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BMC Med Res Methodol. 2012; 12: 35.
Published online Mar 24, 2012. doi:  10.1186/1471-2288-12-35
PMCID: PMC3323461
Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: the randomized controlled trial of balloon kyphoplasty versus non-surgical care for vertebral compression fracture (FREE)
Jonas Ranstam,corresponding author1 Aleksandra Turkiewicz,1 Steven Boonen,2 Jan Van Meirhaeghe,3 Leonard Bastian,4 and Douglas Wardlaw5
1RC Syd, Skåne University Hospital in Lund, and Department of Clinical Sciences, Lund University, SE-22185 Lund, Sweden
2Leuven University Centre for Metabolic Bone Diseases and Division of Geriatric Medicine, Leuven, Belgium
3Algemeen Ziekenhuis St-Jan Brugge-Oostende AV, Brugge, Belgium
4Klinikum Leverkusen, Leverkusen, Germany
5Orthopaedic Department, Woodend Hospital, NHS Grampian, Aberdeen, UK
corresponding authorCorresponding author.
Jonas Ranstam: jonas.ranstam/at/med.lu.se; Aleksandra Turkiewicz: at/at/rcsyd.se; Steven Boonen: steven.boonen/at/uz.kuleuven.be; Jan Van Meirhaeghe: jan.van.meirhaeghe/at/skynet.be; Leonard Bastian: leonard.bastian/at/klinikum-lev.de; Douglas Wardlaw: d.wardlaw/at/nhs.net
Received February 21, 2011; Accepted March 24, 2012.
Abstract
Background
Clinical trial participants may be temporarily absent or withdraw from trials, leading to missing data. In intention-to-treat (ITT) analyses, several approaches are used for handling the missing information - complete case (CC) analysis, mixed-effects model (MM) analysis, last observation carried forward (LOCF) and multiple imputation (MI). This report discusses the consequences of applying the CC, LOCF and MI for the ITT analysis of published data (analysed using the MM method) from the Fracture Reduction Evaluation (FREE) trial.
Methods
The FREE trial was a randomised, non-blinded study comparing balloon kyphoplasty with non-surgical care for the treatment of patients with acute painful vertebral fractures. Patients were randomised to treatment (1:1 ratio), and stratified for gender, fracture aetiology, use of bisphosphonates and use of systemic steroids at the time of enrolment. Six outcome measures - Short-form 36 physical component summary (SF-36 PCS) scale, EuroQol 5-Dimension Questionnaire (EQ-5D), Roland-Morris Disability (RMD) score, back pain, number of days with restricted activity in last 2 weeks, and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC, LOCF, MM and MI analyses.
Results
There were no missing data in baseline covariates values, and only a few missing baseline values in outcome variables. The overall missing-response level increased during follow-up (1 month: 14.5%; 24 months: 28%), corresponding to a mean of 19% missing data during the entire period. Overall patterns of missing response across time were similar for each treatment group. Almost half of all randomised patients were not available for a CC analysis, a maximum of 4% were not included in the LOCF analysis, and all randomised patients were included in the MM and MI analyses. Improved estimates of treatment effect were observed with LOCF, MM and MI compared with CC; only MM provided improved estimates across all six outcomes considered.
Conclusions
The FREE trial results are robust as the alternative methods used for substituting missing data produced similar results. The MM method showed the highest statistical precision suggesting it is the most appropriate method to use for analysing the FREE trial data.
Trial Registration
This trial is registered with ClinicalTrials.gov (number NCT00211211).
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