Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232-2310, USA.
J Ultrasound Med. 2010 Jun;29(6):891-901. doi: 10.7863/jum.2010.29.6.891.
The volume of subcutaneous xenograft tumors is an important metric of disease progression and response to therapy in preclinical drug development. Noninvasive imaging technologies suitable for measuring xenograft volume are increasingly available, yet manual calipers, which are susceptible to inaccuracy and bias, are routinely used. The goal of this study was to quantify and compare the accuracy, precision, and inter-rater variability of xenograft tumor volume assessment by caliper measurements and ultrasound imaging.
Subcutaneous xenograft tumors derived from human colorectal cancer cell lines (DLD1 and SW620) were generated in athymic nude mice. Experienced independent reviewers segmented 3-dimensional ultrasound data sets and collected manual caliper measurements resulting in tumor volumes. Imaging- and caliper-derived volumes were compared with the tumor mass, the reference standard, determined after resection. Bias, precision, and inter-rater differences were estimated for each mouse among reviewers. Bootstrapping was used to estimate mean and confidence intervals of variance components, intraclass correlation coefficients (ICCs), and confidence intervals for each source of variation.
The average deviation from the true volume and inter-rater differences were significantly lower for ultrasound volumes compared with caliper volumes (P = .0005 and .001, respectively). Reviewer ICCs for ultrasound and caliper measurements were similarly low (1%), yet caliper volume variance was 1.3-fold higher than for ultrasound.
Ultrasound imaging more accurately, precisely, and reproducibly reflects xenograft tumor volume than caliper measurements. These data suggest that preclinical studies using the xenograft burden as a surrogate end point measured by ultrasound imaging require up to 30% fewer animals to reach statistical significance compared with analogous studies using caliper measurements.
在临床前药物开发中，皮下异种移植肿瘤的体积是疾病进展和治疗反应的重要指标。适合测量异种移植体积的非侵入性成像技术越来越多，但通常使用的卡尺容易出现不准确和偏差。本研究的目的是量化和比较卡尺测量和超声成像评估异种移植肿瘤体积的准确性、精密度和组内变异。
在裸鼠中生成源自人结直肠癌细胞系（DLD1 和 SW620）的皮下异种移植肿瘤。有经验的独立评审员对 3 维超声数据集进行分割，并收集手动卡尺测量的肿瘤体积。将成像和卡尺衍生的体积与切除后的肿瘤质量（参考标准）进行比较。在评审员之间估计每个小鼠的成像和卡尺测量的偏差、精密度和组内差异。使用自举法估计每个来源的变异分量、组内相关系数（ICC）和变异置信区间的平均值和置信区间。
与卡尺体积相比，超声体积的平均偏差和组内差异明显更低（分别为 P =.0005 和.001）。超声和卡尺测量的评审员 ICC 相似低（1%），但卡尺体积的方差比超声高 1.3 倍。
超声成像比卡尺测量更准确、更精确、更可重复地反映异种移植肿瘤体积。这些数据表明，使用超声成像作为替代终点测量的异种移植负担的临床前研究与使用卡尺测量的类似研究相比，需要减少多达 30%的动物数量才能达到统计学意义。
