In 2009, a new strain of H1N1 influenza A virus caused a pandemic, and its descendant strains are causing seasonal epidemics worldwide. Given the high mutation rate of influenza viruses, variant strains having different amino acids on hemagglutinin (HA) continuously emerge. To prepare vaccine strains for the next influenza seasons, it is an urgent task to predict which variants will be selected in the viral population. An analysis of 24,681 pairs of an amino acid sequence of HA of H1N1pdm2009 viruses and its patient age showed that the empirical fixation probability of new amino acids on HA significantly differed depending on their frequencies in the population, patient age distributions, and epitope flags. The selective advantage of a variant strain having a new amino acid was modeled by linear combinations of patients age distributions and epitope flags, and then the fixation probability of the new amino acid was modeled using Kimura’s formula for advantageous selection. The parameters of models were estimated from the sequence data and models were tested with four-fold cross validations. The frequency of new amino acids alone can achieve high sensitivity, specificity, and precision in predicting the fixation of a new amino acid of which frequency is more than 0.11. The estimated parameter suggested that viruses with a new amino acid having a frequency in the population higher than 0.11 have a significantly higher selective advantage compared to viruses with the old amino acid at the same position. The model considering the Z-value of patient age rank-sums of new amino acids predicted amino acid substitutions on HA with a sensitivity of 0.78, specificity of 0.86, and precision of 0.83, showing significant improvement compared to the constant selective advantage model, which used only the frequency of the amino acid. These results suggested that H1N1 viruses tend to be selected in the adult population, and frequency of viruses having new amino acids and their patient ages are useful to predict amino acid substitutions on HA.

中文翻译：

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使用患者年龄分布模拟新氨基酸对 H1N1 流感病毒血凝素的选择优势

2009年，一种新的甲型H1N1流感病毒株引起了大流行，其后代株正在全球范围内引起季节性流行。鉴于流感病毒的高突变率，血凝素（HA）上具有不同氨基酸的变异株不断出现。为了为下一个流感季节准备疫苗株，预测病毒群体中将选择哪些变体是一项紧迫的任务。对 H1N1pdm2009 病毒的 24,681 对 HA 氨基酸序列及其患者年龄的分析表明，新氨基酸在 HA 上的经验固定概率显着不同，具体取决于它们在人群中的频率、患者年龄分布和表位标志。具有新氨基酸的变异株的选择优势通过患者年龄分布和表位标志的线性组合建模，然后使用木村公式建模新氨基酸的固定概率以进行有利选择。从序列数据估计模型的参数，并用四重交叉验证对模型进行测试。单独使用新氨基酸的频率可以达到较高的灵敏度、特异性和精确度来预测频率大于 0.11 的新氨基酸的固定。估计的参数表明，与具有相同位置的旧氨基酸的病毒相比，具有新氨基酸在群体中频率高于 0.11 的病毒具有显着更高的选择优势。考虑新氨基酸的患者年龄秩和的 Z 值的模型预测 HA 上的氨基酸取代，灵敏度为 0.78，特异性为 0.86，精度为 0.83，与恒定选择性优势模型相比显示出显着改善，后者仅使用氨基酸的频率。这些结果表明，H1N1 病毒倾向于在成年人群中被选择，具有新氨基酸的病毒的频率及其患者年龄有助于预测 HA 上的氨基酸取代。