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Cited by 59Statistical Methods in Clinical TrialsStatistical Methods and Bayesian InferenceMeta-analysis and systematic reviews

The impact of analytic method on interpretation of outcomes in longitudinal clinical trials

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Prakash, A., Risser, R. C., Mallinckrodt, C. H.·2008·International Journal of Clinical Practice
DOI 10.1111/j.1742-1241.2008.01808.xPMC PMC2658028
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Abstract

AIMS: Various analytical strategies for addressing missing data in clinical trials are utilised in reporting study results. The most commonly used analytical methods include the last observation carried forward (LOCF), observed case (OC) and the mixed model for repeated measures (MMRM). Each method requires certain assumptions regarding the characteristics of the missing data. If the assumptions for any particular method are not valid, results from that method can be biased. Results based on these different analytical methods can, therefore, be inconsistent, thereby making interpretation of clinical study results confusing. In this investigation, we compare results from MMRM, LOCF and OC in order to illustrate the potential biases and problems in interpretation. METHODS: Data from an 8-month, double-blind, randomised, placebo-controlled (placebo; n = 137), outpatient depression clinical trial comparing a serotonin-noradrenalin reuptake inhibitor (SNRI; n = 273) with a selective serotonin reuptake inhibitor (SSRI; n = 274) were used. The study visit schedule included efficacy and safety assessments weekly to week 4, bi-weekly to week 8, and then monthly. Visitwise mean changes for the 17-item Hamilton Depression Rating Scale (HAMD(17)) Maier subscale (primary efficacy outcome), blood pressure, and body weight were analysed using LOCF, MMRM and OC. RESULTS: Last observation carried forward consistently underestimated within-group mean changes in efficacy (benefit) and safety (risk) for both drugs compared with MMRM, whereas OC tended to overestimate within-group changes. CONCLUSIONS: Inferences are based on between-group comparisons. Therefore, whether or not underestimating (overestimating) within-group changes was conservative or anticonservative depended on the relative magnitude of the bias in each treatment and on whether within-group changes represented improvement or worsening. Preference should be given in analytic plans to methods whose assumptions are more likely to be valid rather than relying on a method based on the hope that its results, if biased, will be conservative.

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Crossref · 10.1111/j.1742-1241.2008.01808.x

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  • Missing Week 72 data from three participants were imputed using the last observation carried forward method.

    “Missing data at Week 72 from three participants were imputed using the last observation carried forward method.”

    From Body composition changes during weight reduction with tirzepatide in the <scp>SURMOUNT</scp> ‐1 study of adults with obesity or overweight (2025) · cites this paper as [16]

    The Methods section says the paper imputed missing data using last observation carried forward in its LOCF analyses. It does not report missing Week 72 data from three participants; the Results instead describe visits through week 8 and month 8. The method is supported, but its application to those three participants at Week 72 is not. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Prakash, A., Risser, R. C., & Mallinckrodt, C. H.
Affiliations
Eli Lilly (United States) (US)
Corresponding author
Mallinckrodt, C. H.
ORCID
Mallinckrodt, C. H.
Venue
International Journal of Clinical Practice
Publisher
Hindawi Limited
Published
2008-06-28
Volume
62
Issue
8
Pages
1147-1158
ISSN
1368-5031 (ISSN-L)
DOI
10.1111/j.1742-1241.2008.01808.x
PMC
PMC2658028
OpenAlex
W2125029005
Cited by
59
References
6
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 8 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 4
FWCI
2.53
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2621 d)
Locations
  • International Journal of Clinical Practice (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Eli Lilly and Company
Topics
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods and Bayesian Inference
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
Keywords
missing data, last observation carried forward, bias in treatment effect estimation, depression, selective serotonin reuptake inhibitors, Hamilton Depression Rating Scale, blood pressure, body weight
MeSH terms
Adolescent, Adult, Aged, Ambulatory Care, Data Collection, Data Interpretation, Statistical, Depressive Disorder, Double-Blind Method, Female, Humans, Longitudinal Studies, Male, Middle Aged, Randomized Controlled Trials as Topic, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Sample Size, Adrenergic Uptake Inhibitors

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