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Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer
Ting-Yi Lin1, Seyedamirhosein Motamedi1, Susanna Asseyer1
1From the Charité - Universitätsmedizin Berlin (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.); Experimental and Clinical Research Center (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.), a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.); Neuroscience Clinical Research Center (S.M., S.A., C.C., J.B.-S., T.S.-H., H.G.Z., F.P.); Department of Psychiatry and Psychotherapy (C.C.), Charité - Universitätsmedizin Berlin, Germany; Department of Neurology (S. Saidha, P.A.C., K.C.F.); Department of Epidemiology (K.C.F.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Regional Health Research and Molecular Medicine (S. Samadzadeh), University of Southern Denmark, Odense; Department of Neurology (S. Samadzadeh), Slagelse Hospital, Denmark; Department of Neurology (P. Villoslada), Hospital Del Mar - Pompeu Fabra University; Neuroimmunology and Multiple Sclerosis Unit (S.L.), Hospital Clinic Barcelona and IDIBAPS, Barcelona, Spain; Department of Neurology (A.J.G.), University of California San Francisco; Department of Neurology (J.L.P.), Charles University in Prague, Czech Republic; Moorfield's Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square Institute of Neurology, University College London, United Kingdom; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, Netherlands; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute; Vita-Salute San Raffaele University (L.L.), Milan, Italy; Miguel Servet University Hospital (E.G.-M.), Zaragoza; Department of Neurology (C.O.-G.), Hospital Clínico Universitario San Carlos, Madrid, Spain; Department of Neurology (O.O., P. Vermersch); Department of Neuroradiology (O.O., P. Vermersch), Centre Hospitalier Universitaire de Lille, France; Departments of Neurology (L.J.B., R.K.), Population Health and Ophthalmology, NYU Grossman School of Medicine, NY; Department of Neurology (P.A., O.A.), Heinrich-Heine-University, Düsseldorf, Germany; Departments of Clinical Neurosciences and Surgery Cumming School of Medicine (F.C.), University of Calgary, Alberta, Canada; Clinic of Optic Neuritis and Clinic of Multiple Sclerosis (J.F.), Department of Neurology, Rigshospitalet - Glostrup, Denmark; Department of Neurosciences (A.U., M.C.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy; Laboratory of Neuroimmunology (E.M.F., T.C.F.), Professor Lawrence Steinman, Stanford University School of Medicine, Palo Alto, CA; Department of Neurology (K.R., F.P.), Charité - Universitätsmedizin Berlin; and Einstein Center Digital Future (H.G.Z.), Berlin, Germany.
Background And Objectives:
Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS).
Methods:
We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests.
Results:
In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score).
Discussion:
In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.
