Rule-based meta-analysis reveals the major role of PB2 in influencing influenza A virus virulence in mice

Abstract

BackgroundInfluenza A virus (IAV) poses threats to human health and life. Many individual studies have been carried out in mice to uncover the viral factors responsible for the virulence of IAV infections. Nonetheless, a single study may not provide enough confident about virulence factors, hence combining several studies for a meta-analysis is desired to provide better views. For this, we documented more than 500 records of IAV infections in mice, whose viral proteins could be retrieved and the mouse lethal dose 50 or alternatively, weight loss and/or survival data, was/were available for virulence classification.ResultsIAV virulence models were learned from various datasets containing aligned IAV proteins and the corresponding two virulence classes (avirulent and virulent) or three virulence classes (low, intermediate and high virulence). Three proven rule-based learning approaches, i.e., OneR, JRip and PART, and additionally random forest were used for modelling. PART models achieved the best performance, with moderate average model accuracies ranged from 65.0 to 84.4% and from 54.0 to 66.6% for the two-class and three-class problems, respectively. PART models were comparable to or even better than random forest models and should be preferred based on the Occam’s razor principle. Interestingly, the average accuracy of the models was improved when host information was taken into account. For model interpretation, we observed that although many sites in HA were highly correlated with virulence, PART models based on sites in PB2 could compete against and were often better than PART models based on sites in HA. Moreover, PART had a high preference to include sites in PB2 when models were learned from datasets containing the concatenated alignments of all IAV proteins. Several sites with a known contribution to virulence were found as the top protein sites, and site pairs that may synergistically influence virulence were also uncovered.ConclusionModelling IAV virulence is a challenging problem. Rule-based models generated using viral proteins are useful for its advantage in interpretation, but only achieve moderate performance. Development of more advanced approaches that learn models from features extracted from both viral and host proteins shall be considered for future works.

VirPreNet: A weighted ensemble convolutional neural network for the virulence prediction of influenza A virus using all 8 segments

“…The 5-fold cross validation is applied in the training process while the testing set is used for validation on all approaches. We implement three rule-based methods for virulence prediction that are the same in (Ivan and Kwoh, 2019). For traditional machine learning methods, the parameters for these models are set by default.…”

“…Otherwise, it is regarded as virulent. Besides, if the virulence level of infection cannot be determined from the upper or lower bound of MLD50, we follow RULE 1 to 6 in (Ivan and Kwoh, 2019) to classify the remaining samples.…”

“…The datasets contain sequence data and virulence information of influenza A virus infections. We collect virulence information from previous publications and experiments (Ivan and Kwoh, 2019). The MLD 50 information is recorded in each infection with specific influenza A virus strain and mouse strain.…”

“…Three types of baselines are leveraged for influenza virulence prediction comparison. The first baseline directly applies three rule-based methods (Ivan and Kwoh, 2019) to detect the virulence of influenza A viruses. The second baseline is to use traditional machine learning approaches including logistic regression (LR), random forest (RF), neural network (NN) and K-nearest neighbor (KNN) for the predictive tasks.…”

“…Zheng et al showed a novel network-based for identifying the virulence factors in the proteomes based on the protein-protein interaction networks (Zheng et al, 2012). Moreover, Ivan et al developed a small benchmark dataset for the influenza A virus and explored rule-based approaches for classifying the virulent strains (Ivan and Kwoh, 2019). Of these approaches, it has demonstrated the feasibility of utilizing computational methods in exploring viral virulence.…”