Sarkar MK, Fritsma GA, Chapter 3, Quality Assurance in Hematology Testing; Keohane EM, Butina MM, Mirza KM, Walenga JM. Rodak’s Hematology: Clinical Principles and Applications Edition 7 states the following:
“Indirect RIs may be derived from stored patient data. The QC specialist mines the laboratory database to compute the mean and confidence interval. Indirect RI computation removes the need to identify, collect, assay, aliquot, and store representative specimens, while providing for a much larger sample size. The indirect RI may more closely represent facility demographics and permits for partition by age, sex, or physical condition. To eliminate presumed abnormal data points, the QC specialist applies robust statistical tests to exclude outliers and sequester disease-related results in the final computation.”
This information is based on this open-access article: Jones GRD, Haeckel R, Loh TP, et al; IFCC Committee on Reference Intervals and Decision Limits. Indirect methods for reference interval determination–review and recommendations. Clin Chem Lab Med. 2018;57:20–29. doi: 10.1515/cclm-2018-0073. PMID: 29672266.
Please comment if you’ve used the indirect RI method in your facility. Was it easy to implement, and is it working well?
Thanks for sharing the article, George. Advances in AI and laboratory information management systems (LIMS) are expected to significantly influence many practices in clinical laboratories. Indirect reference interval (RI) determination, compared to direct methods, is certainly more cost-effective and faster—especially when supported by a competent team of statisticians, data analysts, and clinicians.
I didn’t have much success accessing some of the links provided at the end of the article. That said, it’s likely we will soon see commercial software packages developed by companies active in the LIMS field to facilitate this approach.
However, the delicate details highlighted in the article—such as differences between commercial assays, lot-to-lot variability, and stability of assay performance over time—must be carefully considered. Indirect RI determination cannot be applied in many situations, such as when introducing new assays into the laboratory or when products undergo significant changes. For these reasons, indirect RI determination should be seen as a complementary tool rather than the primary technique.
In coagulation, I see potential for applying indirect RI methods to routine assays like PT and aPTT, but not for more esoteric tests. This is mainly because screening the general population with specialty assays is not recommended. As a result, the adoption of indirect RI methods for specialty testing is unlikely to become standard practice. Until then, direct RI determination will remain essential for specialty assays.
Hi all, we have evaluated this method, and it is useful to validate or amend an existing reference interval; however, the process needs loads of data points, and kind of implies that the testing is already in process and at least an existing reference interval is already in place to enable the reporting of that testing. But it does provide a reasonable approach to validate an existing reference interval, or tweaking it if the reference interval does not quite look right. Also, there are potential traps if not used correctly. For example, as a hemophilia treatment center, we do loads of FVIII testing, and since we test loads of hemophilia patients, quite a lot of our results are abnormal, and thus will lead to generation of an inaccurate reference interval if included. Due to the continuum of FVIII values (for example) no clear outlier data may be evident. Existing data sets can also be used to verify factor level cut-offs for routine assays such as for the aPTT. For example, check out our recent papers to see the distribution of FVIIIs seen in our lab, and some of the cleaning we would need to do for the latter utility. A different ‘cleaning’ approach would be needed to generate accurate reference intervals, including exclusion of data from hereditary and acquired hemophilia patients. At the other end would be high FVIII levels due to acute phase elevations in sick patients. Most of our inpatients are ‘sick’ patients. Refs: a) Favaloro EJ, Curnow J, Pasalic L. Laboratory assessment of factor VIII inhibitors: when is it required? A perspective informed by local practice. J Clin Med. 2024;14:13. doi: 10.3390/jcm14010013. PMID: 39797095; b) 568. Do L, Favaloro EJ, Pasalic L. An analysis of the sensitivity of the activated pPartial thromboplastin time (APTT) assay, as used in a llarge laboratory network, to coagulation factor deficiencies. Am J Clin Pathol. 2022;158:132-141. doi: 10.1093/ajcp/aqac013. PMID: 35150232; c) 459.Favaloro EJ, Kershaw G, Mohammed S, Lippi G. How to optimize activated partial thromboplastin time (APTT) testing: solutions to establishing and verifying normal reference intervals and assessing APTT reagents for sensitivity to heparin, lupus anticoagulant, and clotting Factors. Semin Thromb Hemost. 2019;45:22-35. doi: 10.1055/s-0038-1677018. PMID: 30630206