Comparative analysis of population-based and personalized reference intervals for biochemical markers in peri-menopausal women: population from the PALM cohort study
Abstract
Objectives
Significant changes in clinical biochemical markers occur during the peri-menopausal period. Traditional population-based reference intervals (popRIs) may not reflect individual physiological variability, limiting clinical interpretation. This study aimed to establish personalized reference intervals (prRIs) for menopausal women and compare them with popRIs.
Methods
We analyzed 899 healthy women aged 35–64 from the Peking Union Medical College Hospital Aging Longitudinal Cohort of Women in Midlife (PALM) cohort. 13 biochemical markers were evaluated across reproductive, menopausal transition, and postmenopausal stages. Six key biomarkers were selected through Kruskal–Wallis tests and ranked by their importance in menopausal status classification using a Random Forest model. Biological variation (BV) data were used to calculate total variation (TV) and index of individuality (II). The prRIs were constructed based on BV estimates, and the reference interval index (RII) was applied to compare popRIs and prRIs.
Results
ALT, TG, and FSH showed significant differences across menopausal stages and ranked highly in the Random Forest model. These markers also had large BV and differed across three menopausal stages. Most II values ranged from 0.6 to 1.4, and all median RII values were below 1.0, suggesting limited utility of popRIs. Crea in reproductive women had the highest proportion of RII>1.0, while FSH showed RII<0.5 in over 90 % of women in the menopausal transition.
Conclusions
For women in the menopausal transition with high BV estimates, combining popRIs with prRIs improves interpretation. Larger, more diverse cohorts are needed to validate and optimize prRIs for clinical application.
Funding source: China Postdoctoral Science Foundation
Award Identifier / Grant number: 2023M740320
Funding source: Special Support Plan for Clinical Research in Central High-level Hospital of PUMCH
Award Identifier / Grant number: Grant 2022-PUMCH-A-116
Acknowledgments
We are grateful to all the staff members for taking part in this study. We thank the participants for their cooperation and sample contributions.
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Research ethics: This study was approved by the Ethics Committee of Peking Union Medical College Hospital.
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Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: Large language models (e.g. ChatGPT) were used to assist in language polishing. All scientific content was created and validated by the authors.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: This work was supported by Special Support Plan for Clinical Research in Central High-level Hospital of PUMCH (Grant 2022-PUMCH-A-116), and China Postdoctoral Science Foundation (2023M740320).
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Data availability: Not applicable.
References
1. Nelson, HD. Menopause. Lancet 2008;371:760–70. https://doi.org/10.1016/s0140-6736-08-60346-3.Search in Google Scholar
2. Ko, SH, Jung, Y. Energy metabolism changes and dysregulated lipid metabolism in postmenopausal women. Nutrients 2021;13:4556. https://doi.org/10.3390/nu13124556.Search in Google Scholar PubMed PubMed Central
3. Anagnostis, P, Stevenson, JC. Cardiovascular health and the menopause, metabolic health. Best Pract Res Clin Endocrinol Metabol 2024;38:101781. https://doi.org/10.1016/j.beem.2023.101781.Search in Google Scholar PubMed
4. Cucinella, L, Martini, E, Tiranini, L, Molinaro, P, Battista, F, Nappi, RE. Genitourinary syndrome of menopause: should we treat symptoms or signs? Curr Opin Endocr Metab Res 2022;26:100386. https://doi.org/10.1016/j.coemr.2022.100386.Search in Google Scholar
5. Than, S, Moran, C, Beare, R, Vincent, A, Lane, E, Collyer, TA, et al.. Cognitive trajectories during the menopausal transition. Front Dement 2023;2:1098693. https://doi.org/10.3389/frdem.2023.1098693.Search in Google Scholar PubMed PubMed Central
6. Fidecicchi, T, Giannini, A, Chedraui, P, Luisi, S, Battipaglia, C, Genazzani, AR, et al.. Neuroendocrine mechanisms of mood disorders during menopause transition: a narrative review and future perspectives. Maturitas 2024;188:108087. https://doi.org/10.1016/j.maturitas.2024.108087.Search in Google Scholar PubMed
