Wockner Leesa F, Hoffmann Isabell, O'Rourke Peter, McCarthy James S, Marquart Louise
QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Institute of Medical Biostatistics, Epidemiology and Informatics, Medical Center of Johannes Gutenberg University, 55101, Mainz, Germany.
Malar J. 2017 Aug 25;16(1):352. doi: 10.1186/s12936-017-1999-1.
The efficacy of vaccines aimed at inhibiting the growth of malaria parasites in the blood can be assessed by comparing the growth rate of parasitaemia in the blood of subjects treated with a test vaccine compared to controls. In studies using induced blood stage malaria (IBSM), a type of controlled human malaria infection, parasite growth rate has been measured using models with the intercept on the y-axis fixed to the inoculum size. A set of statistical models was evaluated to determine an optimal methodology to estimate parasite growth rate in IBSM studies.
Parasite growth rates were estimated using data from 40 subjects published in three IBSM studies. Data was fitted using 12 statistical models: log-linear, sine-wave with the period either fixed to 48 h or not fixed; these models were fitted with the intercept either fixed to the inoculum size or not fixed. All models were fitted by individual, and overall by study using a mixed effects model with a random effect for the individual.
Log-linear models and sine-wave models, with the period fixed or not fixed, resulted in similar parasite growth rate estimates (within 0.05 log parasites per mL/day). Average parasite growth rate estimates for models fitted by individual with the intercept fixed to the inoculum size were substantially lower by an average of 0.17 log parasites per mL/day (range 0.06-0.24) compared with non-fixed intercept models. Variability of parasite growth rate estimates across the three studies analysed was substantially higher (3.5 times) for fixed-intercept models compared with non-fixed intercept models. The same tendency was observed in models fitted overall by study. Modelling data by individual or overall by study had minimal effect on parasite growth estimates.
The analyses presented in this report confirm that fixing the intercept to the inoculum size influences parasite growth estimates. The most appropriate statistical model to estimate the growth rate of blood-stage parasites in IBSM studies appears to be a log-linear model fitted by individual and with the intercept estimated in the log-linear regression. Future studies should use this model to estimate parasite growth rates.
通过比较接受试验疫苗治疗的受试者与对照组受试者血液中疟原虫血症的生长速率，可以评估旨在抑制血液中疟原虫生长的疫苗的疗效。在使用诱导性血液期疟疾（IBSM，一种受控人类疟疾感染类型）的研究中，已使用y轴截距固定为接种量的模型来测量寄生虫生长速率。评估了一组统计模型，以确定在IBSM研究中估计寄生虫生长速率的最佳方法。
使用三项IBSM研究中发表的40名受试者的数据估计寄生虫生长速率。数据用12种统计模型进行拟合：对数线性模型、周期固定为48小时或不固定的正弦波模型；这些模型的截距固定为接种量或不固定。所有模型均按个体进行拟合，并通过使用具有个体随机效应的混合效应模型按研究进行总体拟合。
对数线性模型和周期固定或不固定的正弦波模型得出的寄生虫生长速率估计值相似（相差在0.05 log寄生虫/mL/天以内）。与截距不固定的模型相比，截距固定为接种量的个体拟合模型的平均寄生虫生长速率估计值显著降低，平均低0.17 log寄生虫/mL/天（范围为0.06 - 0.24）。与截距不固定的模型相比，固定截距模型在分析的三项研究中寄生虫生长速率估计值的变异性显著更高（3.5倍）。在按研究进行总体拟合的模型中也观察到相同趋势。按个体或按研究进行总体建模对寄生虫生长估计的影响最小。
本报告中的分析证实，将截距固定为接种量会影响寄生虫生长估计。在IBSM研究中估计血液期寄生虫生长速率的最合适统计模型似乎是按个体拟合且在对数线性回归中估计截距的对数线性模型。未来的研究应使用该模型来估计寄生虫生长速率。
