Talk:Mendelian Randomization

1. 1. A. MR SOP — outstanding items

1. 1. 1. Sections still missing (all cheap, all bit us on smoking→AD)

1. **Steiger directionality / reverse causation** — absent entirely. One line

  (`TwoSampleMR::directionality_test()`). Important for the disease→AD portfolio, where
  reverse causation is plausible.

2. **Sample overlap** — absent. Two-sample MR assumes independent samples; UK Biobank is in

  nearly every GWAS we use (it was in *both* our exposure and outcome). Tool: MRlap
  (needs full genome-wide sumstats + LD scores).

3. **Dataset provenance verification** — absent. We caught **two mislabelled OpenGWAS

  accessions**: `ieu-a-1001` labelled "parental lifespan" is actually Okbay EA;
  `ieu-b-5067` labelled "Wightman" is Woolf 2022 with 954 cases. Rule: verify N,
  case/control split and cohort composition via `gwasinfo()` before use; never trust the label.

1. 1. 1. MR-PRESSO / MR-Egger imbalance (raised, not yet drafted)

Observation: we report MR-PRESSO outlier-corrected far more than MR-Egger. This is

• • structural**, not accidental — Egger intercept tests are underpowered so Scenario 4 rarely

fires, while Cochran's Q is almost always significant so Scenario 2 fires constantly.

Why it matters — our own Layer 0: IVW b=−0.065 **p=0.296** → MR-PRESSO b=−0.112 **p=0.0015**. Outlier removal *manufactured* the significant result later shown to be collider-driven. It removed only 2/22 SNPs (9%), so the existing ">30% removed" tripwire never fired.

Proposed amendments (Scenario 2 currently has **no** conclusion-change tripwire): - Add a **conclusion-change tripwire** to Scenario 2: if outlier removal moves the estimate

 outside the original IVW 95% CI or flips significance → report corrected + uncorrected,
 corrected as sensitivity only. (Key on *effect on conclusion*, not SNP count.)

- Stop treating **Egger intercept p>0.05** as evidence of no directional pleiotropy — it's an

 underpowered null, the same error pattern we rejected in §4.2. Report intercept + CI.

- Elevate **weighted median** to co-primary (better power *and* robustness than Egger; currently

 only "support" in Scenario 2).

- Report the **full estimator panel with a concordance flag** — our estimates spanned

 −0.065 to −0.208 with p from 0.0015 to 0.647; single-winner adjudication hides that.