BACKGROUND: Because secondary progressive multiple sclerosis (SPMS) is associated with worse prognosis, early predictive tools are needed. We aimed to use systematic literature review and advanced methods to create and validate a clinical tool for estimating individual patient risk of transition to SPMS over five years. METHODS: Data from the Jacobs Multiple Sclerosis Center (JMSC) and the Multiple Sclerosis Center Amsterdam (MSCA) was collected between 1994 and 2022. Participants were relapsing-remitting adult patients at initial evaluation. We created the tool in four stages: (1) identification of candidate predictors from systematic literature review, (2) ordinal cutoff determination, (3) feature selection, (4) feature weighting. RESULTS: Patients in the development/internal-validation/external-validation datasets respectively (n = 787/n = 522/n = 877) had a median age of 44.1/42.4/36.6 and disease duration of 7.7/6.2/4.4 years. From these, 12.6 %/10.2 %/15.4 % converted to SPMS (median=4.9/5.2/5.0 years). The DAAE Score was named from included predictors: Disease duration, Age at disease onset, Age, EDSS. It ranges from 0 to 12 points, with risk groups of very-low=0-2, low=3-7, medium=8-9, and high≥10. Risk of transition to SPMS increased proportionally across these groups in development (2.7 %/7.4 %/18.8 %/40.2 %), internal-validation (2.9 %/6.8 %/26.8 %/36.5 %), and external-validation (7.5 %/9.6 %/22.4 %/37.5 %). CONCLUSION: The DAAE Score estimates individual patient risk of transition to SPMS consistently across datasets internationally using clinically-accessible data. With further validation, this tool could be used for clinical risk estimation.

Buffalo Neuroimaging Analysis Center Department of Neurology Jacobs School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo New York United States

Center for Biomedical Imaging at Clinical Translational Research Center Jacobs School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo New York United States

Department of Neurology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Neurology and Psychiatry Jacobs School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo New York United States

MS Center Amsterdam Department of Anatomy and Neurosciences Vrije Universiteit Amsterdam Amsterdam Neuroscience Amsterdam UMC location VUmc De Boelelaan 1108 Amsterdam 1081 HZ the Netherlands

MS Center Amsterdam Department of Neurology Vrije Universiteit Amsterdam Amsterdam Neuroscience Amsterdam UMC Location VUmc the Netherlands

MS Center Amsterdam Department of Radiology and Nuclear Medicine Vrije Universiteit Amsterdam Amsterdam Neuroscience Amsterdam UMC Location VUmc the Netherlands

Queen Square Institute of Neurology and Centre for Medical Image Computing University College London United Kingdom

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