Methods comparison biases due to differing uncertainties and data censoring

Abstract

Background Measurements on clinical specimens that contain no analyte, or very low amounts of analyte, unavoidably generate assay response (signal) measurements that fall on the ‘negative’ side of the fitted zero response. It is virtually universal practice to left-censor such measurements to zero and this is frequently extended by left-censoring to the assay limit of detection (LoD) value for reporting purposes. This study considers the effect of censoring on methods comparison analysis. Methods Paired results were randomly generated from two hypothetical assays with zero bias, firstly assuming equal uncertainty near zero and secondly with uncertainties that differed by a moderate 50% near zero. In both cases results were left-censored to zero and to LoD and further subsets were extracted representing partial and complete removal of censored results. All data sets were subjected to overall bias evaluation and Bland–Altman and Deming regression analyses. Results The combination of differing uncertainties and data censoring produced spurious biases by both Bland–Altman and regression analysis, regardless of whether censored results were retained or discarded. Biases were small for data left-censored to zero but were non-trivial with LoD-censoring. Imposing a lower limit aimed at eliminating the influence of censored results did not resolve the problem. Conclusions When high proportion of clinical results are located near zero, caution is required when using censored data (and especially LoD-censored data) in methods comparison studies. Optional access to negative results would rectify the problem, but requires the cooperation of manufacturers.