Exploring the Utility of MRI-based ‘SuStaIn’ Disease Subtyping for Precision Medicine in Relapsing and Secondary Progressive MS (P15-4.002)
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Abstract
Objective: To explore whether subtyping with the machine learning algorithm ‘Subtype and Staging Inference’ (SuStaIn) can be used to predict responses to dimethyl fumarate (DMF) and natalizumab (NTZ).
Background: Applying SuStaIn to cross-sectional brain MRI data, 3 multiple sclerosis (MS) subtypes (lesion-, normal-appearing white matter-, and cortex-led) can be identified, and may have different rates of disability progression, relapse rate, and treatment response.
Design/Methods: SuStaIn subtype data were available from ASCEND (phase 3 study of NTZ [n=1002] in secondary-progressive MS [SPMS]) and DEFINE/CONFIRM (phase 3 studies of DMF [n = 365] in relapsing-remitting MS [RRMS]). For DEFINE/CONFIRM, comparisons were restricted to the DMF 240mg BID and placebo arms. Associations between baseline SuStaIn subtype probabilities and MS disease characteristics were tested with Spearman correlation. Treatment effect on new T2 lesion count at week 96 within subtypes was estimated by negative binomial regression, adjusting for baseline age, sex, MS duration, and baseline Gd+ count and T2 lesion volume. To determine whether treatment effect differed between subtypes, interaction terms between treatment and subtype were added.
Results: For all studies, the lesion-led subtype correlated with worse brain MRI disease severity at baseline measured by T2 lesion volume, normalized brain volume, and Gd+ lesion count (p<0.05 for all). New T2 lesion count vs placebo in all subtypes was reduced by NTZ in ASCEND SPMS patients (p<0.001) and by DMF in DEFINE/CONFIRM RRMS patients (p<0.05). No significant differences in treatment effect were observed between subtypes for NTZ in SPMS or for DMF in RRMS (p>0.05 for all).
Conclusions: The SuStaIn lesion-led subtype is associated with higher baseline brain MRI disease severity. NTZ and DMF reduced inflammatory disease activity in all SuStaIn subtypes with no significant differences in treatment response. SuStaIn MS subtyping did not discriminate responder heterogeneity as assessed by new lesion formation in these NTZ and DMF trials.
Disclosure: Dr. Gafson has nothing to disclose. Dr. Jiang has received personal compensation for serving as an employee of Biogen. Dr. Jiang has received stock or an ownership interest from Biogen. Dr. Shen has received personal compensation for serving as an employee of Biogen. Dawei Liu has received personal compensation for serving as an employee of Biogen. Dawei Liu has received stock or an ownership interest from Biogen. Mr. Perea has received stock or an ownership interest from Biogen. Mr. Perea has received personal compensation in the range of $100,000-$499,999 for serving as a Sr. Data Scientist with Biogen. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Frequency Therapeutics. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shionogi. Dr. Arnold has received stock or an ownership interest from NeuroRx. The institution of Dr. Arnold has received research support from Novartis. The institution of Dr. Arnold has received research support from Immunotec. Colm Elliott has received personal compensation for serving as an employee of NeuroRx Research. Bing Zhu has received personal compensation for serving as an employee of Biogen. Bing Zhu has received stock or an ownership interest from Biogen. Elizabeth Fisher has received personal compensation for serving as an employee of Biogen. Elizabeth Fisher has received stock or an ownership interest from Biogen. Elizabeth Fisher has received intellectual property interests from a discovery or technology relating to health care. Prof. Ciccarelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Prof. Ciccarelli 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 NEUROLOGY Journal. Declan Chard has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Declan Chard has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Declan Chard has received research support from MS Society. Declan Chard has received research support from Hoffmann-La Roche. Declan Chard has received research support from International Progressive MS Alliance. Declan Chard has received personal compensation in the range of $500-$4,999 for serving as a speaker with Novartis. Declan Chard has a non-compensated relationship as a trustee with MS Trust that is relevant to AAN interests or activities. Declan Chard has a non-compensated relationship as a editorial board member with Neurology that is relevant to AAN interests or activities. Declan Chard has a non-compensated relationship as a co-supervisor of a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, with Merck that is relevant to AAN interests or activities. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Frederik Barkhof has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Combinostics. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for IXICO. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Belachew has received personal compensation for serving as an employee of Biogen Inc. Dr. Belachew has received stock or an ownership interest from Biogen Inc.
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