Abstract Details

Title Integrating Clinical, Genetic, and MRI Biomarkers to Predict Disability Progression in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P5 - Poster Session 5 (11:45 AM-12:45 PM)

Poster/Presentation
Number 19-001

Objective To evaluate the value of clinical, genetic and brain MRI features in predicting time to Expanded Disability Status Scale (EDSS) score ≥6.0 in multiple sclerosis (MS).

Background Reliable predictors of disability progression are crucial to identify high-risk patients and enable personalized treatment. While clinical, MRI, and genetic features may individually predict prognosis, their combined predictive value in real-world cohorts is unclear.

Design/Methods We retrospectively collected demographic, clinical, genetic and 3T brain MRI data from 440 MS patients. Four demographic/clinical factors (sex, age, disease duration, exposure to moderate-efficacy [ME] and high-efficacy [HE]-disease-modifying therapies [DMTs]) and 10 MRI variables (white matter [WM] lesion volume [LV], global/regional volumes, microstructural damage) were pre-specified. Polygenic risk score (PRS) for MS severity (International MS Genetics Consortium) and Leukocyte Telomere Length (UK Biobank) were computed using clumping+thresholding across seven p-value thresholds (<5*10^-6, <5*10^-5, <5*10^-4, <5*10^-3, <0.05, <0.1, <0.2), generating 49 integrated models. Predictors of time to EDSS≥6.0 were identified using lasso-penalized Cox models. Performance was evaluated with the c-index.

Results The cohort (61% females; median age=40.43 years [IQR=32.15;47.92] years; median disease duration=8.38 years [IQR=2.54;15.85]; median EDSS=2.0 [IQR=1.5;4.0]; 78% relapsing-remitting, 22% progressive) was followed for a median of 7.79 years [IQR=4.47;12.30]. Ninety-three patients (21.1%) reached EDSS≥6.0. The best-performing model (c-index=0.795) identified older age (β=0.320), lower exposure to ME-DMTs (β=-0.639) and HE-DMTs (β=-0.356), higher MS severity p<0.2-PRS (β=0.073), higher <5*10^-5-PRS Leukocyte Telomere Length (β=0.114), higher brain WM LV (β=0.140), lower normalized brain volume (β=-0.361), lower normalized gray matter volume (β=-0.061), lower normal-appearing gray matter fractional anisotropy (β=-0.075), and higher mean diffusivity in normal-appearing WM (β=0.119) and WM lesions (β=0.067), as predictors of faster progression.

Conclusions Combining demographic, clinical, genetic, and MRI features provides robust prognostic models of MS disability progression. Multimodal integration may inform individualized monitoring and treatment strategies to delay disability. Validation in independent cohorts will support validity of the top model(s).

Authors/Disclosures
Paolo Preziosa (Ospedale San Raffaele) PRESENTER	Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck.
Massimo Filippi, MD, FAAN (Ospedale San Raffaele, Neuroimaging Research Unit)	Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA. Dr. Filippi has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.
Ferdinando Clarelli	Dr. Clarelli has nothing to disclose.
Melissa Sorosina	Melissa Sorosina has received research support from Italian Multiple Sclerosis Foundation. Melissa Sorosina has received research support from Italian Ministry of Health.
Elisabetta Mascia	Elisabetta Mascia has nothing to disclose.
Antonino Giordano (San Raffaele Scientific Institute)	Mr. Giordano has nothing to disclose.
Rosetta Pedotti (Stanford University Med Center)	Rosetta Pedotti has received personal compensation for serving as an employee of Roche. Rosetta Pedotti has received stock or an ownership interest from Roche.
Catarina Raposo, PhD (F. Hoffmann-La Roche)	Dr. Raposo has received personal compensation for serving as an employee of F. Hoffman-La Roche. Dr. Raposo has received stock or an ownership interest from F.Hoffman-La Roche.
Jens Wuerfel, MD (Hoffmann-LaRoche)	Dr. Wuerfel has received personal compensation for serving as an employee of MIAC AG. The institution of Dr. Wuerfel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Actelion. The institution of Dr. Wuerfel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. The institution of Dr. Wuerfel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche.
Stefano Magon	Stefano Magon has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd.. Stefano Magon has stock in F. Hoffmann-La Roche Ltd..
Martina Rubin, MD (San Raffaele Hospital)	Dr. Rubin has nothing to disclose.
Elisabetta Pagani	Elisabetta Pagani has nothing to disclose.
Paola Valsasina	Paola Valsasina has nothing to disclose.
Paola M. Rancoita, PhD	Prof. Rancoita has nothing to disclose.
Federica Esposito	Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Merck. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Federica Esposito has received research support from Italian MS Society. The institution of Federica Esposito has received research support from Italian Ministry of Health. The institution of Federica Esposito has received research support from ERA Net. The institution of Federica Esposito has received research support from European Commission. Federica Esposito has received intellectual property interests from a discovery or technology relating to health care.
Maria A. Rocca (Neuroimaging Research Unit)	Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. The institution of Maria Assunta Rocca has received research support from MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.

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