable after the inclusion of a flow diagram of study design that outlines participant recruitment, inclusion and exclusion criteria, and the ultimate sample size. We added a flow diagram in Fig 1. � Figure Legend, page 45; Fig 1. Flow diagram for selecting eligible participants from 13 cohorts. 4. The measurement technique and kits used for the quantification of total serum protein and albumin are not described. Clarify the information in the materials and methods section. We added the measurement technique and kits used for the quantification of total serum protein and albumin in Methods/Clinical characteristics. � Methods/Clinical characteristics, line 162-165; “Examination of serum total protein levels was carried out using the Biuret method. Serum albumin levels were examined using bromocresol green (BCG) test or modified bromocresol purple (BCP) test.” 5. What criteria did you use to separate the age groups of 35-49, 50-59, and 60-69 years? In the statistical part, explain it. We added the criteria of separated age group in Methods/Statistical analyses. � Methods/Statistical analyses, line 183-184; “Age was divided into three groups (35–49, 50–59, and 60–69 years) according to similar number of participants.” 6. Mean or median of serum total protein, albumin, and gamma gap level for male and female is necessary for a better understanding. We added the mean and standard deviation of serum total protein, albumin, and gamma gap level criteria of separated age group in Results and Table 1. � Results, line 250-252; “The mean levels of serum total protein, albumin and gamma gap in men and women were 7.22 and 7.30; 4.45 and 4.43; and 2.77 and 2.87, respectively.” 7. What type of information you are providing or recommending to the general population through this study. We added the information providing or recommending to the general population through this study in Conclusion. We also added the description on its related results in Abstract and Discussion. � Conclusion, line 417-421; “The population with low albumin or high gamma gap even without specific diseases may be required careful follow-up in health checkup. Especially, particular attention may be given to people with low albumin and high gamma gap for RSD without pneumonia, and low albumin and low gamma gap for pneumonia.” � Abstract, line 18-22; “Increased HRs of low albumin and high gamma gap levels were respectively observed for deaths from all-causes, cancer, cardiovascular diseases, respiratory system diseases without pneumonia, and other-causes; and the HR was the highest on respiratory system diseases without pneumonia (HR = 7.31, 4.15-12.9). Low albumin and low gamma gap levels were strongly associated for pneumonia death (HR = 12.4, 3.98-38.5).” � Discussion, line 371-373; “The HRs for any deaths, except pneumonia, with low albumin and high gamma gap levels was higher than those with low albumin and medium gamma gap levels, and the HR was the highest for RSD without pneumonia.” � Discussion, line 376-379; “On the other hand, low albumin and low gamma gap levels were strongly associated for pneumonia death, and significant interaction was also observed between low albumin and low gamma gap levels for pneumonia death.” 8. Please briefly discuss the physiological and clinical significance of low albumin and high levels of gamma gap level in respect to the diseases. We added the description on the physiological and clinical significance of low albumin and high levels of gamma gap level in respect to the diseases, although the present results did not suggest the risk of specific diseases, except pneumonia. � Introduction, line 51-58; “Therefore, in addition to insufficient nutritional intake, serum albumin levels decline due to impaired absorption of amino acids because of a breakdown in the gastrointestinal mucosal epithelium, decreased synthesis capacity in the liver from cirrhosis, protein leakage from the gastrointestinal tract and kidneys due to protein-leaking gastroenteropathy and nephrotic syndrome, and hyper-catabolism from severe infections and chronic inflammatory diseases. Among them, production disorder has a great influence on a serum albumin decrease, which depends on the ability of the liver to synthesize [3]. � Introduction, line 91-97; “Physiologically, a high gamma gap suggests increased immunoglobulin levels. This indicates the possibility of ongoing chronic inflammation within the body or abnormal plasma cell proliferation. Clinically, it can serve as a differential diagnostic indicator for conditions such as multiple myeloma, macroglobulinemia, and primary amyloidosis. It is also used as a screening indicator for plasma cell disorders, and when a marked elevated gamma gap is observed, further investigation such as protein electrophoresis is recommended.” � Discussion, line 352-354; “Various factors which were associated with gamma gap levels in cross-sectional observation are concordant with those for latent inflammation, cancer, and autoimmune diseases, in which the gamma gap is used as a clinical screening index [7-10].” � Discussion, line 363-366; “This study suggests that high serum gamma gap levels are an indicator of a high risk for mortality due to various diseases in a Japanese population, which may be involved in chronic inflammation across the lifespan [29].” 9. There have repetitions of some information and typos error. You should revise the manuscript properly. We deleted the parts of information and corrected typos error. 10. Show the relationship among serum total protein, albumin, and gamma gap levels, if there have. We added the analysis of the relationship among serum total protein, albumin, and gamma gap levels and added it in Methods//Statistical analyses, Results and Discussion. � Methods//Statistical analyses, line 235-236; “The relationship among serum total protein, albumin, and gamma gap levels were also tested using correlation coefficients.” � Results, line 252-256; “The correlation coefficients between serum total protein levels, and albumin and gamma gap levels were 0.523 (p<0.001) and 0.777 (p<0.001) in men, and 0.536 (p<0.001) and 0.794 (p<0.001) in women, respectively (data not shown in Table). The correlation coefficients between albumin and gamma gap levels were -0.130 (p<0.001) in men and -0.088 (p<0.001) in women.” � Discussion, line 369-371; “Although levels of albumin and gamma gaps had a weak negative relationship, this study showed an apparent combined effect on the HRs for death between albumin and gamma gap levels.” Attachments Attachment Submitted filename: Reviewer2.docx https://doi.org/10.1371/journal.pone.0336926.r002
2 Nov 2025 Decision Letter - Nayan Chandra Mohanto, Editor Serum albumin and gamma gap levels, and combined effect for risk of mortality in a Japanese population from the J-MICC study PONE-D-24-16646R1 Dear Dr. Takezaki, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Nayan Chandra Mohanto, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Dear author (s), Please address the comments from the reviewer 2 and resubmit the revised manuscript. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 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??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: I Don't Know Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: No Reviewer #2: No ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: No more additional comments for the authors from my side. I would like to appreciate all the authors to have their efforts and patients go through our whole reviewing process. Overall the manuscript is now well written and technically sounds with a better version. Reviewer #2: 1. It would be better to make the Fig 1 as a supplementary figure. 2. Could you please clarify whether the differences in total protein, albumin, and gamma gap levels between men and women were significant? 3. “Examination of serum total protein levels was carried out using the Biuret method. Serum albumin levels were examined using bromocresol green (BCG) test or modified bromocresol purple (BCP) test.” these two sentences can be combined and written in a following way- “Examination of serum total protein and albumin levels were carried out using the Biuret method and bromocresol green (BCG) test or modified bromocresol purple (BCP) test, respectively.” ****** 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: Dr. Momotaj Jahan Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0336926.r003
Formally Accepted
Acceptance Letter - Nayan Chandra Mohanto, Editor PONE-D-24-16646R1 PLOS ONE Dear Dr. Takezaki, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@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. Nayan Chandra Mohanto Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0336926.r004

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