Davebrid1: Fixed formatting

2026-07-18T18:20:07Z

Fixed formatting

← Older revision		Revision as of 18:20, 18 July 2026
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			== MR SOP — outstanding items (selection/collider bias work, 2026-07-18) ==

	~~## A~~. MR SOP ~~— outstanding items~~		Context: §4 "Selection and Collider Bias" was added to the [https://bridgeslab.sph.umich.edu/protocols/index.php/Mendelian_Randomization MR SOP] after the smoking→AD project found its headline result was most plausibly a survival-collider artefact.

	~~###~~ Sections still missing ~~(all~~ cheap, all bit us on smoking→AD)		=== Sections still missing ===
	~~1. Steiger directionality / reverse causation — absent entirely. One line~~		All three are cheap, and all three bit us on smoking→AD.
	~~(`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~~.

	##~~# MR~~-~~PRESSO /~~ MR-~~Egger imbalance (raised, not yet drafted~~)		# '''Steiger directionality / reverse causation''' — absent entirely. One line (<code>TwoSampleMR::directionality_test()</code>). Important for the disease→AD portfolio, where reverse causation is plausible.
	~~Observation~~: ~~we report MR~~-~~PRESSO outlier~~-~~corrected far more than MR~~-~~Egger~~. ~~This is~~		# '''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).
	~~structural~~, ~~not accidental — Egger intercept tests are underpowered so Scenario 4 rarely~~		# '''Dataset provenance verification''' — absent. We caught '''two mislabelled OpenGWAS accessions''': <code>ieu-a-1001</code> labelled "parental lifespan" is actually Okbay EA; <code>ieu-b-5067</code> labelled "Wightman" is Woolf 2022 with 954 cases. Rule: verify N, case/control split and cohort composition via <code>gwasinfo()</code> before use; never trust the label.
	~~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.~~		=== MR-PRESSO / MR-Egger imbalance (raised, not yet drafted) ===
	~~Outlier removal manufactured the significant result later shown to be collider~~-~~driven~~. It		Observation: we report MR-PRESSO outlier-corrected far more often 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.
	~~removed only 2/22 SNPs (9%)~~, so ~~the existing ">30% removed" tripwire never fired~~.

	Proposed amendments (Scenario 2 currently has no conclusion-change tripwire):		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.
	- 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,		Proposed amendments (Scenario 2 currently has '''no''' conclusion-change tripwire):
	corrected as sensitivity only. (Key on effect on conclusion, not SNP count.)		* 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, with the corrected value as sensitivity only. Key on ''effect on the conclusion'', not SNP count.
	- Stop treating Egger intercept p>0.05 as evidence of no directional pleiotropy — it's an		* Stop treating '''Egger intercept p>0.05''' as evidence of no directional pleiotropy — it is an underpowered null, the same error pattern we rejected in §4.2. Report the intercept estimate with CI.
	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 MR-Egger; currently only "support" in Scenario 2).
	- Elevate ~~weighted median~~ to co-primary (better power and robustness than Egger; currently		* 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 spread.
	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.

Davebrid1: Added notes on what to add to MR SOP

2026-07-18T18:18:52Z

Added notes on what to add to MR SOP

New page

## A. MR SOP — outstanding items

### 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.

### 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.

Talk:Mendelian Randomization - Revision history

Davebrid1: Fixed formatting

Davebrid1: Added notes on what to add to MR SOP