Polygenic prediction of treatment response for precision medicine is vulnerable to collider bias

Recent reanalyses of major lipid-lowering trials have reported substantially greater treatment benefit in individuals with higher polygenic risk scores (PRSs) for coronary artery disease (CAD).

By Tudball, Cirulli, Holmes +2Oct 20, 2026

Score█████░░░░░4.7

Caveats

Preprint; not yet peer reviewed.

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Abstract

Recent reanalyses of major lipid-lowering trials have reported substantially greater treatment benefit in individuals with higher polygenic risk scores (PRSs) for coronary artery disease (CAD). We tested whether trial eligibility criteria could generate this pattern through collider bias. In simulations where the true PRS-by-treatment interaction was set to zero, we reproduced apparent PRS-dependent treatment effects similar to those observed in reanalyses of three trials. This included FOURIER-like hazard ratios for lipid-lowering treatment versus placebo of 0.77 in the high CAD PRS stratum and 0.95 in the low CAD PRS stratum. In the Helix Research Network (n = 175,106) and UK Biobank (n = 92,859) cohorts, where we did not apply the trial eligibility criteria, the CAD PRS showed little evidence of modifying the effect of statin use on acute coronary events. We then used LDL cholesterol response as a better-powered test of collider bias: we found no evidence that LDL PRS modified statin response in population cohorts, yet stratifying on baseline LDL cholesterol induced apparent PRS-dependent response matching the simulations. Importantly, treatment randomization does not protect against eligibility-induced collider bias. PRS-dependent response may therefore reflect bias from eligibility rather than biology. These results should inform the planning and execution of clinical trials for precision medicine.

M. J. Tudball, E. T. Cirulli, M. V. Holmes, G. Davey Smith, J. B. Richards

The editor's rubric

Heuristic review

Leverage2 / 5: Reusable within one subfield (a technique, dataset, or protocol a few groups will adopt).; 10% of this desk’s rubric
Magnitude2 / 5: Solid incremental gain on a meaningful problem.; 20% of this desk’s rubric
Evidence5 / 5: Definitive: phase 3 randomized evidence on hard endpoints, multi-lab replication, or community verification at scale.; 32% of this desk’s rubric
Novelty2 / 5: A new combination of known ideas.; 8% of this desk’s rubric
Trajectory2 / 5: Some room to improve with obvious engineering.; 5% of this desk’s rubric
Stakes2 / 5: Benefits a professional community (practitioners, clinicians, engineers).; 25% of this desk’s rubric

Dimension	Level	Weight	What that level means
Leverage	██░░░ 2	10%	Reusable within one subfield (a technique, dataset, or protocol a few groups will adopt).
Magnitude	██░░░ 2	20%	Solid incremental gain on a meaningful problem.
Evidence	█████ 5	32%	Definitive: phase 3 randomized evidence on hard endpoints, multi-lab replication, or community verification at scale.
Novelty	██░░░ 2	8%	A new combination of known ideas.
Trajectory	██░░░ 2	5%	Some room to improve with obvious engineering.
Stakes	██░░░ 2	25%	Benefits a professional community (practitioners, clinicians, engineers).

Editor’s rationale

Heuristic triage from title and abstract text only, not a reading of the paper. Cues found: novelty (alternative to status quo); design (randomized, placebo-controlled); verification (independent replication); stakes (prevention or cure).

How the score was computed

rank-2026-10-18

Score█████░░░░░4.7

Score = 10 × (80% × adjusted merit / 10 + 10% × attention + 10% × freshness)

Desks place stronger verdicts first, then use this score to order work within the same verdict.

Merit: 5.9 / 10; Weighted rubric, evidence-gated.
Adjusted merit: 4.8 / 10; Shrunk toward the desk prior by editor confidence (40%).
Attention: 0%; Citations, upvotes, points, mentions.
Freshness: 92%; Half-life decay since publication.

Citations0 (reference 20, via semantic-scholar, Oct 21, 2026, 06:17 UTC)

The record

Reviewed by heuristic-v7 on Oct 21, 2026, 06:17 UTC. Paper type: clinical.
Categories: genetic and genomic medicine
BRIEF, No.6 in the Medicine edition of October 21, 2026.