The authors asked whether trial eligibility criteria can manufacture apparent polygenic score by treatment interactions. They simulated trials with no true interaction. They also analysed statin use, not randomised, in Helix Research Network (n = 175,106) and UK Biobank (n = 92,859). Simulated treatment hazard ratios were 0.77 in the high CAD PRS stratum and 0.95 in the low. In the cohorts, the CAD PRS barely modified statin effects on acute coronary events. An LDL PRS did not modify LDL cholesterol response, but stratifying on baseline LDL induced apparent modification.
Why it is interesting: Reanalyses of lipid-lowering trials are being used to argue for polygenic targeting of statins. This work shows entry criteria alone can produce that pattern, and randomisation does not remove it.
Abstract — the authors' own words, CC BY
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.
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