Improving accuracy in genome-wide association studies: a two-step approach for handling below limit of detection biomarker measurements

Advances in high-throughput technologies enable large-scale studies on genomics and molecular phenotypes. However, the trade-off between quality and quantity reduces assay sensitivity, and several measurements in large-scale proteomics and metabolomics analytes fall below the limit of detection (LOD). If not properly addressed, this may introduce bias in effect estimates. To address this, we conducted a simulation study to evaluate the performance of linear, Tobit, Cox, and logistic modeling in the presence of below-LOD measurements in genome-wide association studies. We identified the optimal strategy as a two-step Linear-Tobit scheme, including rapid screening with linear regression followed by refinement with Tobit regression to retrieve accurate effect estimates. This higher accuracy helps mitigate a 1.3-fold and 2.7-fold inflation in causal estimates in a Mendelian randomization (MR) study, which would otherwise be present with 50% and 90% values below LOD. Validation through case studies on estradiol and testosterone levels in the UK Biobank confirmed the simulation results across subgroups with varying proportions of below-LOD measurements. The Linear-Tobit scheme offers optimal detection power and efficiency, with a focus on its applicability to biobank-scale datasets and accuracy in effect estimates to mitigate bias in downstream applications such as MR and polygenic risk scores.