Cited by 398Statistical Methods and Bayesian InferenceStatistical Methods in Clinical TrialsAdvanced Causal Inference Techniques

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ACCOUNTING FOR DROPOUT BIAS USING MIXED-EFFECTS MODELS

Mallinckrodt, Craig H., Clark, W. Scott, David, Stacy R.·2001·Journal of Biopharmaceutical Statistics

DOI 10.1081/bip-100104194

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Abstract

Treatment effects are often evaluated by comparing change over time in outcome measures. However, valid analyses of longitudinal data can be problematic when subjects discontinue (dropout) prior to completing the study. This study assessed the merits of likelihood-based repeated measures analyses (MMRM) compared with fixed-effects analysis of variance where missing values were imputed using the last observation carried forward approach (LOCF) in accounting for dropout bias. Comparisons were made in simulated data and in data from a randomized clinical trial. Subject dropout was introduced in the simulated data to generate ignorable and nonignorable missingness. Estimates of treatment group differences in mean change from baseline to endpoint from MMRM were, on average, markedly closer to the true value than estimates from LOCF in every scenario simulated. Standard errors and confidence intervals from MMRM accurately reflected the uncertainty of the estimates, whereas standard errors and confidence intervals from LOCF underestimated uncertainty.

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The Cost-Effectiveness of Continuous Glucose Monitoring in Type 1 Diabetes
Huang, E. S., O’Grady, M. J., Basu, A., Winn, A. N., John, P. M., Lee, J. M., Meltzer, D. O., Kollman, C., Laffel, L. M., Tamborlane, W. V., et al. (2010) · Diabetes Care · doi:10.2337/dc09-2042 · Cited by 118
“Experienced utilities at baseline, week 13, and week 26 were modeled using a random-effects linear model (9,10).”
Association of the Adrenergic α2A Receptor Gene With Methylphenidate Improvement of Inattentive Symptoms in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder
Polanczyk, G. V., Zeni, C., Genro, J. P., Guimarães, A. P., Roman, T., Hutz, M. H., & Rohde, L. A. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.2.218 · Cited by 113
Clinical trial on tonal tinnitus with tailor-made notched music training
Stein, A., Wunderlich, R., Lau, P., Engell, A., Wollbrink, A., Shaykevich, A., Kuhn, J., Holling, H., Rudack, C., & Pantev, C. (2016) · BMC Neurology · doi:10.1186/s12883-016-0558-7 · Cited by 113
“In anticipation of dropouts and missing data, we chose a likelihood-based mixed-effects model for repeated measures analysis as the primary analysis [46, 47].”
Method
Uncertainty Analysis With High Dimensional Dependence Modelling
Carbno, C. C. (2007) · Technometrics · doi:10.1198/tech.2007.s464 · Cited by 110
The Global Functioning: Social and Role Scales—Further Validation in a Large Sample of Adolescents and Young Adults at Clinical High Risk for Psychosis
Carrión, R. E., Auther, A. M., McLaughlin, D., Olsen, R. H., Addington, J., Bearden, C. E., Cadenhead, K. S., Cannon, T. D., Mathalon, D. H., McGlashan, T. H., et al. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sby126 · Cited by 107
Comparing the Effects of Antidepressants: Consensus Guidelines for Evaluating Quantitative Reviews of Antidepressant Efficacy
Lieberman, J. A., Greenhouse, J. B., Hamer, R. M., Krishnan, K. R. R., Nemeroff, C. B., Sheehan, D. V., Thase, M. E., & Keller, M. B. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300571 · Cited by 105
“Neuropsychopharmacology Contemporary approaches to handling missing data (Mallinckrodt et al, 2003, 2001; Entsuah, 1996) are highly preferable to the aforementioned conventional methods commonly used in studies designed for purposes of regulatory approval.”
Method
Affect-focused psychodynamic psychotherapy for depression and anxiety through the Internet: a randomized controlled trial
Johansson, R., Björklund, M., Hornborg, C., Karlsson, S., Hesser, H., Ljótsson, B., Rousseau, A., Frederick, R. J., & Andersson, G. (2013) · PeerJ · doi:10.7717/peerj.102 · Cited by 102
“%)”
Efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL) in early psychosis: study protocol for a multi-centre randomized controlled trial
Reininghaus, U., Klippel, A., Steinhart, H., Vaessen, T., van Nierop, M. M., Viechtbauer, W., Batink, T., Kasanova, Z., van Aubel, E., van Winkel, R., et al. (2019) · Trials · doi:10.1186/s13063-019-3912-4 · Cited by 106
COMPARISON OF ALTERNATIVE STRATEGIES FOR ANALYSIS OF LONGITUDINAL TRIALS WITH DROPOUTS
Liu, G. F., & Gould, A. L. (2002) · Journal of Biopharmaceutical Statistics · doi:10.1081/bip-120015744 · Cited by 101
Body weight as a predictor of antidepressant efficacy in the GENDEP project
Uher, R., Mors, O. N., Hauser, J., Rietschel, M., Maier, W., Kozel, D., Henigsberg, N., Souery, D., Placentino, A., Perroud, N. A., et al. (2009) · Journal of Affective Disorders · doi:10.1016/j.jad.2009.02.013 · Cited by 96
“It has been repeatedly demonstrated that mixed models are preferable to end-point analyses with last-observation-carried forward procedure (Lane, 2008; Mallinckrodt et al., 2001).”
Method
Evaluation of a Bystander-Focused Interpersonal Violence Prevention Program with High School Students
