not sure I get the second point. Sure there is variability and we need to do better in people of non Euro ancestry, but common genetic variants and their association with disease are precisely measured now and becoming more so.
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I'll clarify that I'm not against adding PRS to risk models, despite the variability. Quite the opposite. And I don't think the variability is a statistical problem (I agree with @mikeinouye.bsky.social).
(But it's certainly a serious clinical/practical problem.) 1/3
Re. your question, let me try to refine the argument. For LDLC, there is an actual number of molecules in the sample. We can (hypothetically) count them and always reach the same answer. A genetic risk is a statistical construct, which depends on assumptions. 2/3
For example, it depends on the definition of the disease, and on which ages, environments, and sub-populations were used to estimate the risk. We have to make decisions on what we're estimating, even when sample sizes are very large. 3/3
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(But it's certainly a serious clinical/practical problem.) 1/3