Background: There is great interest in understanding the viral genomic predictors of phenotypic traits that allow influenza A viruses to adapt to or become more virulent in different hosts. Machine learning techniques have demonstrated promise in addressing this critical need for other pathogens because the underlying algorithms are especially well equipped to uncover complex patterns in large datasets and produce generalizable predictions for new data. As the body of research where these techniques are applied for influenza A virus phenotype prediction continues to grow, it is useful to consider the strengths and weaknesses of these approaches to understand what has prevented these models from seeing widespread use by surveillance laboratories and to identify gaps that are underexplored with this technology.

Methods and results: We present a systematic review of English literature published to date of studies employing machine learning methods to generate predictions of influenza A virus phenotypes from genomic or proteomic input. Forty nine studies were included in this review, spanning the topics of host discrimination, human adaptability, subtype and clade assignment, pandemic lineage assignment, characteristics of infection, and antiviral drug resistance.

Conclusions: Our findings suggest that biases in model design and a dearth of wet laboratory follow-up may explain why these models often go underused. We, therefore, offer guidance to overcome these limitations, aid in improving predictive models of previously studied influenza A virus phenotypes, and extend those models to unexplored phenotypes in the ultimate pursuit of tools to enable the characterization of virus isolates across surveillance laboratories.