Joint Modeling of Multivariate Longitudinal Measurements and Survival Data: Application to Hemodialysis Data

Authors

  • Asma Pourhoseingholi Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Author https://orcid.org/0000-0003-4380-6453
  • Shahrzad Ossareh Nephrology Section, Hasheminejad Kidney Center, Iran University of Medical Sciences; Tehran, Iran. Author https://orcid.org/0000-0003-3020-9465
  • Erfan Ghasemi Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada. Author
  • Ali Akbar Jafari Department of Statistics, Yazd University, Yazd, Iran. Author
  • Bijan Moghimi-Dehkordi Department of Prevention and Control of Noncommunicable Diseases, Deputy of Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Author
  • Mohsen Vahedi Department of Biostatistics and Epidemiology, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Author https://orcid.org/0000-0002-4645-6770

DOI:

https://doi.org/10.61882/ijkd.3.03.9536

Keywords:

Hemodialysis, Joint models, Survival analysis;, Longitudinal studies, Creatinine, Calcium

Abstract

Introduction. In studies involving hemodialysis patients, repeated laboratory measurements (longitudinal data) and survival outcomes are often analyzed separately, which can lead to biased results due to ignoring measurement errors and the intrinsic dependency between the two analyses. Joint modeling has emerged as a powerful approach to handle such data. This study aims to investigate the impact of six time-varying biochemical markers, along with baseline covariates, on the survival of hemodialysis patients using a multivariate joint model.
Methods. A longitudinal cohort of 894 maintenance hemodialysis (MHD) patients, who had started dialysis between 2004 and 2023, were included. Baseline and follow-up clinical information and monthly laboratory measurements were analyzed. A multivariate linear mixed-effects model was jointly fitted with a Cox proportional hazards model to simultaneously assess the longitudinal biomarkers and time-to-event data. Analyses were performed using R software. Results. The model indicated that older age (Hazard Ratio, HR = 1.02, P < .001), male gender (HR = 1.72, P < .001), diabetes mellitus (HR = 1.61, P < .001), walking disability at admission (HR = 1.78, P < .001), and catheter-based vascular access (HR = 1.71, P < .001) were significantly associated with an increased risk of mortality. Higher square root of phosphate levels (HR = 13.97, P < .001) were linked to increased, and higher square root of creatinine (HR = 0.32, P < .001), hemoglobin (HR = 0.75, P = .009) and albumin (HR = 0.31, P < .001) levels were associated with decreased mortality. Conclusion. Findings of the joint model confirm the importance of baseline clinical risk factors and modifiable biochemical markers on the survival outcomes of hemodialysis patients.

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Author Biographies

  • Asma Pourhoseingholi, Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

    Iranian Research Center on Aging 

  • Shahrzad Ossareh, Nephrology Section, Hasheminejad Kidney Center, Iran University of Medical Sciences; Tehran, Iran.

    Nephrology Section, Hasheminejad Kidney Center

  • Erfan Ghasemi, Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada.

    Department of Public Health Sciences, School of Public Health

  • Ali Akbar Jafari, Department of Statistics, Yazd University, Yazd, Iran.

    Department of Statistics

  • Bijan Moghimi-Dehkordi, Department of Prevention and Control of Noncommunicable Diseases, Deputy of Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    Department of Prevention and Control of Noncommunicable Diseases, Deputy of Health

  • Mohsen Vahedi, Department of Biostatistics and Epidemiology, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

    Department of Biostatistics and Epidemiology, School of Rehabilitation

References

1. Ibrahim JG, Chu H, Chen LM. Basic concepts and methods for joint models of longitudinal and survival data. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(16):2796-801.

2. Locatelli F, D’Amico M, Cernevskis H, et al. The epidemiology of end-stage renal disease in the Baltic countries: an evolving picture. Nephrol Dial Transplant. 2001;16(7):1338-42.

3. Li L, Hu B, Greene T. A semiparametric joint model

for longitudinal and survival data with application to hemodialysis study. Biometrics. 2009;65(3):737-45.

4. Ratcliffe SJ, Guo W, Ten Have TR. Joint modeling of longitudinal and survival data via a common frailty. Biometrics. 2004;60(4):892-9.

