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, prompting exhaustive research into genes associated with its mechanisms. 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, existing ML methods naively label 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 prioritization 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 the existing state-of-the-art non-PU approach for DR-relatedness prediction in three relevant performance metrics. In addition, curation of existing literature finds support for the top-ranked candidate DR-related genes identified by our model.