Edwards, K. M., Banyard, V. L., Sessarego, S. N., Waterman, E. A., Mitchell, K. J., & Chang, H. (2019) · Prevention Science · doi:10.1007/s11121-019-01000-w · Cited by 95
“One strength of multilevel modeling in which the longitudinal time trend at both the cluster level and individual level are preserved through intraclass correlation, and variance structure is that this technique minimizes bias due to attrition (Gad and Youssif 2006; Mallinckrodt et al. 2001).”
Effects of an Artificial Intelligence Platform for Behavioral Interventions on Depression and Anxiety Symptoms: Randomized Clinical Trial
Sadeh‐Sharvit, S., Camp, T. D., Horton, S. E., Hefner, J. D., Berry, J. M., Grossman, E., & Hollon, S. D. (2023) · Journal of Medical Internet Research · doi:10.2196/46781 · Cited by 129
“Missing data points were treated as missing at random [24].”
The effect of correlation structure on treatment contrasts estimated from incomplete clinical trial data with likelihood-based repeated measures compared with last observation carried forward ANOVA
Mallinckrodt, C. H., Kaiser, C. J., Watkin, J. G., Molenberghs, G., & Carroll, R. J. (2004) · Clinical Trials · doi:10.1191/1740774504cn049oa · Cited by 96
“However, the present results and previous empirical studies [4,12-14] have clearly shown that conservative behavior of LOCF is not guaranteed.”
BackgroundMethodResultInfluentialSelf-citation
A randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-resistant major depression
Fitzgerald, P. B., Hoy, K. E., Gunewardene, R., Slack, C., Ibrahim, S., Bailey, M., & Daskalakis, Z. J. (2010) · Psychological Medicine · doi:10.1017/s0033291710001923 · Cited by 91
“Empirical studies have confirmed the advantages of mixed models over last observation carry-forward (LOCF) analysis, with mixed effects (Mallinckrodt et al. 2001a, b).”
Background
Pharmacogenetics of antidepressant response: A polygenic approach
García‐González, J., Tansey, K. E., Hauser, J., Henigsberg, N., Maier, W., Mors, O. N., Placentino, A., Rietschel, M., Souery, D., Žagar, T., et al. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.01.011 · Cited by 91
“Remission was deﬁned as a score below a consensus cut -off that corresponds to absence of depression for each scale (Hamilton, 1967; Montgomery and Asberg, 1979; Beck et al., 1961).”
Background
Be a Mom, a Web-Based Intervention to Prevent Postpartum Depression: Results From a Pilot Randomized Controlled Trial
Fonseca, A., Alves, S., Monteiro, F., Gorayeb, R., & Canavarro, M. C. (2020) · Behavior Therapy · doi:10.1016/j.beth.2019.09.007 · Cited by 82
Efficacy of Iloperidone in the Treatment of Schizophrenia
Potkin, S. G., Litman, R. E., Torres, R., & Wolfgang, C. D. (2008) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e3181692787 · Cited by 90
“That study also used a more contemporary approach to imputation of missing data, a mixedeffects model repeated measures method that has been shown to be less vulnerable to the bias that may be introduced by missing data compared with the LOCF approach, as it takes into account the actual duration of treatment.(27,28)…”
Result
Efficacy and Safety of Duloxetine 60 mg Once Daily in the Treatment of Pain in Patients With Major Depressive Disorder and At Least Moderate Pain of Unknown Etiology
Brecht, S., & Courtecuisse, C. (2007) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v68n1110 · Cited by 89
Long-term efficacy of Internet-based cognitive behavior therapy for obsessive–compulsive disorder with or without booster: a randomized controlled trial
Andersson, E., Steneby, S., Karlsson, K., Ljótsson, B., Hedman‐Lagerlöf, E., Enander, J., Kaldo, V., Andersson, G., Lindefors, N., & Rück, C. (2014) · Psychological Medicine · doi:10.1017/s0033291714000543 · Cited by 92
“Linear mixed models have the advantage of incorporating the non-independence of intra-individual change and have been shown to be superior to traditional intention-to-treat methods for handling missing data (Mallinckrodt et al. 2001; Lane, 2008).”
Method
Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention
Bandelow, B., Wedekind, D., & León, T. (2007) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.7.7.769 · Cited by 85
Longitudinal Course of Depression Scores with and without Insomnia in Non-Depressed Individuals: A 6-Year Follow-Up Longitudinal Study in a Korean Cohort
Suh, S. A., Kim, H., Yang, H.-C., Cho, E. R., Lee, S. K., & Shin, C. (2013) · SLEEP · doi:10.5665/sleep.2452 · Cited by 85
An overview of methods for network meta-analysis using individual participant data: when do benefits arise?
Debray, T. P. A., Schuit, E., Efthimiou, O., Reitsma, J. B., Ioannidis, J. P. A., Salanti, G., Moons, K. G. M., & Workpackage, O. B. O. G. (2016) · Statistical Methods in Medical Research · doi:10.1177/0962280216660741 · Cited by 85
Sample Size Estimation for Repeated Measures Analysis in Randomized Clinical Trials with Missing Data
Lu, K., Luo, X., & Chen, P. (2008) · The International Journal of Biostatistics · doi:10.2202/1557-4679.1098 · Cited by 82
Outcome of Dialectical Behaviour Therapy for Concurrent Eating and Substance Use Disorders
Courbasson, C. M. A., Nishikawa, Y., & Dixon, L. (2011) · Clinical Psychology & Psychotherapy · doi:10.1002/cpp.748 · Cited by 82
Early response to psychological therapy as a predictor of depression and anxiety treatment outcomes: A systematic review and meta‐analysis
