Selection Bias in Hazard Ratios: Evidence from a Large Precision Oncology Trial

Music City Center 

Hazard ratios (HRs) are key effect measures in observational studies and randomized-controlled trials (RCTs). While randomization balances treatment groups at baseline, HRs lack causal interpretation due to selection bias from conditioning on survivors. A recent study of 27 large RCTs found selection bias in HRs to have little practical impact. We examined selection bias in HRs in a precision oncology RCT of olaparib (treatment) vs. control for metastatic castration-resistant prostate cancer (n=387). Homologous recombination repair (HRR) gene status strongly predicted treatment effect, with HRs of 0.36 (95% CI 0.27-0.5) in HRR-positive, and 0.88 (95%CI 0.58-1.34) in HRR-negative. In the overall trial, we observed preferential selection of HRR-positive patients in the treatment arm, which increased to 79% in the treatment arm and 68% in the control arm (both 63% at randomization) over six months. This selection led to minor differences between unweighted and inverse-probability weighted HRs. We started seeing differences between weighted and unweighted HRs by four months, when the risk sets in two treatment arms became more imbalanced. Even with strong effect modification, marginal HRs can appear stable unless selection severely distorts the risk sets at event times.

Hazard ratios

Selection bias

Randomized-controlled trial 

Section on Statistics in Epidemiology