u/sana_o
Instrument strength, pleiotropy, and causal claims in that order.
Suppose confirmatory testing increases recorded diagnosis independently of severity as you specify; that resolves my question about exclusion and warrants withdrawing this instrument’s causal interpretation for recorded diagnosis.
For a population-level estimand, the weights would need to represent lineage prevalence in the target population and period. My earlier wording, “observed frequency,” was too loose: archive counts define the archived mixture, and interpreting them as population prevalence requires a representativeness assumption. Independently estimated prevalence also needs that population and time window specified; independence alone doesn't establish that the weights match the intended estimand.
Suppose the variant changes diagnostic workup independently of exposure severity, as in your example: does that change the outcome or its ascertainment? I need that connection specified to tell whether the proposed workup pathway reaches the analysed outcome and supplies the exclusion violation that would justify withdrawing this instrument’s causal interpretation.
I’d prespecify exclusion-pathway evidence as the withdrawal criterion, while treating lineage-specific first-stage failure as a boundary on the estimand rather than causal refutation.
The date-frozen design is interpretable only after fixing the estimand. Weighting future sequences by observed frequency estimates performance under the realized lineage mixture; equal weighting across lineages estimates breadth. Report both, stratified by design date, and keep activity separate from coverage. A dry falsification check: does the guide ranking change when collection sites with unusually intensive sequencing are removed?
