Indirect methods for reference interval determination – review and recommendations

Abstract

Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies.

Reference intervals established using indirect method for serum ferritin assayed on Abbott Architect i2000SR analyzer in Chinese adults

“…In the indirect method, RIs can be calculated using various statistical approaches . Of these statistical approaches, the standard parametric or non‐parametric percentile approach is usually used in the direct method for RIs as described in the CLSI EP‐A3 guidelines .…”

“…Of these statistical approaches, the standard parametric or non‐parametric percentile approach is usually used in the direct method for RIs as described in the CLSI EP‐A3 guidelines . Jones et al suggested that the standard parametric or non‐parametric statistical approach can be used in the indirect method for RIs when the data were collected at a community screening project or similar. In fact, the parametric approach has been used in the analysis of data from NHANES, and the non‐parametric approach has been used in a Chinese and a Turkish study, respectively .…”

“…24 Thus, as an alternative method, the "indirect" method via large collections of laboratory data stored in laboratory information systems (LIS) and statistical program is widely used to establish the RIs in recent years. [24][25][26][27][28][29][30] Relative to the direct method, the "indirect" method is much simpler, faster, and cheaper 25 and therefore is a convenient way for the clinical laboratory to set up their own RIs. In previous studies, however, most of which focused on the data obtained from hospital patient records and a group of "healthy" subjects was selected as the reference population from these hospital patients based on some statistical criteria, 24,[27][28][29][30] very few of which determined the RIs for analytes using the data from hospital database of health examination records.…”

“…In the “direct” method, a major problem that the laboratory faces is to obtain a sufficient number of specimens from healthy individuals representative of the reference population that the laboratory serves . Thus, as an alternative method, the “indirect” method via large collections of laboratory data stored in laboratory information systems (LIS) and statistical program is widely used to establish the RIs in recent years . Relative to the direct method, the “indirect” method is much simpler, faster, and cheaper and therefore is a convenient way for the clinical laboratory to set up their own RIs.…”

Pre‐ and postanalytical errors in haematology

“…Establishment of reference intervals by conventional means entails direct testing of specimens from a number of “healthy” individuals; in many cases, these may be preselected from a limited age range, socio‐economic status and ethnicity. More recently, indirect methods for setting reference intervals using an evaluation of patients’ data have been suggested as a better approach towards harmonisation of ranges . The use of harmonised reference intervals for key analytes such as Hb will not preclude the laboratory from producing local ranges for the purpose of validation but will be a driver for improved traceability of patients’ results to higher order reference materials and methods and potentially reduce the variability in the postanalytical phase.…”