CONFIRM · CELL STATE
03Which cells and developmental states cross a dosage threshold?
Broad tissue expression does not show which human cell identities or maturation states become functionally limited by a particular allele, nor the residual dosage at which a phenotype emerges.
POPULATION / COMPARATOR
Who or what should be compared?
The same allele-control pairs across prespecified cell identities and maturation states, with independent differentiations, multiple clones, blinded quality checks, and cell-composition measurement.
STUDY DESIGN
How could the question be tested?
Compare the same allele and isogenic correction across prioritized progenitor, excitatory-neuron, inhibitory-neuron, astrocyte, and evidence-directed extra-neural states. Use matched differentiation quality, cell composition, maturation, dosage, and repeated functional assays rather than a generic brain-versus-body comparison.
EVIDENCE GATE
What would support the proposed link?
a genotype-by-cell-state or genotype-by-maturation interaction survives correction for differentiation quality and cell composition, replicates in independent clones or donors, and shows directional attenuation after correction or rescue.
STOP RULE
What would weaken it?
the apparent state effect is explained by unequal differentiation, viability, cell composition, batch, or maturation, or fails to reproduce in the same prespecified state.