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1. Toward precision medicine using a 'digital twin' approach: modeling the onset of disease-specific brain atrophy in individuals with multiple sclerosis

Author

Steven Cen, Mulugeta Gebregziabher, Saeed Moazami, Christina J. Azevedo, and Daniel Pelletier

Subjects
Medicine, Science
Abstract

Abstract Digital Twin (DT) is a novel concept that may bring a paradigm shift for precision medicine. In this study we demonstrate a DT application for estimating the age of onset of disease-specific brain atrophy in individuals with multiple sclerosis (MS) using brain MRI. We first augmented longitudinal data from a well-fitted spline model derived from a large cross-sectional normal aging data. Then we compared different mixed spline models through both simulated and real-life data and identified the mixed spline model with the best fit. Using the appropriate covariate structure selected from 52 different candidate structures, we augmented the thalamic atrophy trajectory over the lifespan for each individual MS patient and a corresponding hypothetical twin with normal aging. Theoretically, the age at which the brain atrophy trajectory of an MS patient deviates from the trajectory of their hypothetical healthy twin can be considered as the onset of progressive brain tissue loss. With a tenfold cross validation procedure through 1000 bootstrapping samples, we found the onset age of progressive brain tissue loss was, on average, 5–6 years prior to clinical symptom onset. Our novel approach also discovered two clear patterns of patient clusters: earlier onset versus simultaneous onset of brain atrophy.

Published
2023
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2. High-dose vitamin D3 supplementation in relapsing-remitting multiple sclerosis: a randomised clinical trialResearch in context

Author

Sandra D. Cassard, Kathryn C. Fitzgerald, Peiqing Qian, Susan A. Emrich, Christina J. Azevedo, Andrew D. Goodman, Elizabeth A. Sugar, Daniel Pelletier, Emmanuelle Waubant, and Ellen M. Mowry

Subjects
Relapsing-remitting multiple sclerosis, Vitamin D supplementation, Disease activity, Medicine (General), R5-920
Abstract

Summary: Background: Vitamin D insufficiency is associated with risk of multiple sclerosis (MS) relapse; whether supplementation influences prognosis is unknown. The Vitamin D to Ameliorate MS (VIDAMS) trial aimed to determine if high dose (5000 International Units (IU)/day) versus low dose (600 IU/day) vitamin D3, added to daily glatiramer acetate (GA), reduced the risk of clinical relapse in people with established relapsing remitting MS (RRMS) over 96 weeks. Methods: VIDAMS is a randomised, phase 3, double-blind, multi-centre, controlled trial conducted at sixteen neurology clinics in the United States. Participants with MAGNIMS 2010 RRMS, aged 18–50 years, with recent disease activity were eligible to enroll if they had an Expanded Disability Status Scale score ≤4.0; minimum serum 25-hydroxyvitamin D level of 15 ng/ml within 30 days of screening; and average ≤ 1000 IU supplemental vitamin D3 daily in the 90 days prior to screening. Of 203 screened, 183 were eligible for the 30-day run-in to assess GA adherence, after which 172 were randomised 1:1 to low dose vitamin D3 (LDVD) or high dose vitamin D3 (HDVD), and were followed every 12 weeks for 96 weeks. The primary outcome was the proportion that experienced a confirmed relapse and analyses used Kaplan Meier and Cox proportional hazards models. 165 participants returned for ≥1 follow-up visit and were included in the primary and safety analyses; 140 completed a week 96 visit. This study was registered with ClinicalTrials.gov, NCT01490502. Findings: Between March 22, 2012 and March 8, 2019, 172 participants were enrolled and randomised (83 LDVD, 89 HDVD) and differed at baseline only in gender and race: more males received HDVD (31%) than LDVD (16%), and fewer Black participants received HDVD (12%) than LDVD (22%). Among 165 participants with at least one follow-up visit, the proportion experiencing confirmed relapse did not differ between LDVD and HDVD [at 96 weeks: 32% vs. 34%, p = 0.60; hazard ratio (HR): 1.17 (0.67, 2.05), p = 0.57]. There was no hypercalcaemia. Three participants developed nephrolithiasis or ureterolithiasis (1 in the LDVD and 2 in the HDVD group). Two were possibly related to study drug; and one was presumed related to concomitant treatment with topiramate for migraine. Interpretation: VIDAMS provides evidence that HDVD supplementation, added to GA, does not reduce the risk of clinical relapse in people with RRMS. Taken together with the null findings of previous trials, these results suggest that prescribing higher doses of vitamin D for purposes of modifying the RRMS course may not be beneficial. Funding: This investigation was supported by a grant from the National Multiple Sclerosis Society (RG 4407A2/1). Teva Neuroscience, Inc. provided Copaxone (GA) for the duration of the trial.

