Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR.
PLoS Negl Trop Dis. 2022 Feb 10;16(2):e0010116. doi: 10.1371/journal.pntd.0010116. eCollection 2022 Feb.
Japanese encephalitis (JE) virus (JEV) remains a leading cause of neurological infection across Asia. The high lethality of disease and absence of effective therapies mean that standardised animal models will be crucial in developing therapeutics. However, published mouse models are heterogeneous. We performed a systematic review, meta-analysis and meta-regression of published JEV mouse experiments to investigate the variation in model parameters, assess homogeneity and test the relationship of key variables against mortality.
METHODOLOGY/ PRINCIPAL FINDINGS: A PubMed search was performed up to August 2020. 1991 publications were identified, of which 127 met inclusion criteria, with data for 5026 individual mice across 487 experimental groups. Quality assessment was performed using a modified CAMARADES criteria and demonstrated incomplete reporting with a median quality score of 10/17. The pooled estimate of mortality in mice after JEV challenge was 64.7% (95% confidence interval 60.9 to 68.3) with substantial heterogeneity between experimental groups (I^2 70.1%, df 486). Using meta-regression to identify key moderators, a refined dataset was used to model outcome dependent on five variables: mouse age, mouse strain, virus strain, virus dose (in log10PFU) and route of inoculation. The final model reduced the heterogeneity substantially (I^2 38.9, df 265), explaining 54% of the variability.
CONCLUSION/ SIGNIFICANCE: This is the first systematic review of mouse models of JEV infection. Better adherence to CAMARADES guidelines may reduce bias and variability of reporting. In particular, sample size calculations were notably absent. We report that mouse age, mouse strain, virus strain, virus dose and route of inoculation account for much, though not all, of the variation in mortality. This dataset is available for researchers to access and use as a guideline for JEV mouse experiments.
日本脑炎病毒（JEV）仍然是亚洲各地神经感染的主要原因。疾病的高致死率和缺乏有效的治疗方法意味着标准化的动物模型对于开发疗法至关重要。然而，已发表的小鼠模型存在异质性。我们对已发表的 JEV 小鼠实验进行了系统评价、荟萃分析和荟萃回归，以研究模型参数的变化，评估同质性，并测试关键变量与死亡率的关系。
方法/主要发现：对截至 2020 年 8 月的 PubMed 进行了搜索。确定了 1991 篇出版物，其中 127 篇符合纳入标准，共有 5026 只个体小鼠分布在 487 个实验组中。使用修改后的 CAMARADES 标准进行了质量评估，结果表明报告不完整，中位数质量评分为 10/17。JEV 攻击后小鼠的死亡率汇总估计为 64.7%（95%置信区间 60.9 至 68.3），实验组之间存在很大的异质性（I^2 70.1%，df 486）。使用荟萃回归来确定关键调节变量，使用精炼数据集来模拟依赖于五个变量的结果：小鼠年龄、小鼠品系、病毒株、病毒剂量（以 log10PFU 表示）和接种途径。最终模型大大降低了异质性（I^2 38.9，df 265），解释了 54%的变异性。
结论/意义：这是对 JEV 感染小鼠模型的首次系统评价。更好地遵守 CAMARADES 指南可能会减少报告的偏差和变异性。特别是明显缺乏样本量计算。我们报告说，小鼠年龄、小鼠品系、病毒株、病毒剂量和接种途径解释了死亡率变化的大部分（尽管不是全部）。该数据集可供研究人员访问和用于 JEV 小鼠实验的指南。
