Statistical methods used in the calculation of geriatric reference intervals: a systematic review

Background: Geriatric reference intervals (RIs) are not commonly available and are rarely used. It is difficult to select a reference population from a cohort with a high degree of morbidity. Also important are the statistical approaches used to determine health-associated reference values. It is the aim of this study to examine the statistical methods used in the calculation of geriatric RIs. Methods: A search was conducted on EMBASE and Medline for articles between January 1989 and January 2014. Studies were selected if they: 1) were English primary articles; 2) performed a clinical chemistry test on a blood fraction; 3) had a population sub-group consisting of individuals >= 65 years of age; and 4) calculated a RI for the subgroup >= 65 years of age. Results: There were 64 articles identified, of which 78.1% described the RI calculation method used. RI calculation was performed by non-parametric (21.9%), parametric (42.2%), robust (3.1%), or other (17.2%) methods. Outlier detection (SD, Grubb's test, Tukey's fence, Dixon) was infrequently used and although most studies performed partitioning, only 57.8% tested the statistical significance of the partitions. Few studies (17.2%) reported confidence intervals for the RI estimates. Overall, only 14.1% of studies provided RI estimates which followed the CLSI guideline EP28-A3c. Conclusions: Statistical methods for RI calculation and partitioning varied considerably between studies and many failed to provide adequate descriptions of these methods. Challenges in analyses arose from insufficient sample sizes and heterogeneity in the elderly population. Geriatric RIs, although present in the literature, may not be properly calculated and should be carefully considered before applying them for clinical care.