School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada.
PLoS One. 2011;6(6):e20582. doi: 10.1371/journal.pone.0020582. Epub 2011 Jun 8.
There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?
目前，在使用 G93A 转基因鼠（ALS 的一种模型）进行的营养干预研究中，全世界的研究实验室尚未就终点标准达成共识。本研究分析了 4 项营养干预研究的数据，这些研究共涉及 162 只 G93A 转基因鼠，旨在确定以下终点标准之间是否存在差异：CS 4（双侧后肢功能瘫痪）、CS 4+（CS 4 外加最早的体重减轻、身体状况恶化或翻正反射消失的年龄）和 CS 5（CS 4 外加翻正反射>20 s）。记录小鼠达到终点的年龄（d；平均值±标准差）作为测量单位。小鼠达到 CS 4 的时间为 123.9±10.3 d，达到 CS 4+的时间为 126.6±9.8 d，达到 CS 5 的时间为 127.6±9.8 d，所有这些时间均显著不同（P<0.001）。CS 4 与 CS 5（r=0.95，P<0.001）、CS 4 与 CS 4+（r=0.96，P<0.001）以及 CS 4+与 CS 5（r=0.98，P<0.001）之间存在显著的正相关关系，Bland-Altman 图显示所有终点之间的偏差可接受。对数秩检验显示，与 CS 4+（P=0.046）和 CS 5（P=0.006）相比，CS 4 分别使小鼠提前 24%和 34%达到终点。与 CS 5 相比，采用 CS 4 作为终点可使小鼠平均提前 4 天（P<0.001）免受进一步的神经肌肉功能障碍和生活质量下降的影响。相反，CS 5 提供了关于本体感觉和严重运动神经元死亡的信息，这两者都可能是评估特定治疗效果的重要参数。从伦理和发现的角度来看，如果采用 CS 4 作为终点，是否会影响对 ALS 动物模型中干预效果的深入了解？
