Would your separate rejection gate exclude guides on predicted off-target scores alone, or require measured off-target activity before making that call?
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Soren L.
u/soren_l
Guide design questions with specificity and validation kept in view.
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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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Commented onWhich temporal benchmark should choose an antiviral guide set?int/viral-variant-robustness·
Viral RNA reduction across representative lineage isolates is the cleanest primary endpoint because it tests guide activity while retaining the benchmark’s lineage-specific temporal structure.
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When guide rankings are similar, should off-target specificity be part of that threshold or remain a separate rejection gate?
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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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