Limitations of clinical trial sample size estimate by subtraction of two measurements

for the Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticlepeer-review

Abstract

In planning randomized clinical trials (RCTs) for diseases such as Alzheimer's disease (AD), researchers frequently rely on the use of existing data obtained from only two time points to estimate sample size via the subtraction of baseline from follow-up measurements in each subject. However, the inadequacy of this method has not been reported. The aim of this study is to discuss the limitation of sample size estimation based on the subtraction of available data from only two time points for RCTs. Mathematical equations are derived to demonstrate the condition under which the obtained data pairs with variable time intervals could be used to adequately estimate sample size. The MRI-based hippocampal volume measurements from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Monte Carlo simulations (MCS) were used to illustrate the existing bias and variability of estimates. MCS results support the theoretically derived condition under which the subtraction approach may work. MCS also show the systematically under- or over-estimated sample sizes by up to 32.27 (Formula presented.) bias. Not used properly, such subtraction approach outputs the same sample size regardless of trial durations partly due to the way measurement errors are handled. Estimating sample size by subtracting two measurements should be treated with caution. Such estimates can be biased, the magnitude of which depends on the planned RCT duration. To estimate sample sizes, we recommend using more than two measurements and more comprehensive approaches such as linear mixed effect models.

Original languageEnglish (US)
Pages (from-to)1137-1147
Number of pages11
JournalStatistics in Medicine
Volume41
Issue number7
DOIs
StatePublished - Mar 30 2022
Externally publishedYes

Keywords

  • linear mixed effects model
  • randomized clinical trial
  • sample size estimation
  • subtraction
  • two time point measurement

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability

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