The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Multiple imputation of missing values was not necessary before performing a longitudinal mixed-model analysis
Abstract
Background and objectives As a result of the development of sophisticated techniques, such as multiple imputation, the interest in handling missing data in longitudinal studies has increased enormously in past years. Within the field of longitudinal data analysis, there is a current debate on whether it is necessary to use multiple imputations before performing a mixed-model analysis to analyze the longitudinal data. In the current study this necessity is evaluated.Study design and setting The results of mixed-model analyses with and without multiple imputation were compared with each other. Four data sets with missing values were created-one data set with missing completely at random, two data sets with missing at random, and one data set with missing not at random). In all data sets, the relationship between a continuous outcome variable and two different covariates were analyzed: a time-independent dichotomous covariate and a time-dependent continuous covariate.Results Although for all types of missing data, the results of the mixed-model analysis with or without multiple imputations were slightly different, they were not in favor of one of the two approaches. In addition, repeating the multiple imputations 100 times showed that the results of the mixed-model analysis with multiple imputation were quite unstable.Conclusion It is not necessary to handle missing data using multiple imputations before performing a mixed-model analysis on longitudinal data.
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In the citing paper
“Multiple imputation when performing mixed models analyses can lead to unstable results [26]”
In the citing paper
“Linear mixed modelling has been demonstrated to control for missing data, and therefore, multiple imputation was not required (Peters et al., 2012;Twisk et al., 2013).”
From Exercise combined with Acceptance and Commitment Therapy for chronic pain: One-year follow-up from a randomized controlled trial (2024) · cites this paper as Twisk et al., 2013
In the citing paper
“Twisk et al 71 provided evidence that multiple imputation for missing data is not necessary before computing longitudinal mixed models.”
In the citing paper
“However, completely missing measurements will not be imputed as this is not necessary for multilevel analysis (63).”
From Timing of imagery rescripting during schema therapy for borderline personality disorder: the LUCY trial (2023) · cites this paper as [63]
In the citing paper
“Therefore, patterns of missingness were not found to be MNAR and the decision to continue the analysis with the available data was made [84,85].”
From Negative and positive affect regulation in a transdiagnostic internet-based protocol for emotional disorders: Randomized controlled trial (2021) · cites this paper as [84]
In the citing paper
“Mixed model analysis handles missing data; no imputation method was applied since there are reports that imputations before a mixed model analysis is not necessary and simulations indicated that imputations before mixed models could result in unstable results [30].”
From Is sleep disturbance in patients with chronic pain affected by physical exercise or ACT-based stress management? - A randomized controlled study (2018) · cites this paper as [30]
In the citing paper
“We also performed all analyses on the data for 100 imputations. Because there is a current debate whether it is necessary to perform multiple imputations in combination with mixed-model analyses in longitudinal studies [65], we also performed the LMM analyses without multiple imputations.”
From Long-Term Results of a Web-Based Guided Self-Help Intervention for Employees With Depressive Symptoms: Randomized Controlled Trial (2014) · cites this paper as [65]
In the citing paper
“Because of the current debate on the necessity of multiple imputations in combination with mixed-model analysis in longitudinal studies [65], we also performed mixed-model analysis without multiple imputations. The results were comparable, indicating that data were robust and multiple imputations may not have been needed.”
From Long-Term Results of a Web-Based Guided Self-Help Intervention for Employees With Depressive Symptoms: Randomized Controlled Trial (2014) · cites this paper as [65]
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“A longitudinal mixed-model analysis with maximum likelihood method of estimation can handle missing data, imputation prior to analysis was not necessary (Twisk et al., 2013).”
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Brabander, E. Y. D., Leibold, N. K., van Amelsvoort, T., van Westrhenen, R., Alizadeh, B. Z., Cahn, W., de Haan, L., van der Pluijm, M., Simons, C. J. P., van Os, J., et al. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111363 · Cited by 3
“Furthermore, the Bayesian mixed models applied in the current study are able to handle missing data and the potential for systematic miss-ingness, accounting for potential impact of bias without imputation (Feng, 2021; Gadbury et al., 2003; Twisk et al., 2013).”
