Supplementary Figures and Tables.

<div><p>Machine learning-based approaches are particularly suitable for identifying essential genes as they allow the generation of predictive models trained on features from multi-source data. Gene essentiality is neither binary nor static but determined by the context. The databases for essential gene annotation do not permit the personalisation of the context, and their update can be slower than the publication of new experimental data. We propose HELP (<u>H</u>uman Gene <u>E</u>ssentiality <u>L</u>abelling & <u>P</u>rediction), a computational framework for labelling and predicting essential genes. Its double scope allows for identifying genes based on dependency or not on experimental data. The effectiveness of the labelling method was demonstrated by comparing it with other approaches in overlapping the reference sets of essential gene annotations, where HELP demonstrated the best compromise between false and true positive rates. The gene attributes, including multi-omics and network embedding features, lead to high-performance prediction of essential genes while confirming the existence of essentiality nuances.</p></div>