How should lineage coverage enter off-target comparison?
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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