Blankers, M., van Beek, R. J. J., Spronk, D. B., den Hollander, W., Andree, R., Freeman, T. P., Grabski, M., Curran, H. V., Waldron, J., & van Laar, M. (2025) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2025.112881 · Cited by 3
Sensitivity Analyses for Missing in Repeatedly Measured Outcome Data
Troendle, J. F., Sur, A., Leifer, E., & Powell‐Wiley, T. M. (2025) · Statistics in Medicine · doi:10.1002/sim.70282 · Cited by 3
Hadjistavropoulos, H. D., Dear, B. F., Titov, N., & Sapkota, R. P. (2025) · Internet Interventions · doi:10.1016/j.invent.2025.100894 · Cited by 3
“Missing data in longitudinal mixed-model analyses were handled using maximum likelihood (ML) estimation, which accommodates MAR without requiring imputation (Twisk et al., 2013).”
Health-related quality of life outcomes and recovery trajectories following burn injury
Tracy, L. M., Capell, E. L., Cleland, H. J., Edgar, D. W., Singer, Y. M., Teague, W. J., & Gabbe, P. B. (2026) · Burns · doi:10.1016/j.burns.2026.107891 · Cited by 3
Wei, X., Yu, H., Dai, W., Huang, L., Liu, Y., Cheng, L., Yang, D. C., Zhang, K., Liao, J. X., Wang, Y., et al. (2026) · Annals of Surgical Oncology · doi:10.1245/s10434-025-18834-0 · Cited by 3
Progression of GBA1 severe and risk variants: a longitudinal mixed model analysis
Hanff, A.-M. R., McCrum, C. L., Rauschenberger, A., Pachchek, S., Aguayo, G., Pauly, C., Jónsdóttir, S. R., Tsurkalenko, O., Pauly, L., Landoulsi, Z., et al. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1771789 · Cited by 4
“As individuals with PD were enrolled at different time points (Twisk, 2013) due to the dynamic cohort study design, the disease progression could be distinguished from cohort or period effects.”
Lowe, D. M., Zhang, S., Ellis, S., Buggiotti, L., Miller, C., Harris, V., Shields, A. M., Richter, A. G., Ashmore, E., Yu, L.-M., et al. (2026) · The Lancet Microbe · doi:10.1016/j.lanmic.2026.101360 · Cited by 3
Stilling, M. N., Lindberg, L., Tuck, L. D., Sørensen, O. H., Holtermann, A., & Rasmussen, C. D. N. (2025) · BMC Public Health · doi:10.1186/s12889-025-24463-9 · Cited by 3
“All analyses will be performed according to the intention-to-treat principle, including all eligible participants without imputations because mixed models inherently account for missing values [39].”
de Zwart, A. H., van der Leeden, M., Roorda, L. D., van der Esch, M., Twisk, J. W. R., Lems, W. F., & Dekker, J. (2020) · Osteoarthritis and Cartilage Open · doi:10.1016/j.ocarto.2020.100038 · Cited by 3
Self-citationExplaining Differences between Groups
Twisk, J. W. R. (2019) · Cambridge University Press eBooks · doi:10.1017/9781108635660.007 · Cited by 3
Self-citationFrailty measures in immuno-metabolic subtypes of late-life depression; A two-year prospective study
Kokkeler, K. J. E., Voshaar, R. C. O., Rhebergen, D., van den Brink, R. H. S., Spijker, J., & Marijnissen, R. M. (2021) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2021.104603 · Cited by 3
Yorozuya, K., Kubo, Y., Asaoka, Y., Hayashi, H., Fujita, T., & Hanaoka, H. (2024) · Psychogeriatrics · doi:10.1111/psyg.13186 · Cited by 3
“31,41 The explanatory variables were the baseline score on the indicator (the objective variable) and the presence or absence of the MNPI (MNPI = 1 vs. control = 0).”
Analysis of Longitudinal Outcome Data with Missing Values in Total Knee Arthroplasty
Kang, Y. G., Lee, J. T., Kang, J. Y., Kim, G. H., & Kim, T. K. (2015) · The Journal of Arthroplasty · doi:10.1016/j.arth.2015.06.067 · Cited by 3
“A previous study found that multiple imputation was not necessary when analyzing data with mixed model [15].”