Published
2023
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4. Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome

Author

Olivier Casez, Mikael Cohen, Eric Thouvenot, Adil Maarouf, C. Bensa, Céline Callier, Jonathan Ciron, Pierre Labauge, David Laplaud, Naila Makhani, Bertrand Bourre, Abdulatif Al Khedr, Guillaume Mathey, Thibault Moreau, Sfsep Risc, Sandra Vukusic, Pierre Clavelou, Fabien Rollot, Céline Louapre, Jérôme De Seze, Eric Berger, Daniel Pelletier, A.-M. Guennoc, Aksel Siva, Christina J. Azevedo, Ayman Tourbah, Darin T. Okuda, Alain Créange, F. Durand-Dubief, Philippe Cabre, Jean-Philippe Camdessanché, Hélène Zéphir, Emmanuelle Le Page, Nathalie Derache, Orhun H. Kantarci, Jean-Philippe Neau, Patrick Vermersch, Aurélie Ruet, Lydiane Mondot, Ofsep Investigators, Christine Lebrun-Frénay, Université Côte d'Azur (UCA), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN), CHU Strasbourg, CHU Toulouse [Toulouse], Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Rouen, Normandie Université (NU), CHU de la Martinique [Fort de France], Centre Hospitalier Universitaire [Grenoble] (CHU), Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Amiens-Picardie, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Henri Mondor, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Raymond Poincaré [AP-HP], Maladies et hormones du système nerveux (DHNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Hôpital de la Timone [CHU - APHM] (TIMONE), Mayo Clinic [Jacksonville], Cerrahpasa Faculty of Medicine, Istanbul University, University of Southern California (USC), Yale University School of Medicine, University of Texas Southwestern Medical Center [Dallas], This study was funded through the Observatoire Français de la Sclérose En Plaques, which is supported by grant ANR-10-COHO-002 provided by the French State and handled by the Agence Nationale de la Recherche within the framework of the Investments for the Future program by the Eugène Devic European Database for Multiple Sclerosis Foundation against multiple sclerosis and by the Aide pour la Recherche sur la Sclérose En Plaques Foundation., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lille Neurosciences & Cognition - U 1172 (LilNCog), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Yale School of Medicine [New Haven, Connecticut] (YSM), Jonchère, Laurent, and Cohortes - Observatoire Français de la Sclérose en Plaques - - OFSEP2010 - ANR-10-COHO-0002 - COHO - VALID

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Multivariate analysis, Multiple Sclerosis, Adolescent, [SDV]Life Sciences [q-bio], 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Humans, 0101 mathematics, Original Investigation, Clinically isolated syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Radiotherapy, business.industry, Multiple sclerosis, Research, Hazard ratio, Magnetic resonance imaging, Conversion, General Medicine, Middle Aged, medicine.disease, 3. Good health, Clinical trial, [SDV] Life Sciences [q-bio], Online Only, Cross-Sectional Studies, Neurology, Sample size determination, Female, France, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cohort study
Abstract

This cohort study investigates risk factors associated with time to a multiple sclerosis clinical event among patients with radiologically isolated syndrome., Key Points Question Are there clinical or demographic factors associated with time to clinical symptoms of multiple sclerosis among patients with radiologically isolated syndrome? Findings In this cohort study of 372 individuals with radiologically isolated syndrome, young age, the presence of spinal cord lesions, and gadolinium-enhancing lesions on the index magnetic resonance imaging scan were associated with increased risk of onset of clinical symptoms of multiple sclerosis. Meaning These findings identify 3 risk factors associated with multiple sclerosis at the preclinical stage of central nervous system demyelinating disease defined by radiologically isolated syndrome., Importance Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure Diagnosis of RIS. Main Outcomes and Measures Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P

Published
2021
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5. Gender Inequities in the Multiple Sclerosis Community: A Call for Action

