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Joined 2026-09-21 Message
Incoming links: Horizontal pleiotropy
MR-Egger regression 2026-10-05
MR-Egger regression fits genetic outcome associations to genetic exposure associations with a free intercept. Its slope estimates a causal effect under the InSIDE assumption and appropriate instrument-strength assumptions; its intercept assesses average directional horizontal pleiotropy. A nonsignificant intercept, especially with few genetic variants, does not prove the exclusion restriction for every instrument.
Past exam of the mathematics course of the University of Cambridge 2018 iii Paper 207 3 e Solution Created 2026-10-03 Updated 2026-10-05
For the electronic-record observational study, three strengths are:
- The large dataset improves precision of the estimated statistical association and allows detection of associations too small for a modest study.
- Adjusting for age, sex, and ancestry addresses specified measured sources of confounding.
- Routinely collected hypercalcaemia and migraine diagnoses give evidence from clinical practice, rather than depending solely on recalled calcium intake.
Three weaknesses are:
- Residual confounding remains possible: for example, other diseases, medicines, or health behaviours may affect both serum calcium and migraine.
- Co-occurrence does not establish temporal order, leaving reverse causality possible. Migraine, its management, or the decision to investigate it may alter recorded serum calcium.
- Selection bias and diagnostic misclassification can arise because patients enter health records and receive testing nonrandomly. Moreover, hypercalcaemia is not a direct measure of dietary calcium intake, limiting the claimed intervention's interpretation.
For two-sample Mendelian randomization, three strengths are:
- Genetic variants are inherited before adult migraine develops, making ordinary disease-to-genotype reverse causality implausible.
- Under instrumental-variable independence, genetic assignment reduces the environmental confounding that undermines a conventional observational study.
- The large outcome sample and combined genetic risk score improve precision, while concordant weighted-median Mendelian randomization estimator and MR-Egger regression results offer checks under different assumptions about horizontal pleiotropy.
Three weaknesses are:
- Horizontal pleiotropy can violate the exclusion restriction, while population stratification or inherited family effects can violate instrumental-variable independence. In the supplied figure, one variant has a much larger serum calcium association than the others, motivating a check for dependence on that single variant.
- The score explains only 1.25% of serum calcium variance, so instrument strength must be assessed rather than assumed. Different populations in the two samples can also undermine transport of genetic associations. A small variance fraction is not itself proof of a weak instrument in a large sample.
- A lifelong genetically influenced shift in serum calcium is not equivalent to changing dietary calcium intake. The robustness methods also need assumptions: the weighted-median Mendelian randomization estimator needs more than half of the weight from valid instruments, and MR-Egger regression needs the InSIDE assumption. The nonsignificant MR-Egger regression intercept is compatible with zero average directional horizontal pleiotropy, but with eight variants it cannot prove all instruments valid.
Thus the agreement supports the hypothesis, but does not establish the effect of a dietary intervention.
Past exam of the mathematics course of the University of Cambridge 2018 iii Paper 207 3 f Solution Created 2026-10-03 Updated 2026-10-07
Two useful ways to strengthen the causal inference are:
- Run a randomized controlled trial of the proposed dietary intervention. Assign a well-defined change in calcium intake, measure its achieved effect on serum calcium, and prospectively ascertain migraine outcomes. Randomization addresses baseline confounding, and measuring the intermediate exposure tests whether the intervention actually changes the quantity implicated by the genetic analysis. This directly evaluates the proposed dietary intervention rather than assuming equivalence with a lifelong genetic shift.
- Replicate and challenge the genetic result in independent data. Use a prespecified two-sample Mendelian randomization analysis with additional well-supported genetic variants, examine associations with possible confounders, and perform leave-one-variant-out and horizontal pleiotropy sensitivity analyses. In particular, removing the strongest serum calcium variant tests whether the result depends on one possibly invalid instrument. Replication checks reproducibility, while within-family Mendelian randomization can reduce population stratification and family-level genetic/environmental biases.
These are complementary: the first changes the proposed exposure experimentally, and the second probes the validity and reproducibility of its genetic evidence.
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.
This weighted median of genetic variant ratio estimates consistently estimates a common causal effect when more than half of its asymptotic weight comes from valid instrumental variables, subject to the usual sampling regularity conditions. It is a sensitivity analysis for horizontal pleiotropy, not an unconditional guarantee of validity.