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

TY - JOUR

T1 - Comparison of results from different imputation techniques for missing data from an anti-obesity drug trial

AU - Jørgensen, Anders W.

AU - Lundstrøm, Lars H

AU - Wetterslev, Jørn

AU - Astrup, Arne

AU - Gøtzsche, Peter C.

N1 - CURIS 2014 NEXS 350

PY - 2014/11/19

Y1 - 2014/11/19

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0111964

DO - 10.1371/journal.pone.0111964

M3 - Journal article

C2 - 25409438

SN - 1932-6203

VL - 9

JO - P L o S One

JF - P L o S One

IS - 11

M1 - e111964

ER -