Author

Jacqueline A Quandt, Christina J. Azevedo, Etty Tika Benveniste, Patricia K. Coyle, Emmanuelle Waubant, Yunyan Zhang, Valerie Block, Vijay Yadav, Elisabeth Gulowsen Celius, Amy Waldman, Matilde Inglese, Jill Conway, Helen Tremlett, Olga Ciccarelli, Sandra Vukusic, Elisabeth Maillart, Christine Lebrun-Frenay, Brenda Banwell, Ellen M. Mowry, Seema K. Tiwari-Woodruff, Cornelia Laule, Jodie M Burton, Laure Michel, Afsaneh Shirani, Tanuja Chitnis, Elaine Kingwell, Myla D. Goldman, Nasrin Asgari, Rana Zabad, Carolina Ionete, Nancy L. Monson, Hanne F. Harbo, Naila Makhani, Carrie M. Hersh, Tamara Castillo-Triviño, Claire S Riley, Ingrid van der Mei, Anneke van der Walt, Annette Langer-Gould, Ruth Ann Marrie, Eva Havrdova, Lauren B. Krupp, Katherine Whartenby, Maria Pia Amato, Rhonda R. Voskuhl, Judith B. Grinspan, Vilija Jokubaitis, Monica J. Carson, Bibi Bielekova, Elizabeth Crabtree, Jiwon Oh, Le H. Hua, Julia Pakpoor, Mariko Kita, Fiona Costello, Lisa F. Barcellos, Georgina Arrambide, Margaret Burnett, Fabienne Brilot-Turville, Luanne M. Metz, Emmanuelle Leray, Ann Yeh, Maria Petracca, Prue Plummer, Robyn M. Lucas, Dalia Dimitri, Caroline Papeix, Leslie Benson, Wendy B. Macklin, Sarah A Morrow, Jennifer Graves, Soe Mar, Carolyn Bevan, Frauke Zipp, Jacqueline Palace, Ruth Dobson, Idanis Berrios Morales, Rosa Cortese, Lilyana Amezcua, Joan Goverman, Orla Gray, Mar Tintoré, Kerstin Hellwig, Katerina Akassoglou, Jennifer Orthmann Murphy, Penelope Smyth, Teri Schreiner, Nancy L. Sicotte, May H. Han, Maria Trojano, Mary Rensel, Wendy Gilmore, Laura Airas, Laura Piccio, Silvia Tenembaum, Rebecca Spain, Claudia F. Lucchinetti, Jana Lizrova Preiningerova, Maria Pia Sormani, Giulia Bommarito, Riley Bove, Ilana Katz Sand, Dina A. Jacobs, Bianca Weinstock-Guttman, Eve E Kelland, Leigh Charvet, Catherine Lubetzki, Anne H. Cross, and Erin E. Longbrake

Subjects
0301 basic medicine, medicine.medical_specialty, Multiple Sclerosis, Multiple sclerosis, Sexism, medicine.disease, Authorship, Clinical neurology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Clinical Trials, Phase III as Topic, Neurology, Action (philosophy), Female, Healthcare Disparities, Humans, Letters/Replies, Committee Membership, medicine, Neurology (clinical), Psychiatry, Psychology, 030217 neurology & neurosurgery
Published
2018

6. Primary Progressive Multiple Sclerosis Evolving from Radiologically Isolated Syndrome

Author

Orhun H, Kantarci, Christine, Lebrun, Aksel, Siva, Mark B, Keegan, Christina J, Azevedo, Matilde, Inglese, Mar, Tintoré, Braeden D, Newton, Francoise, Durand-Dubief, Maria Pia, Amato, Nicola, De Stefano, Maria Pia, Sormani, Daniel, Pelletier, and Darin T, Okuda

Subjects
Adult, Male, Adolescent, Age Factors, Child, Demyelinating Diseases, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Middle Aged, Multiple Sclerosis, Chronic Progressive, Multiple Sclerosis, Relapsing-Remitting, Sex Factors, Young Adult, Disease Progression, Neurology, Neurology (clinical), Multiple Sclerosis, Medicine (all), Relapsing-Remitting, Chronic Progressive
Abstract

The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS).A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome [CIS] or relapsing-remitting MS) and were also compared to two other population- and clinic-based PPMS cohorts.Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p 0.05). Median time to PPMS was 3.5 years (range, 1.6-5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p 0.001) when compared to CIS/MS, independent of follow-up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow-up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS.Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age-dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum.

Published
2016

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