7. Maki, PM, Panay, N, Simon, JA. Sleep disturbance associated with the menopause. Menopause 2024;31:724–33. https://doi.org/10.1097/gme.0000000000002386.Search in Google Scholar PubMed
8. Gatenby, C, Simpson, P. Menopause: physiology, definitions, and symptoms. Best Pract Res Clin Endocrinol Metabol 2024;38:101855. https://doi.org/10.1016/j.beem.2023.101855.Search in Google Scholar PubMed
9. Andrews, R, Lacey, A, Bache, K, Kidd, EJ. The role of menopausal symptoms on future health and longevity: a systematic scoping review of longitudinal evidence. Maturitas 2024;190:108130. https://doi.org/10.1016/j.maturitas.2024.108130.Search in Google Scholar PubMed
10. Doyle, K, Bunch, DR. Reference intervals: past, present, and future. Crit Rev Clin Lab Sci 2023;60:466–82. https://doi.org/10.1080/10408363.2023.2196746.Search in Google Scholar PubMed
11. Ozarda, Y. Reference intervals: current status, recent developments and future considerations. Biochem Med (Zagreb) 2016;26:5–16. https://doi.org/10.11613/bm.2016.001.Search in Google Scholar
12. Coskun, A, Sandberg, S, Unsal, I, Serteser, M, Aarsand, AK. Personalized reference intervals: from theory to practice. Crit Rev Clin Lab Sci 2022;59:501–16. https://doi.org/10.1080/10408363.2022.2070905.Search in Google Scholar PubMed
13. Coşkun, A, Sandberg, S, Unsal, I, Cavusoglu, C, Serteser, M, Kilercik, M, et al.. Personalized reference intervals in laboratory medicine: a new model based on within-subject biological variation. Clin Chem 2021;67:374–84. https://doi.org/10.1093/clinchem/hvaa233.Search in Google Scholar PubMed
14. Coskun, A, Sandberg, S, Unsal, I, Yavuz, FG, Cavusoglu, C, Serteser, M, et al.. Personalized reference intervals – statistical approaches and considerations. Clin Chem Lab Med 2021;60:629–35. https://doi.org/10.1515/cclm-2021-1066.Search in Google Scholar PubMed
15. Jameson, JL, Longo, DL. Precision medicine-personalized, problematic, and promising. N Engl J Med 2015;372:2229–34. https://doi.org/10.1056/nejmsb1503104.Search in Google Scholar
16. Ashley, EA. Towards precision medicine. Nat Rev Genet 2016;17:507–22. https://doi.org/10.1038/nrg.2016.86.Search in Google Scholar PubMed
17. Ma, C, Yu, Z, Qiu, L. Development of next-generation reference interval models to establish reference intervals based on medical data: current status, algorithms and future consideration. Crit Rev Clin Lab Sci 2024;61:298–316. https://doi.org/10.1080/10408363.2023.2291379.Search in Google Scholar PubMed
18. Sun, X, Luo, M, Ma, M, Tang, R, Wang, Y, Liu, G, et al.. Ovarian aging: an ongoing prospective community-based cohort study in middle-aged Chinese women. Climacteric 2018;21:404–10. https://doi.org/10.1080/13697137.2018.1458833.Search in Google Scholar PubMed
19. Tang, R, Fan, Y, Luo, M, Zhang, D, Xie, Z, Huang, F, et al.. General and central obesity are associated with increased severity of the vms and sexual symptoms of menopause among Chinese women: a longitudinal study. Front Endocrinol 2022;13:814872. https://doi.org/10.3389/fendo.2022.814872.Search in Google Scholar PubMed PubMed Central
20. Harlow, SD, Gass, M, Hall, JE, Lobo, R, Maki, P, Rebar, RW, et al.. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab 2012;97:1159–68. https://doi.org/10.1016/j.fertnstert.2012.01.128.Search in Google Scholar PubMed PubMed Central
21. Breiman, L. Random forests. Mach Learn 2001;45:5–32. https://doi.org/10.1023/a:1010933404324.10.1023/A:1010933404324Search in Google Scholar
22. Hu, J, Szymczak, S. A review on longitudinal data analysis with random forest. Briefings Bioinf 2023;24:bbad002. https://doi.org/10.1093/bib/bbad002.Search in Google Scholar PubMed PubMed Central
23. Røraas, T, Støve, B, Petersen, PH, Sandberg, S. Biological variation: the effect of different distributions on estimated within-person variation and reference change values. Clin Chem 2016;62:725–36. https://doi.org/10.1373/clinchem.2015.252296.Search in Google Scholar PubMed
24. Carobene, A, Banfi, G, Locatelli, M, Vidali, M. Within-person biological variation estimates from the European Biological Variation Study (EuBIVAS) for serum potassium and creatinine used to obtain personalized reference intervals. Clin Chim Acta 2021;523:205–7. https://doi.org/10.1016/j.cca.2021.09.018.Search in Google Scholar PubMed
25. Fokkema, MR, Herrmann, Z, Muskiet, FA, Moecks, J. Reference change values for brain natriuretic peptides revisited. Clin Chem 2006;52:1602–3. https://doi.org/10.1373/clinchem.2006.069369.Search in Google Scholar PubMed
