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Randomized Controlled Trial
. 2014 Nov 19;9(11):e111964.
doi: 10.1371/journal.pone.0111964. eCollection 2014.

Comparison of results from different imputation techniques for missing data from an anti-obesity drug trial

Anders W Jørgensen  1 , Lars H Lundstrøm  2 , Jørn Wetterslev  2 , Arne Astrup  3 , Peter C Gøtzsche  4
Affiliations
Randomized Controlled Trial

Comparison of results from different imputation techniques for missing data from an anti-obesity drug trial

Anders W Jørgensen et al. PLoS One. .

Abstract

Background: In randomised trials of medical interventions, the most reliable analysis follows the intention-to-treat (ITT) principle. However, the ITT analysis requires that missing outcome data have to be imputed. Different imputation techniques may give different results and some may lead to bias. In anti-obesity drug trials, many data are usually missing, and the most used imputation method is last observation carried forward (LOCF). LOCF is generally considered conservative, but there are more reliable methods such as multiple imputation (MI).

Objectives: To compare four different methods of handling missing data in a 60-week placebo controlled anti-obesity drug trial on topiramate.

Methods: We compared an analysis of complete cases with datasets where missing body weight measurements had been replaced using three different imputation methods: LOCF, baseline carried forward (BOCF) and MI.

Results: 561 participants were randomised. Compared to placebo, there was a significantly greater weight loss with topiramate in all analyses: 9.5 kg (SE 1.17) in the complete case analysis (N = 86), 6.8 kg (SE 0.66) using LOCF (N = 561), 6.4 kg (SE 0.90) using MI (N = 561) and 1.5 kg (SE 0.28) using BOCF (N = 561).

Conclusions: The different imputation methods gave very different results. Contrary to widely stated claims, LOCF did not produce a conservative (i.e., lower) efficacy estimate compared to MI. Also, LOCF had a lower SE than MI.

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Conflict of interest statement

Competing Interests: This trial was supported by Johnson & Johnson Pharmaceutical Research and Development, LLP, the producer of topiramate, to conduct the clinical trial from which the data for this paper originated (see reference 10). Arne Astrup is currently consultant or member of advisory boards for a number companies, including: Arena Pharmaceuticals Inc., USA; Basic Research, USA; BioCare Copenhagen, DenmarK; Boehringer Ingelheim Pharma, Germany; Gelesis, USA; Novo Nordisk, Denmark; Pathway Genomics Corporation, USA; S-Biotek, Denmark; Twinlab, USA; Vivus Inc., USA. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Mean weight of participants attending or missing the next visit.
Some patients return after a missed visit. Therefore no change in number of patients at week 28 and 32.
Figure 2
Figure 2. Analysis of difference in weight loss between placebo and topiramate pooled (96 and 192 mg/day) from baseline to week 60 using different methods.
Figure 3
Figure 3. Analysis of weight loss over time in topiramate pooled (96 or 192 mg/day) group using different imputation methods.
Figure 4
Figure 4. Analysis of weight loss over time in the placebo group using different imputation methods.
See this image and copyright information in PMC

References

    1. Fabricatore AN, Wadden TA, Moore RH, Butryn ML, Gravallese EA, et al. (2009) Attrition from randomized controlled trials of pharmacological weight loss agents: a systematic review and analysis. Obes Rev 10: 333–341. - PMC - PubMed
    1. Elobeid MA, Padilla MA, McVie T, Thomas O, Brock DW, et al. (2009) Missing data in randomized clinical trials for weight loss: scope of the problem, state of the field, and performance of statistical methods. PLoS ONE 4: e6624. - PMC - PubMed
    1. Sterne JAC, White IR, Carlin JB, Spratt M, Royston P, et al. (2009) Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 338: b2393. - PMC - PubMed
    1. Donders ART, van der Heijden GJMG, Stijnen T, Moons KGM (2006) Review: a gentle introduction to imputation of missing values. J Clin Epidemiol 5: 1087–1091. - PubMed
    1. Methods for voluntary weight loss and control (1992) NIH Technology Assessment Conference Panel. Consensus Development Conference, 30 March to 1 April 1992. Ann Intern Med 1993 119: 764–770. - PubMed

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