Positive-Unlabelled Learning for identifying new candidate Dietary Restriction-related genes among Ageing-related genes

Dietary Restriction (DR) is one of the most popular anti-ageing interventions; recently, Machine Learning (ML) has been explored to identify potential DR-related genes among ageing-related genes, aiming to minimize costly wet lab experiments needed to expand our knowledge on DR. However, to train a model from positive (DR-related) and negative (non-DR-related) examples, the existing ML approach naively labels genes without known DR relation as negative examples, assuming that lack of DR-related annotation for a gene represents evidence of absence of DR-relatedness, rather than absence of evidence. This hinders the reliability of the negative examples (non-DR-related genes) and the method's ability to identify novel DR-related genes. This work introduces a novel gene prioritisation method based on the two-step Positive-Unlabelled (PU) Learning paradigm: using a similarity-based, KNN-inspired approach, our method first selects reliable negative examples among the genes without known DR associations. Then, these reliable negatives and all known positives are used to train a classifier that effectively differentiates DR-related and non-DR-related genes, which is finally employed to generate a more reliable ranking of promising genes for novel DR-relatedness. Our method significantly outperforms (p<0.05) the existing state-of-the-art approach in three predictive accuracy metrics with up to 40% lower computational cost in the best case, and we identify 4 new promising DR-related genes (PRKAB1, PRKAB2, IRS2, PRKAG1), all with evidence from the existing literature supporting their potential DR-related role.