Genetic Epidemiology Research Institute, University of California-Irvine, 92697-7550, USA.
Cancer Prev Res (Phila). 2010 Feb;3(2):136-9. doi: 10.1158/1940-6207.CAPR-09-0114. Epub 2010 Jan 19.
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.
病变前区域的变化是评估化学预防剂疗效的一个终点。当检查者测量病变长度和宽度时，他们引入了可变性，这会干扰病变面积的相对百分比变化，从而影响表现出临床反应的受试者的百分比。当受试药物有效减少病变面积时，我们使用模拟来说明由此产生的偏差。我们模拟了每次运行 500 个口腔白斑病变，每个药物有效水平有 2500 次运行，药物有效水平分别为面积的真实相对减少 25%、45%、50%、55%和 75%。病变长度和宽度的真实值是随机生成的，然后舍入到最接近的 5 的倍数。结果是病变面积的平均相对百分比变化的分布以及表现出临床反应的受试者的相应百分比。即使是病变面积平均相对百分比变化分布的第五个百分位数也始终低估了真实值，大约低了 6 个百分点。对于病变面积减少的真实值分别为 50%、55%和 75%，表现出临床反应的百分比分别低估了 50%、37%和 11%。这可能会使适度的 II 期研究所需的样本量增加一倍。我们建议，在化学预防环境中，培训病变长度和宽度的观察者避免舍入测量值是具有成本效益的。