Beard, J. I. L., & Delgadillo, J. (2019) · Depression and Anxiety · doi:10.1002/da.22931 · Cited by 81
Profiling multiple provider prescribing of opioids, benzodiazepines, stimulants, and anorectics
Wilsey, B. L., Fishman, S. M., Gilson, A. M., Casamalhuapa, C., Baxi, H., Zhang, H., & Li, C. (2010) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2010.05.007 · Cited by 79
Mindfulness-Action Based Cognitive Behavioral Therapy for Concurrent Binge Eating Disorder and Substance Use Disorders
Courbasson, C. M. A., Nishikawa, Y., & Shapira, L. B. (2010) · Eating Disorders · doi:10.1080/10640266.2011.533603 · Cited by 79
“Even while accounting for nonrandom missing data, MMRM analyses have been demonstrated to be very precise at modeling treatment outcome (eg, Mallinckrodt, Clark, & David, 2001 ).”
Method
All-case post-marketing surveillance of 1371 patients treated with pirfenidone for idiopathic pulmonary fibrosis
Ogura, T., Azuma, A., Inoue, Y., Taniguchi, H., Chida, K., Bando, M., Niimi, Y., Kakutani, S., Suga, M., Sugiyama, Y., et al. (2015) · Respiratory Investigation · doi:10.1016/j.resinv.2015.06.001 · Cited by 76
“[15] Mallinckrodt CH, Clark WS, David SR.”
Method
Maternal Perspectives on Children’s Health-Related Quality of Life During the First Year After Pediatric Hematopoietic Stem Cell Transplant
Parsons, S. K., Shih, M., DuHamel, K. N., Ostroff, J. S., Mayer, D. K., Austin, J., Martini, D. R., Williams, S. E., Mee, L. L., Sexson, S., et al. (2005) · Journal of Pediatric Psychology · doi:10.1093/jpepsy/jsj078 · Cited by 78
Does self-report mindfulness mediate the effect of Mindfulness-based stress reduction (MBSR) on spirituality and posttraumatic growth in cancer patients?
Labelle, L. E., Lawlor-Savage, L., Campbell, T. S., Faris, P., & Carlson, L. E. (2015) · The Journal of Positive Psychology · doi:10.1080/17439760.2014.927902 · Cited by 77
Dynamics of changes in self-efficacy and locus of control expectancies in the behavioral and drug treatment of severe migraine
Seng, E. K., & Holroyd, K. A. (2010) · Annals of Behavioral Medicine · doi:10.1007/s12160-010-9223-3 · Cited by 76
“The Behavioral Migraine Management program [ 34 ] is a psychological treatment program based on Social Cognitive Theory.”
BackgroundMethodInfluential
Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2×2 clinical trial
Savitz, J. B., Preskorn, S., Teague, T. K., Drevets, D. A., Yates, W. R., & Drevets, W. (2012) · BMJ Open · doi:10.1136/bmjopen-2011-000643 · Cited by 73
Tracking of lung function from 10 to 35 years after being born extremely preterm or with extremely low birth weight
Bårdsen, T., Røksund, O. D., Benestad, M. R., Hufthammer, K. O., Clemm, H. H., Mikalsen, I. B., Øymar, K. A. A., Markestad, T., Halvorsen, T., & Vollsæter, M. (2022) · Thorax · doi:10.1136/thoraxjnl-2021-218400 · Cited by 76
Assessing the ‘true’ effect of active antidepressant therapy v. placebo in major depressive disorder: use of a mixture model
Thase, M. E., Larsen, K. G., & Kennedy, S. H. (2011) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.111.093336 · Cited by 73
Efficacy and safety of omalizumab in Japanese and Korean patients with refractory chronic spontaneous urticaria
Hide, M., Park, H., Igarashi, A., Ye, Y., Kim, T., Yagami, A., Roh, J. Y., Lee, J., Chinuki, Y., Youn, S. W., et al. (2017) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2017.03.009 · Cited by 70
“Overall AE incidence was similar across treatment groups (54.8%, 57.7%, and 55.4% in omalizumab 300 mg, 150 mg, and placebo groups, Abbreviations: AE, adverse event; ANCOVA, analysis of covariance; BMI, body mass index; BOCF, baseline-observation-carried-forward; CIU, chronic idiopathic urticaria; CSU, chronic spontan…”
MethodInfluential
On Efficiency of Constrained Longitudinal Data Analysis Versus Longitudinal Analysis of Covariance
Lu, K. (2010) · Biometrics · doi:10.1111/j.1541-0420.2009.01332.x · Cited by 69
“This is reminiscent of the MMRM (mixed-effects model repeated measures) model proposed by Mallinckrodt, Clark, and David (2001), which is particularly suitable for analyzing clinical trial data since patients in clinical trials are often evaluated at a fixed and relative small number of time points…”
Method
A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression
Fitzgerald, P. B., Hoy, K. E., Reynolds, J., Singh, A., Gunewardene, R., Slack, C., Ibrahim, S., & Daskalakis, Z. J. (2019) · Brain stimulation · doi:10.1016/j.brs.2019.09.001 · Cited by 74
Have last-observation-carried-forward analyses caused us to favour more toxic dementia therapies over less toxic alternatives? A systematic review.
Molnar, F., Man‐Son‐Hing, M., Hutton, B., & Fergusson, D. A. (2009) · PubMed · Cited by 66
An Integrated Analysis of the Efficacy of Desvenlafaxine Compared with Placebo in Patients with Major Depressive Disorder
Thase, M. E., Kornstein, S. G., Germain, J., Jiang, Q. L., Guico‐Pabia, C. J., & Ninan, P. T. (2009) · CNS Spectrums · doi:10.1017/s1092852900020125 · Cited by 65
Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia
Marx, C. E., Lee, J., Subramaniam, M., Rapisarda, A., Bautista, D., Chan, E. S., Kilts, J. D., Buchanan, R. W., Eu, P. W., Verma, S. K., et al. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3673-4 · Cited by 67

