Deriving reference limits from historical data - A comparison of four novel methods

Tomasz Szymon Szczepanski; Petter Moe Omland; Øystein Dunker; Trond Sand; Martijn Tannemaat; Robert Reijntjes; Anis Yazidi; Kerstin Bach; John Anker Zwart; Joe Jabre; Kristian Bernhard Nilsen

doi:10.1016/j.clinph.2025.2111451

Deriving reference limits from historical data - A comparison of four novel methods

Clin Neurophysiol. 2025 Nov 20:182:2111451. doi: 10.1016/j.clinph.2025.2111451. Online ahead of print.

Authors

Affiliations

¹ Section for Clinical Neurophysiology, Department of Neurology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: tomszc@ous-hf.no.
² Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim, Norway; Department of Radiology and Nuclear Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; NorHEAD - Norwegian Centre for Headache Research , NTNU, Trondheim, Norway.
³ Section for Clinical Neurophysiology, Department of Neurology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Research and Innovation, Division of Neuroscience, Oslo University Hospital, Oslo, Norway.
⁴ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim, Norway.
⁵ Leiden University Medical Center, Netherlands.
⁶ OsloMet, Oslo, Norway.
⁷ Department of Computer Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁸ Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Research and Innovation, Division of Neuroscience, Oslo University Hospital, Oslo, Norway.
⁹ Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA.
¹⁰ Section for Clinical Neurophysiology, Department of Neurology, Oslo University Hospital, Oslo, Norway.

PMID: 41317512
DOI: 10.1016/j.clinph.2025.2111451

Abstract

Objective: To compare four novel methods - extrapolated norms (E-norms), extrapolated reference values (E-Ref), multivariable extrapolated reference values (MeRef) and mixture model clustering (MMC) - for obtaining reference limits for nerve conduction studies (NCS) from historical data containing both normal and abnormal studies.

Methods: Reference limits for 29 commonly clinically used NCS measurements were calculated from a historical database containing measurements from 24618 patients using E-norms, E-ref, MeRef and MMC. The resulting reference limits were compared to reference limits for NCS calculated from 680 healthy subjects using Youden's J statistics.

Results: Except for distal latencies, E-norms produced reference limits with the highest Youden's J statistics with higher sensitivity, but lower specificity. E-Ref, MeRef and MMC produced reference limits with high specificity, but lower sensitivity than E-norms.

Conclusions: There are substantial differences in the performance of E-norms, E-Ref, MeRef and MMC. A dynamic approach, where the methods used are changed based on the type of NCS measurement and the amount of historical data available, may yield the highest accuracy.

Significance: When combining the different novel methods, it is possible to create clinically useful reference limits using historical data.

Keywords: Clinical neurophysiology; Extrapolated norms; Mixture model clustering; Multivariable extrapolated reference values; Nerve conduction studies; Reference limits.