5. Asar O, Ritchie J, Kalra PA, Diggle PJ. Joint modelling of repeated measurement and time-to-event data: an introductory tutorial. International journal of epidemiology. 2015;44(1):334-44.

6. Rizopoulos D. Joint Models for Longitudinal and Time-to-Event Data, with Applications in R. Boca Raton: Chapman and Hall/CRC; 2012.

7. Proust-Lima C, Sene M, Taylor JM, Jacqmin-Gadda H. Joint latent class models for longitudinal and time-to-event data: a review. Statistical methods in medical research. 2014;23(1):74-90.

8. Tsiatis AA, Degruttola V, Wulfsohn MS. Modeling the Relationship of Survival to Longitudinal Data Measured with Error. Applications to Survival and CD4 Counts in Patients with AIDS. Journal of the American Statistical Association. 1995;90(429):27-37.

9. Andrinopoulou ER, Rizopoulos D, Jin R, Bogers AJ, Lesaffre E, Takkenberg JJ. An introduction to mixed models and joint modeling: analysis of valve function over time. The Annals of thoracic surgery. 2012;93(6):1765-72.

10. Ediebah DE, Galindo-Garre F, Uitdehaag BM, et al. Joint modeling of longitudinal health-related quality of life data and survival. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2015;24(4):795-804.

11. Madreseh E, Mahmoodi M, Hosseini S, Zeraati H, Najafi

I. The application of joint model for longitudinal and survival data in peritoneal dialysis patients. Journal of the School of Public Health and Institute of Public Health Research(sjsph). 2014;11(4):49-64.

12. Guler I, Faes C, Cadarso-Suárez C, Teixeira L, Rodrigues A, Mendonça D. Two-stage model for multivariate longitudinal and survival data with application to nephrology research. Biom J. 2017;59(6):1204-20.

13. Therneau T. A Package for Survival Analysis in R. version 3.8-3 [Available from: http://CRAN.R-project.org/package = survival.

14. Pinheiro J, Bates D, DebRoy S, Sarkar D, Team RC. nlme: Linear and Nonlinear Mixed Effects Models. R package version 3.1-168 [Available from: http://CRAN.R-project. org/package = nlme.

15. Hickey GL, Philipson P, Jorgensen A, Kolamunnage-Dona R, Williamson P, Rizopoulos D, Gasparini A. joineRML: Joint Modelling of Multivariate Longitudinal Data and Time-to-Event Outcomes. R package version 0.4.7

[Available from: https://cran.r-project.org/web/packages/joineRML/index.html.

16. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease Kidney Int. 2024;105(4S):S117-S314.

17. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8):2208-18.

18. Coric A, Resic H, Celik D, et al. Mortality in hemodialysis patients over 65 years of age. Materia socio-medica. 2015;27(2):91-4.

19. Mailloux LU, Bellucci AG, Napolitano B, Mossey T, Wilkes BM, Bluestone PA. Survival estimates for 683 patients starting dialysis from 1970 through 1989: identification

of risk factors for survival. Clinical nephrology.

1994;42(2):127-35.

20. Schiller A, Gadalean F, Schiller O, et al. Vitamin D deficiency--prognostic marker or mortality risk factor in end stage renal disease patients with diabetes mellitus treated with hemodialysis--a prospective multicenter study. PloS one. 2015;10(5):e0126586.

21. Tsai CC, Lee JJ, Liu TP, Ko WC, Wu CJ, Pan CF, Cheng SP. Effects of age and diabetes mellitus on clinical outcomes in patients with peritoneal dialysis-related peritonitis. Surgical infections. 2013;14(6):540-6.

22. Vavallo A, Simone S, Lucarelli G, et al. Pre-existing type 2 diabetes mellitus is an independent risk factor for mortality and progression in patients with renal cell carcinoma. Medicine. 2014;93(27):e183.

23. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis. 1990;15(5):458-82.

24. Kalantar-Zadeh K, Kilpatrick RD, Kuwae N, McAllister CJ, Alcorn H, Jr., Kopple JD, Greenland S. Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction. Nephrol Dial Transplant. 2005;20(9):1880-8.

