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Optimal methods for analyzing targeted pairwise knockout screens

Chou, J.; Anvar, N. E.; Elghaish, R.; Chen, J.; Hart, T.

2024-08-20 systems biology
10.1101/2024.08.19.608665 bioRxiv
Show abstract

BackgroundSynthetic lethality offers a promising strategy for cancer treatment by targeting genetic vulnerabilities unique to tumor cells, leading to selective tumor cell death. However, single-gene knockout screens often miss functional redundancy due to paralog genes. Multiplex CRISPR systems, including various Cas9 and Cas12a platforms, have been developed to assay genetic interactions, yet no systematic comparison of method to identify synthetic lethality from CRISPR screens has been conducted. ResultsWe evaluated data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using three bioinformatic approaches to identify synthetic lethal interactions: delta log fold change (dLFC), Z-transformed dLFC (ZdLFC), and rescaled dLFC (RdLFC). Both ZdLFC and RdLFC provided more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method. ConclusionsThe ZdLFC method offers a robust framework for scoring synthetic lethal interactions from paralog screens, providing consistent results across different cell lines without requiring a training set of known positive interactors.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.