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Published on: February 6, 2015
The effectiveness of chemoprevention agents is underestimated when lesion sizes are rounded
Thomas H Taylor1, William B Armstrong, Frank L Meyskens
1Genetic Epidemiology Research Institute, University of California-Irvine, 92697-7550, USA. thtaylor@uci.edu
Abstract:
Change in the area of premalignant lesions is an end point in estimating the efficacy of chemopreventive agents. When examiners round measurements of lesion length and width, they introduce variability, which perturbs the relative percent change in lesion area and, consequently, the percent of subjects showing a clinical response. We use simulations to illustrate the resulting bias when the agent under test is effective in reducing lesion area. We simulated 500 oral leukoplakia lesions per run, with 2,500 runs at each of five levels of agent effectiveness, namely, true relative percent reduction in area of 25%, 45%, 50%, 55%, and 75%. Realistic values of lesion lengths and widths were generated randomly and then rounded to the nearest multiple of five. The product is the distribution of mean relative percent change in lesion area and the corresponding percent of subjects showing a clinical response. Even the fifth percentile of the distribution of mean relative percent change in lesion area consistently underestimated the true value, by about 6 percentage points. The percent showing a clinical response was underestimated by 50%, 37%, and 11% for true values of reduction in lesion area of 50%, 55%, and 75%, respectively. This could easily double the required sample size for a modest phase II study. We suggest that it is cost-effective to train observers of lesion length and width to eschew rounding of measurements in the chemoprevention setting.
Insights
Rounding lesion measurements significantly biases chemoprevention studies. This rounding underestimates lesion area reduction and clinical response rates, potentially doubling required sample sizes for oral leukoplakia research.
Area of Science:
- Oncology
- Biostatistics
- Clinical Trial Design
Background:
- Estimating chemopreventive agent efficacy relies on changes in premalignant lesion area.
- Measurement variability, specifically rounding of lesion dimensions, can distort efficacy assessments.
- This distortion impacts the relative percent change in lesion area and clinical response rates.
Purpose of the Study:
- To simulate and quantify the bias introduced by rounding lesion measurements in chemoprevention studies.
- To assess the impact of this bias on estimating the efficacy of chemopreventive agents for oral leukoplakia.
- To provide recommendations for improving measurement accuracy in clinical trials.
Main Methods:
- Simulated 500 oral leukoplakia lesions per run across 2,500 runs.
- Applied five levels of true relative percent reduction in lesion area (25% to 75%).
- Generated realistic lesion dimensions, rounded them to the nearest multiple of five, and analyzed the resulting bias.
Main Results:
- Rounding consistently underestimated the mean relative percent change in lesion area by approximately 6 percentage points.
- Clinical response rates were underestimated by 50%, 37%, and 11% for true area reductions of 50%, 55%, and 75%, respectively.
- The observed bias could potentially double the sample size needed for Phase II studies.
Conclusions:
- Rounding lesion measurements introduces significant bias in chemoprevention efficacy studies.
- Accurate measurement is crucial to avoid underestimation of treatment effects and inflated sample size requirements.
- Training observers to avoid rounding measurements is a cost-effective strategy to improve data integrity.
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