25. Uludag K, Arikan T. Longitudinal effects of modified creatinine index on all-cause mortality in individuals receiving hemodialysis treatment. Ann Saudi Med.

2021;41(6):361-8.

26. Canaud B, Ye X, Usvyat L, et al. Clinical and predictive value of simplified creatinine index used as muscle mass surrogate in end-stage kidney disease haemodialysis patients-results from the international MONitoring Dialysis Outcome initiative. Nephrol Dial Transplant. 2020;35(12):2161-71.

27. Belay S, Melese D, Muhammed K. Joint modeling on serum creatinine and time to end stage of renal disease for chronic kidney disease patients under treatment at the University of Gondar Referral Hospital. Health Sci Rep. 2023;6(9):e1563.

28. Ossareh S, Farrokhi F, Zebarjadi M. Survival of Patients on Hemodialysis and Predictors of Mortality: a Single-Centre Analysis of Time-Dependent Factors. Iran J Kidney Dis. 2016;10(6):369-80.

29. Hashemi S, Vahedi M, Ossareh S. Evaluation of Long-term Survival and Predictors of Mortality in Hemodialysis Patients by Using Time Dependent Variables, A

Single Centre Cohort Analysis. Iran J Kidney Dis.

2021;15(5):373-84.

30. D’Arrigo G, Mallamaci F, Pizzini P, Leonardis D, Tripepi G, Zoccali C. CKD-MBD biomarkers and CKD progression: an analysis by the joint model. Nephrol Dial Transplant. 2023;38(4):932-8.

31. McCrink L, Marshall A, Cairns K. Joint Modelling of Longitudinal and Survival Data:A Comparison of Joint and Independent Models. Int Statistical Inst: Proc58th World Statistical Congress; Dublin2011.

32. Qian Q, Nguyen DV, Kurum E, Banerjee S, Rhee CM, Senturk D. Bayesian Multivariate Joint Modeling of Longitudinal, Recurrent, and Competing Risk Terminal Events in Patients with Chronic Kidney Disease. Journal of Data Science. 2025:1-21.

33. Diggle PJ, Heagerty P, Liang K-Y, Zeger S. Analysis of Longitudinal Data. 2nd ed. Oxford. UK: Oxford University Press; 2002.

34. Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. 2nd ed. Hoboken, NJ: John Wiley&Sons; 2011.

35. Kalbfeisch JD, Prentice RL. The Statistical Analysis

of Failure Time Data. 2nd ed. New York, NY: John Wiley&Sons; 2002.

36. Kleinbaum DG, Klein M. Survival Analysis: A Self Learning Text. 3rd ed. New York, NY: Springer; 2012.

37. Wulfsohn MS, Tsiatis AA. A joint model for survival

and longitudinal data measured with error. Biometrics. 1997;53(1):330-9.

38. Bhattacharjee A, Nath DC. Joint Longitudinal and Survival Data Modelling: an Application in Anti-Diabetes Drug Therapeutic Effect. Statistics in Transition.

2014;15(3):437-52.

39. Daher Abdi Z, Essig M, Rizopoulos D, et al. Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach. Pharmacological research : the official journal of the Italian Pharmacological Society. 2013;72:52-60.

40. Ferede MM, Mwalili S, Dagne G, Karanja S, Hailu W,

El-Morshedy M, Al-Bossly A. A Semiparametric Bayesian Joint Modelling of Skewed Longitudinal and Competing Risks Failure Time Data: With Application to Chronic Kidney Disease. Mathematics. 2022;10(24):4816.

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Published

2026-05-31

Data Availability Statement

The datasets generated and analyzed during the current study are not publicly available due to the reason why data are not public but are available from the corresponding author upon reasonable request.

Issue

Section

ORIGINAL | Dialysis

How to Cite

Joint Modeling of Multivariate Longitudinal Measurements and Survival Data: Application to Hemodialysis Data. (2026). Iranian Journal of Kidney Diseases, 20(03), 138-148. https://doi.org/10.61882/ijkd.3.03.9536

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