BackgroundMethodNagler, B., Gleiss, A., Füreder, L., Buchtele, N., Hermann, A., Bojic, A., Schellongowski, P., Staudinger, T., & Robak, O. (2022) · ASAIO Journal · doi:10.1097/mat.0000000000001675 · Cited by 3
Scott, I. C., Bajpai, R. C., Hider, S., Helliwell, T., Mallen, C. D., & Müller, S. (2024) · Rheumatology Advances in Practice · doi:10.1093/rap/rkae081 · Cited by 3
“As multiple imputation is recommended in longitudinal data analysis with missing covariates [22], sensitivity analyses imputed missing baseline covariates and missing outcomes at any follow-up time using multiple imputation techniques with 20 imputations (based on the missingness pattern) following…”
BackgroundMethodGenerative Adversarial Networks Imputation for High Rate Missing Values
Wang, H., Chen, Y., Shen, B., Wu, D., & Ban, X. (2018) · IEEE International Conference on Internet of Things (iThings) and IEEE Green Computing and Communications (GreenCom) and IEEE Cyber, Physical and Social Computing (CPSCom) and IEEE Smart Data (SmartData) · doi:10.1109/cybermatics_2018.2018.00121 · Cited by 3
Danielsen, E., Ingebrigtsen, T., Gulati, S., Salvesen, Ø. O., Johansen, T. O., Nygaard, O. P., & Solberg, T. K. (2024) · Neurosurgery · doi:10.1227/neu.0000000000002852 · Cited by 2
Ayres, J., Chen, Y., Forbush, K. T., Bottera, A. R., & Christensen, K. A. (2025) · Appetite · doi:10.1016/j.appet.2025.108052 · Cited by 2
Belimbegovski, W., Schaap, L. S., Linn, A. J., Medlock, S. K., van Weert, J. C. M., van der Velde, N., & van Schoor, N. M. (2025) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2025.105936 · Cited by 2
Liu, Y., Sommer, I. E., Begemann, M., Gangadin, S. S., Perry, B. I., Scheurink, T. A. W., van Beveren, N. J. M., Sommer, I. E., de Haan, L., Veling, W., et al. (2025) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaf116 · Cited by 2
“59 Further more, when we compared the baseline characteristics of participants with and without missing weight and movement disorder measurements, no differences were found in age, sex, smoking status, or olanzapine equivalent dose between the 2 groups.”
Arts, J., Altenburg, T. M., Lettink, A., Verhoeff, A. P., Gubbels, J. S., & Chinapaw, M. J. M. (2025) · Journal of Activity Sedentary and Sleep Behaviors · doi:10.1186/s44167-025-00085-9 · Cited by 2
“Linear mixed models use maximum likelihood estimation to handle missing data, eliminating the need for data imputation [40, 41].”
Liu, R. Y., & Liu, E. (2025) · Nutrients · doi:10.3390/nu17233660 · Cited by 2
“No specific imputation procedures were applied, as linear mixed models can appropriately handle missing data under the MAR assumption [24,25].”
Murtazin, K., Shvets, O., Karu, K.-E., Puusep, V., Vendelin, J., Meeter, M., & Piho, G. (2025) · Frontiers in Education · doi:10.3389/feduc.2025.1621644 · Cited by 2
Houtvast, D. C. J., Hendriks, F. K., Weijzen, M. E. G., Zorenc, A. H. G., Smeets, J. S. J., Emans, P. J., Wodzig, W. K. W. H., Larsen, M. S., Mikkelsen, U. R., Schotanus, M. G. M., et al. (2026) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2026.101349 · Cited by 2
“Missing data were not imputed, because linear mixed models use maximum likelihood estimations to use all the available data under the assumption that data are missing at random [31,32].”
Vangen-Lønne, V., Madsbu, M. A., Salvesen, Ø. O., Nygaard, O. P., Solberg, T. K., & Gulati, S. (2022) · Brain and Spine · doi:10.1016/j.bas.2022.100894 · Cited by 2
“Our study is strengthened by prospective data collection, high external validity, and widely applied and validated outcome measures (Fairbank et al., 1980; Grotle et al., 2003; Solberg et al., 2005; Ostelo et al., 1976; Twisk et al., 2013) Although this is a single center study, it is the largest to date with prospect…”
MethodKleijburg, A., Wijnen, B. F. M., Evers, S., Kroon, H., & Lokkerbol, J. (2022) · BMC Psychiatry · doi:10.1186/s12888-022-04346-8 · Cited by 2
“Because longitudinal mixed-modelling performs internal HoNOS ∼ condition + time + condition ∶ time + site + (1|id) imputation, no other procedures for missing data are required [24].”