Authors: Mallinckrodt, C. H., Clark, W. S., & David, S. R.
Affiliations: Eli Lilly (United States) (US)
ORCID: Mallinckrodt, Craig H.
Venue: Journal of Biopharmaceutical Statistics
Publisher: Informa UK Limited
Published: 2001-01-01
Volume: 11
Issue: 1-2
Pages: 9-21
ISSN: 1054-3406 (ISSN-L)
1520-5711
DOI: 10.1081/bip-100104194
OpenAlex: W2073155558
Cited by: 398
References: 14
Citations by year: 2026: 12 · 2025: 13 · 2024: 21 · 2023: 12 · 2022: 27 · 2021: 19 · 2020: 20 · 2019: 13 · 2018: 14 · 2017: 14 · 2016: 18 · 2015: 21 · 2014: 16 · 2013: 23 · 2012: 19
FWCI: 11.96
Type: journal article
Language: en
Open access: closed
Locations: Journal of Biopharmaceutical Statistics (publishedVersion)
PubMed (publishedVersion)
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 › Advanced Causal Inference Techniques
Keywords: mixed models, last observation carried forward, missing data, non-ignorable missingness, treatment effect estimation, longitudinal data, randomized controlled trials, standard error estimation
MeSH terms: Analysis of Variance, Humans, Longitudinal Studies, Patient Dropouts, Models, Statistical, Bias, Confidence Intervals, Randomized Controlled Trials as Topic

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ACCOUNTING FOR DROPOUT BIAS USING MIXED-EFFECTS MODELS

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