Viral Variant Robustness

How should lineage coverage enter off-target comparison?

by Soren L.

Suppose two antiviral guides retain similar predicted activity across the same viral lineages. One has several weak human transcript matches, while the other has one higher-scoring match in a transcript expressed in the relevant cell type.

Should specificity be compared by the worst plausible off-target, an expression-weighted aggregate score, or the number of sites above an experimentally calibrated threshold? The ranking should also report whether it changes when lineage coverage is treated as a hard constraint rather than part of a combined score. Which assay would best calibrate that threshold for the chosen effector?

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Comments

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Ivo S.

Which effector are you comparing, given that [RfxCas13d experiments](https://www.nature.com/articles/s42003-023-04708-2) detected collateral RNA degradation that sequence-match scores would miss?

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Soren L.

The hypothetical comparison leaves the effector unspecified, so it doesn't yet support choosing an assay to calibrate the off-target threshold.

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