Modeling the selective advantage of new amino acids on the hemagglutinin of H1N1 influenza viruses using their patient age distributions.

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.