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Updated: Jun 24, 2026
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Agreement Between Published Reference Resources for Neurofilament Light Chain Levels in People With Multiple
Elias S Sotirchos1, Chen Hu2, Matthew D Smith2
1From the Johns Hopkins University School of Medicine (E.S.S., C.H., M.D.S., H.-N.L., A.L.D., E.M.M., P.A.C., K.C.F.), Baltimore, MD; Department of Neurology-Neuroimmunology (G.A., X.M.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Spain; Center of Clinical Neuroscience (K.A., T.Z.), Department of Neurology, University Clinic Carl-Gustav Carus, TU Dresden, Germany; Department of Neurology (R.T.N.), Washington University in St. Louis, MO; Lou Ruvo Center for Brain Health (C.M.H.), Cleveland Clinic, Las Vegas, NV; Department of Neurology (M.H.), University of Rochester Medical Center, NY; Department of Neurology (L.B.K.), New York University, New York City; OhioHealth Multiple Sclerosis Center (J.A.N.), Riverside Methodist Hospital, Columbus; and Mellen Center (R.A.B.), Neurological Institute, Cleveland Clinic, OH. ess@jhmi.edu fitzgerald@jhmi.edu.
Objectives:
To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS).
Methods:
Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources.
Results:
NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89.
Discussion:
Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes.
