Development of an objective gene expression panel as an alternative to self-reported symptom scores in human influenza challenge trials.
Development of an objective gene expression panel as an alternative to self-reported symptom scores in human influenza challenge trials.
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DOI：
10.1186/s12967-017-1235-3
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发表时间：
2017-06-08
影响因子：
7.4
通讯作者：
Gilbert SC
中科院分区：
文献类型：
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作者：
Muller J;Parizotto E;Antrobus R;Francis J;Bunce C;Stranks A;Nichols M;McClain M;Hill AVS;Ramasamy A;Gilbert SC
流感挑战试验对于疫苗效力测试很重要。目前，疾病的严重程度是通过自我报告的症状列表得分来确定的，这可能是高度主观的。一种更客观的措施将允许改进数据分析。21名志愿者参加了一项流感挑战试验。我们计算了16种流感症状的每日总分(DSS)。在基线和挑战后24、48、72和96小时采集全血，在Illumina HT12v4芯片上进行分析。选择与DSS最相关的基因表达变化来训练随机森林模型，并在两个独立的测试集上进行测试，该测试集由41个在不同微阵列平台上描述的个体和33名志愿者组成，通过qRT-PCR进行分析。1456个探针与DSS显著相关，错误发现率为1%。我们选择了19个折叠变化最大的基因来训练一个随机森林模型。我们在第一个测试集中观察到预测分数和实际分数之间有很好的一致性(r=0.57；RMSE=−16.1%)，在挑战后大约72小时收集的样本上取得了最大的一致性。因此，我们在第二次测试中对基线和攻击后72小时收集的样本进行了定量RT-PCR法检测，观察到了良好的一致性(r=0.81；RMSE=−=36.1%)。我们开发了一个19个基因的qRT-PCR小组来预测DSS，并在两个独立的数据集上进行了验证。基于转录组学的专家小组可以在未来的流感挑战研究中提供更客观的症状评分标准。试验注册样本来自于2013年12月5日首次注册的ClinicalTrials.gov的临床试验。本文的在线版本(DOI：10.1186/s12967-017-1235-3)包含补充材料，授权用户可以使用。
Influenza challenge trials are important for vaccine efficacy testing. Currently, disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. A more objective measure would allow for improved data analysis. Twenty-one volunteers participated in an influenza challenge trial. We calculated the daily sum of scores (DSS) for a list of 16 influenza symptoms. Whole blood collected at baseline and 24, 48, 72 and 96 h post challenge was profiled on Illumina HT12v4 microarrays. Changes in gene expression most strongly correlated with DSS were selected to train a Random Forest model and tested on two independent test sets consisting of 41 individuals profiled on a different microarray platform and 33 volunteers assayed by qRT-PCR. 1456 probes are significantly associated with DSS at 1% false discovery rate. We selected 19 genes with the largest fold change to train a random forest model. We observed good concordance between predicted and actual scores in the first test set (r = 0.57; RMSE = −16.1%) with the greatest agreement achieved on samples collected approximately 72 h post challenge. Therefore, we assayed samples collected at baseline and 72 h post challenge in the second test set by qRT-PCR and observed good concordance (r = 0.81; RMSE = −36.1%). We developed a 19-gene qRT-PCR panel to predict DSS, validated on two independent datasets. A transcriptomics based panel could provide a more objective measure of symptom scoring in future influenza challenge studies. Trial registration Samples were obtained from a clinical trial with the ClinicalTrials.gov Identifier: NCT02014870, first registered on December 5, 2013 The online version of this article (doi:10.1186/s12967-017-1235-3) contains supplementary material, which is available to authorized users.