26. Coşkun, A, Sandberg, S, Unsal, I, Cavusoglu, C, Serteser, M, Kilercik, M, et al.. Personalized and population-based reference intervals for 48 common clinical chemistry and hematology measurands: a comparative study. Clin Chem 2023;69:1009–30. https://doi.org/10.1093/clinchem/hvad113.Search in Google Scholar PubMed
27. Wang, S, Zhao, M, Su, Z, Mu, R. Annual biological variation and personalized reference intervals of clinical chemistry and hematology analytes. Clin Chem Lab Med 2022;60:606–17. https://doi.org/10.1515/cclm-2021-0479.Search in Google Scholar PubMed
28. EFLM. 2025. Available from: https://biologicalvariation.eu/.Search in Google Scholar
29. Sandberg, S, Carobene, A, Bartlett, B, Coskun, A, Fernandez-Calle, P, Jonker, N, et al.. Biological variation: recent development and future challenges. Clin Chem Lab Med 2022;61:741–50. https://doi.org/10.1515/cclm-2022-1255.Search in Google Scholar PubMed
30. Bartlett, WA, Sandberg, S, Carobene, A, Fernandez-Calle, P, Diaz-Garzon, J, Coskun, A, et al.. A standard to report biological variation data studies - based on an expert opinion. Clin Chem Lab Med 2024;63:52–9. https://doi.org/10.1515/cclm-2024-0489.Search in Google Scholar PubMed
31. Jonker, N, Aslan, B, Boned, B, Marqués-García, F, Ricós, C, Alvarez, V, et al.. Critical appraisal and meta-analysis of biological variation estimates for kidney related analytes. Clin Chem Lab Med 2022;60:469–78. https://doi.org/10.1515/cclm-2020-1168.Search in Google Scholar PubMed
32. Casarini, L, Crepieux, P. Molecular mechanisms of action of FSH. Front Endocrinol 2019;10:305. https://doi.org/10.3389/fendo.2019.00305.Search in Google Scholar PubMed PubMed Central
33. Fraser, CG, Harris, EK. Generation and application of data on biological variation in clinical chemistry. Crit Rev Clin Lab Sci 1989;27:409–37. https://doi.org/10.3109/10408368909106595.Search in Google Scholar PubMed
34. Wang, S, Zhao, M, Su, Z, Yang, D, Mu, R. Annual biological variation and personalized reference intervals of 8 serum liver enzymes and 3 noninvasive tests in fatty liver patients. Clin Chim Acta 2025;569:120156. https://doi.org/10.1016/j.cca.2025.120156.Search in Google Scholar PubMed
35. Johnson, PR, Shahangian, S, Astles, JR. Managing biological variation data: modern approaches for study design and clinical application. Crit Rev Clin Lab Sci 2021;58:493–512. https://doi.org/10.1080/10408363.2021.1932718.Search in Google Scholar PubMed
36. Nikniaz, L, Nikniaz, Z, Tabrizi, JS, Sadeghi-Bazargani, H, Farahbakhsh, M. Is within-normal range liver enzymes associated with metabolic syndrome in adults? Clin Res Hepatol Gastroenterol 2018;42:92–8. https://doi.org/10.1016/j.clinre.2017.06.006.Search in Google Scholar PubMed
37. Polyzos, SA, Goulis, DG. Menopause and metabolic dysfunction-associated steatotic liver disease. Maturitas 2024;186:108024. https://doi.org/10.1016/j.maturitas.2024.108024.Search in Google Scholar PubMed
38. Yang, J, Xu, M, Wang, Z, He, M, Zhang, G, Jin, L, et al.. Unraveling estrogen and PCSK9’s roles in lipid metabolism disorders among ovariectomized mice. Reprod Sci 2025;32:316–25. https://doi.org/10.1007/s43032-024-01614-8.Search in Google Scholar PubMed
39. Zhang, X, Chang, KM, Yu, J, Loomba, R. Unraveling mechanisms of genetic risks in metabolic dysfunction-associated steatotic liver diseases: a pathway to precision medicine. Annu Rev Pathol 2025;20:375–403. https://doi.org/10.1146/annurev-pathmechdis-111523-023430.Search in Google Scholar PubMed
40. Martínez-Espartosa, D, Alegre, E, Casero-Ramírez, H, Díaz-Garzón, J, Fernández-Calle, P, Fuentes-Bullejos, P, et al.. Clinical utility of personalized reference intervals for CEA in the early detection of oncologic disease. Clin Chem Lab Med 2025;63:376–86. https://doi.org/10.1515/cclm-2024-0546.Search in Google Scholar PubMed
41. Foy, BH, Petherbridge, R, Roth, MT, Zhang, C, De Souza, DC, Mow, C, et al.. Haematological setpoints are a stable and patient-specific deep phenotype. Nature 2025;637:430–8. https://doi.org/10.1038/s41586-024-08264-5.Search in Google Scholar PubMed PubMed Central
42. Greene, DN, Ahmed, SB, Daccarett, S, Kling, JM, Lorey, TS, Rytz, CL, et al.. A comprehensive review of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone in the context of laboratory medicine to support women’s health. Clin Chem 2025;71:842–57. https://doi.org/10.1093/clinchem/hvaf039.Search in Google Scholar PubMed
Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/cclm-2025-0658).
