Past exam of the mathematics course of the University of Cambridge 2021 iii Paper 207 2 c Solution 2026-09-28
The core instrumental variable assumptions are:
- Instrument relevance: the genetic variant changes educational attainment.
- Instrumental-variable independence: it is independent of unmeasured common causes of education and myopia, after any justified ancestry adjustment.
- The exclusion restriction: it affects myopia only through education, with no horizontal pleiotropy.
For a local average effect one additionally uses instrumental-variable monotonicity. Because the valid instrument supplies variation in education independent of the confounders and has no direct route to the outcome, the instrument-outcome association can be attributed to the education changed by the instrument without measuring every confounder.
Past exam of the mathematics course of the University of Cambridge 2022 iii Paper 207 1 1 3 Solution 2026-09-28
The plots test the plausibility of the instrumental-variable independence and exclusion restriction assumptions. Both candidate instruments are strongly associated with 25(OH)D, supporting instrument relevance. The focused instrument has estimates near zero for the other measured traits. The polygenic instrument is strongly associated with LDL cholesterol and triglycerides, suggesting horizontal pleiotropy: it may influence mortality through lipid pathways that do not pass through vitamin D.
I would therefore prefer the focused instrument. Its use of fewer biologically understood variants may reduce precision, but its cleaner associations make the causal assumptions more credible.
Past exam of the mathematics course of the University of Cambridge 2022 iii Paper 207 1 1 6 Solution 2026-09-28
One check is to use measured risk factors as negative control outcomes. A valid instrument should not predict traits that cannot plausibly be downstream consequences of vitamin D; persistent associations would expose horizontal pleiotropy or population structure.
A second check is to repeat the analysis with separate biologically motivated variants or gene-region scores and compare their ratio estimates. Agreement across instruments with distinct biological pathways supports the common vitamin-D mechanism, whereas excess between-instrument heterogeneity suggests direct effects. The same data can also support sensitivity analyses that adjust for measured pleiotropic pathways.