Ahrens Richard C, Standaert Thomas A, Launspach Janice, Han Seung-Ho, Teresi Mary E, Aitken Moira L, Kelley Thomas J, Hilliard Kathleen A, Milgram Laura J H, Konstan Michael W, Weatherly Mark R, McCarty Nael A
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242-1083, USA.
Pediatr Pulmonol. 2002 Feb;33(2):142-50. doi: 10.1002/ppul.10043.
One of the goals of current research in cystic fibrosis (CF) is to develop treatments that correct or compensate for defects in function of the cystic fibrosis transmembrane regulator (CFTR) gene. The use of outcome measures that assess CFTR function such as nasal potential difference (NPD) measurements and sweat chloride determinations will be required to evaluate the efficacy of such treatments in multicenter clinical trials. The purpose of this work was to identify the sources and magnitude of variability in NPD and sweat chloride measurements when performed at multiple centers. For the variance component analysis presented here, we used NPD and sweat chloride measurements from 37 subjects with CF participating in a phase I, four-center clinical trial of CPX (8-cyclopentyl-1,3-dipropylxanthine), a drug intended to enhance trafficking of Delta F508 CFTR to the cell membrane. The specific techniques used to measure these outcomes were not standardized, and varied between the four sites. Variability of both NPD measurements (baseline potential difference during infusion with Ringer's solution; change in response to addition of 0.1 mM amiloride; and subsequent change in response to perfusion with low chloride solution containing 0.1 mM amiloride and 0.01 mM isoproterenol) and sweat chloride measurements differed significantly between study sites. For change in NPD, one study site had significantly greater variability (lower reproducibility) of measurement than the other three sites. For sweat chloride measurements, reproducibility was lower at two of the sites relative to the other two sites. Sample size calculations showed that lower reproducibility at one or more sites can substantially reduce the power of studies using NPD or sweat chloride determinations as outcome measures. Standardization of measurement protocols, careful operator training and certification, and ongoing monitoring of individual operator performance may help to improve reliability in multicenter trials.
囊性纤维化（CF）当前研究的目标之一是开发能够纠正或弥补囊性纤维化跨膜传导调节因子（CFTR）基因功能缺陷的治疗方法。在多中心临床试验中评估此类治疗方法的疗效时，需要使用评估CFTR功能的结果指标，如鼻电位差（NPD）测量和汗液氯化物测定。这项工作的目的是确定在多个中心进行NPD和汗液氯化物测量时变异性的来源和程度。对于此处呈现的方差成分分析，我们使用了37名CF患者的NPD和汗液氯化物测量数据，这些患者参与了CPX（8-环戊基-1,3-二丙基黄嘌呤）的I期四中心临床试验，CPX是一种旨在增强Delta F508 CFTR向细胞膜转运的药物。用于测量这些结果的具体技术并未标准化，且在四个研究地点之间存在差异。研究地点之间，NPD测量值（输注林格氏液期间的基线电位差；添加0.1 mM氨氯吡咪后的反应变化；以及随后灌注含0.1 mM氨氯吡咪和0.01 mM异丙肾上腺素的低氯溶液后的反应变化）和汗液氯化物测量值的变异性均存在显著差异。对于NPD的变化，一个研究地点的测量变异性（再现性较低）显著大于其他三个地点。对于汗液氯化物测量，相对于其他两个地点，其中两个地点的再现性较低。样本量计算表明，一个或多个地点较低的再现性会大幅降低将NPD或汗液氯化物测定作为结果指标的研究效能。测量方案的标准化、对操作人员的仔细培训与认证以及对个体操作人员表现的持续监测，可能有助于提高多中心试验的可靠性。