© 2025 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Editorials
- Challenging the dogma: why reviewers should be allowed to use AI tools
- Multivariate approaches to improve the interpretation of laboratory data
- Review
- Interference of therapeutic monoclonal antibodies with electrophoresis and immunofixation of serum proteins: state of knowledge and systematic review
- Opinion Papers
- Urgent call to the European Commission to simplify and contextualize IVDR Article 5.5 for tailored and precision diagnostics
- The importance of laboratory medicine in the management of CKD-MBD: insights from the KDIGO 2023 controversies conference
- Supplementation of pyridoxal-5′-phosphate in aminotransferase reagents: a matter of patient safety
- HCV serology: an unfinished agenda
- From metabolic profiles to clinical interpretation: multivariate approaches to population-based and personalized reference intervals and reference change values
- Genetics and Molecular Diagnostics
- A multiplex allele specific PCR capillary electrophoresis (mASPCR-CE) assay for simultaneously analysis of SMN1/SMN2/NAIP copy number and SMN1 loss-of-function variants
- General Clinical Chemistry and Laboratory Medicine
- From assessment to action: experience from a quality improvement initiative integrating indicator evaluation and adverse event analysis in a clinical laboratory
- Evaluation of measurement uncertainty of 11 serum proteins measured by immunoturbidimetric methods according to ISO/TS 20914: a 1-year laboratory data analysis
- Assessing the harmonization of current total vitamin B12 measurement methods: relevance and implications
- The current status of serum insulin measurements and the need for standardization
- Method comparison of plasma and CSF GFAP immunoassays across multiple platforms
- Cerebrospinal fluid leptin in Alzheimer’s disease: relationship to plasma levels and to cerebrospinal amyloid
- Verification of the T50 Calciprotein Crystallization test: bias estimation and interferences
- An innovative immunoassay for accurate aldosterone quantification: overcoming low-level inaccuracy and renal dysfunction-associated interference
- Oral salt loading combined with postural stimulation tests for confirming and subtyping primary aldosteronism
- Evaluating the performance of a multiparametric IgA assay for celiac disease diagnosis
- Clinical significance of anti-mitochondrial antibodies and PBC-specific anti-nuclear antibodies in evaluating atypical primary biliary cholangitis with normal alkaline phosphatase levels
- Reference Values and Biological Variations
- Establishment of region-, age- and sex-specific reference intervals for aldosterone and renin with sandwich chemiluminescence immunoassays
- Validation of a plasma GFAP immunoassay and establishment of age-related reference values: bridging analytical performance and routine implementation
- Comparative analysis of population-based and personalized reference intervals for biochemical markers in peri-menopausal women: population from the PALM cohort study
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- Evaluation of stability and potential interference on the α-thalassaemia early eluting peak and immunochromatographic strip test for α-thalassaemia --SEA carrier screening
- Cardiovascular Diseases
- Analytical and clinical evaluation of an automated high-sensitivity cardiac troponin I assay for whole blood
- Diabetes
- Method comparison of diabetes mellitus associated autoantibodies in serum specimens
- Letters to the Editor
- Permitting disclosed AI assistance in peer review: parity, confidentiality, and recognition
- Response to the editorial by Karl Lackner
- Hemolysis detection using the GEM 7000 at the point of care in a pediatric hospital setting: does it affect outcomes?
- Estimation of measurement uncertainty for free drug concentrations using ultrafiltration
- Cryoglobulin pre-analysis over the weekend
- Accelerating time from result to clinical action: impact of an automated critical results reporting system
- Recent decline in patient serum folate test levels using Roche Diagnostics Folate III assay
- Kidney stones consisting of 1-methyluric acid
- Congress Abstracts
- 7th EFLM Conference on Preanalytical Phase
- Association of Clinical Biochemists in Ireland Annual Conference
- Association of Clinical Biochemists in Ireland Annual Conference
- 17th Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine