Direct, age- and gender-specific reference intervals: applying a modified M-estimator of the Yeo-Johnson transformation to clinical real-world data

Objectives Reference intervals for the general clinical practice are expected to cover non-pathological values, but also reflect the underlying biological variation present in age- and gender-specific patient populations. Reference intervals can be inferred from routine patient data measured in high capacity using parametric approaches. Stratified reference distributions are obtained which may be transformed to normality via e.g. a Yeo-Johnson transformation. The estimation of the optimal transformation parameter for Yeo-Johnson through maximum likelihood can be highly influenced by the presence of outlying observations, resulting in biased reference interval estimates. Methods To reduce the influence of outlying observations on parametric reference interval estimation, a reweighted M-estimator approach for the Yeo-Johnson (YJ) transformation was utilised to achieve central normality in stratified reference populations for a variety of laboratory test results. The reweighted M-estimator for the YJ transformation offers a robust parametric approach to infer relevant reference intervals. Results The proposed method showcases robustness up to 15 % of outliers present in routine patient data, highlighting the applicability of the reweighted M-estimator in laboratory medicine. Furthermore, reference intervals are personalised based on the patients’ age and gender for a variety of analytes from routine patient data collected in a tertiary hospital, robustly reducing the dimensionality of the data for more data-driven approaches. Conclusions The method shows the advantages for estimating reference intervals directly and parametrically from routine patient data in order to provide expected reference ranges. This approach to locally inferred reference intervals allows a more nuanced comparison of patients’ test results.