MethodStapleton, J. R., Ard, J. D., Beavers, D. P., Cogdill, L. S., Fernandez, A., Howard, M. J., Justice, J. N., Lynch, S. D., Newman, J. J., Weaver, A. A., et al. (2023) · Contemporary Clinical Trials Communications · doi:10.1016/j.conctc.2023.101181 · Cited by 2
“All models will use completers only, noting that mixed models with baseline covariate adjustments are fairly robust to missing data; [57,58] however, sensitivity analyses will be conducted to ensure results are not biased due to differential missing data.”
MethodBehavioral and Psychological Factors in Buffering Diabetes-related Disability Development
Tsai, Y., Chuang, L.-L., Lee, Y., & Chiu, C. (2023) · Annals of Behavioral Medicine · doi:10.1093/abm/kaad038 · Cited by 2
Eriksen, B., Fasiolo, M., Mathisen, U., Jenssen, T., Stefansson, V., & Melsom, T. (2023) · Scientific Reports · doi:10.1038/s41598-023-41181-7 · Cited by 1
“All study participants were included in the GAMM analyses regardless of whether they were examined at follow-up because mixed models allow for missing observations at one or more points in time 27,28 .”
Hung, S., Tierney, C., Klassen, T. D., Schneeberg, A., Bayley, M. T., Dukelow, S. P., Hill, M. D., Krassioukov, A. V., Pooyania, S., Poulin, M. J., et al. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1245881 · Cited by 3
“The package lme4: Linear Mixed-Effects Models used “Eigen” and S4 (R software), which utilizes all available data and has been demonstrated to be valid in the presence of data missing at random (28).”
Schlegl, S., Maier, J., Dieffenbacher, A., & Voderholzer, U. (2023) · European Eating Disorders Review · doi:10.1002/erv.3047 · Cited by 2
Badia-Aguarón, T., Royuela-Colomer, E., Pera-Guardiola, V., Balasch, P. V., Cebolla, A., Luciano, J. V., Soler, J., Feliu‐Soler, A., & Huguet, A. (2024) · Frontiers in Psychology · doi:10.3389/fpsyg.2024.1291198 · Cited by 2
“No imputation of missing data will be performed since it has been reported that multiple imputation is unnecessary for certain types of missing data (missing completely at random, missing at random, and missing not at random) when conducting longitudinal mixed model analysis (Twisk et al., 2013).”
MethodChrist, C., van Schaik, A., Kikkert, M., de Waal, M. M., Dozeman, E., Hulstijn, H. L., Koomen, L. E. M., Krah, I. M., Schut, D. M., Beekman, A. T. F., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.03.028 · Cited by 2
Zink, J., Weniger, M., Porst, P. T., Siegmund, C. B., McDonald, M., Rückert, F., Roessner, V., Knappe, S., & Beesdo‐Baum, K. (2024) · Research on Child and Adolescent Psychopathology · doi:10.1007/s10802-024-01221-w · Cited by 2
“Mixed model analyses have been shown to produce robust results even without prior multiple imputation (MI) (Twisk et al., 2013), but baseline values are needed to determine whether initial symptom severity moderates the effectiveness of the prevention program.”
Metadata
- Authors
- Twisk, J., de Boer, M., de Vente, W., & Heymans, M.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Twisk, Jos
- Venue
- Journal of Clinical Epidemiology
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 66
- Issue
- 9
- Pages
- 1022-1028
- ISSN
- 0895-4356 (ISSN-L)
- OpenAlex
- W1974992958
- Cited by
- 568
- References
- 43
- Citations by year
- 2026: 58 · 2025: 68 · 2024: 74 · 2023: 57 · 2022: 61 · 2021: 52 · 2020: 46 · 2019: 45 · 2018: 27 · 2017: 26 · 2016: 21 · 2015: 19 · 2014: 10 · 2013: 4
- FWCI
- 15.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods and Bayesian Inference
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Keywords
- multiple imputation, missing data, longitudinal analysis, mixed models, missing completely at random, missing at random, missing not at random, time-varying covariates
- MeSH terms
- Data Interpretation, Statistical, Humans, Longitudinal Studies, Patient Dropouts, Research Design, Models, Statistical
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