The utility of wearable devices in assessing ambulatory impairments of people with multiple sclerosis in free-living conditions

Ambulatory impairments; Machine learning; Multiple sclerosisDeficiencias ambulatorias; Aprendizaje automático; Esclerosis múltipleDeficiències ambulatòries; Aprenentatge automàtic; Esclerosi múltipleAbstract Background and objectives Multiple sclerosis (MS) is a progressive inflammatory and neurodegenerative disease of the central nervous system affecting over 2.5 million people globally. In-clinic six-minute walk test (6MWT) is a widely used objective measure to evaluate the progression of MS. Yet, it has limitations such as the need for a clinical visit and a proper walkway. The widespread use of wearable devices capable of depicting patients’ activity profiles has the potential to assess the level of MS-induced disability in free-living conditions. Methods In this work, we extracted 96 features in different temporal granularities (from minute-level to day-level) from wearable data and explored their utility in estimating 6MWT scores in a European (Italy, Spain, and Denmark) MS cohort of 337 participants over an average of 10 months’ duration. We combined these features with participants’ demographics using three regression models including elastic net, gradient boosted trees and random forest. In addition, we quantified the individual feature's contribution using feature importance in these regression models, linear mixed-effects models, generalized estimating equations, and correlation-based feature selection (CFS). Results The results showed promising estimation performance with R2 of 0.30, which was derived using random forest after CFS. This model was able to distinguish the participants with low disability from those with high disability. Furthermore, we observed that the minute-level (≤ 8 minutes) step count, particularly those capturing the upper end of the step count distribution, had a stronger association with 6MWT. The use of a walking aid was indicative of ambulatory function measured through 6MWT. Conclusions This study demonstrates the utility of wearables devices in assessing ambulatory impairments in people with MS in free-living conditions and provides a basis for future investigation into the clinical relevance.The RADAR-CNS project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115902. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA, www.imi.europa.eu. This paper reflects the views of the RADAR-CNS consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. The funding body have not been involved in the design of the study, the collection or analysis of data, or the interpretation of data. RJBD is supported by the following: (1) NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; (2) Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust; (3) The BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No. 116074. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA; it is chaired by DE Grobbee and SD Anker, partnering with 20 academic and industry partners and ESC; (4) the National Institute for Health Research University College London Hospitals Biomedical Research Centre; (5) the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; (6) the UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare; (7) the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust

Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity

COVID-19; Severe acute respiratory syndrome; Data setCOVID-19; Síndrome respiratorio agudo severo; Conjunto de datosCOVID-19; Síndrome respiratòria aguda severa; Conjunt de dadesBackground and Objectives Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. Methods Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. Results Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1–7] and 7% [95% CI 4–11]), ICU/artificial ventilation (2% [95% CI 0–4] and 4% [95% CI 2–6]), and death (1% [95% CI 0–2] and 2% [95% CI 1–4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2–8), 3% (95% CI 1–5), and 1% (95% CI 0–3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. Discussion Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the operational costs linked to this study are funded by the Multiple Sclerosis International Federation (MSIF) and the Multiple Sclerosis Data Alliance (MSDA), acting under the umbrella of the European Charcot Foundation (ECF). The MSDA receives income from a range of corporate sponsors, recently including Biogen, Bristol-Myers Squibb (formerly Celgene), Canopy Growth Corporation, Genzyme, Icometrix, Merck, Mylan, Novartis, QMENTA, Quanterix, and Roche. MSIF receives income from a range of corporate sponsors, recently including Biogen, Bristol-Myers Squibb (formerly Celgene), Genzyme, Med-Day, Merck, Mylan, Novartis, and Roche. This work was supported by the Flemish Government under the Onderzoeksprogramma Artificiële Intelligentie (AI) Vlaanderen programme and the Research Foundation Fladers (FWO) for ELIXIR Belgium—Flanders (FWO) for ELIXIR Belgium. The central platform was provided by QMENTA, and the computational resources used in this work were provided by Amazon. The statistical analysis was carried out at CORe, The University of Melbourne, with support from NHMRC (1129189 and 1140766)

Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Esclerosi múltipleCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Esclerosis múltipleCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Multiple SclerosisBackground and Objectives People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. Methods Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1–12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. Results Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01–2.41; aOR 2.43, 95% CI 1.48–4.02) and ICU admission (aOR 2.30, 95% CI 0.98–5.39; aOR 3.93, 95% CI 1.56–9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54–10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29–2.38; aOR 2.76, 95% CI 1.87–4.07) and ICU admission (aOR 2.55, 95% CI 1.49–4.36; aOR 4.32, 95% CI 2.27–8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09–12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13–3.07; aOR 2.88, 95% CI 1.68–4.92) and ICU admission (aOR 2.13, 95% CI 0.85–5.35; aOR 3.23, 95% CI 1.17–8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71–17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. Discussion Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. The operational costs linked to this study are funded by the Multiple Sclerosis International Federation (MSIF) and the Multiple Sclerosis Data Alliance (MSDA), acting under the umbrella of the European Charcot Foundation. The MSDA receives income from a range of corporate sponsors, recently including Biogen, Bristol-Myers Squibb (formerly Celgene), Canopy Growth Corp, Genzyme, Icometrix, Merck, Mylan, Novartis, QMENTA, Quanterix, and Roche. MSIF receives income from a range of corporate sponsors, recently including Biogen, Bristol-Myers Squibb (formerly Celgene), Genzyme, Med-Day, Merck, Mylan, Novartis, and Roche. This work was supported by the Flemish government under the Onderzoeksprogramma Artificiële Intelligentie Vlaanderen programme and the Research Foundation Fladers (FWO) for ELIXIR Belgium–Flanders (FWO) for ELIXIR Belgium. The central platform was provided by QMENTA, and the computational resources used in this work were provided by Amazon. The statistical analysis was carried out at CORe, The University of Melbourne, with support from the National Health and Medical Research Council (NHMRC; 1129189 and 1140766)

Immunoglobulin G immune response to SARS-CoV-2 vaccination in people living with multiple sclerosis within Multiple Sclerosis Partners Advancing Technology and Health Solutions

Multiple sclerosis; SARS-COV-2 vaccination; Humoral immune responseEsclerosis múltiple; Vacunación SARS-COV-2; Respuesta inmune humoralEsclerosi múltiple; Vacunació SARS-COV-2; Resposta immune humoralBackground: The impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on SARS-CoV-2 vaccination response is uncertain. Methods: Post-SARS-CoV-2 vaccination blood samples across multiple DMTs were tested for SARS-CoV-2 immunoglobulin G (IgG) response. Results: Three hundred twenty-two people with MS were included; 91.9% received an mRNA vaccine. Post-vaccination reactive IgG rates (IgG index > 1) were 40% for anti-CD20 (32/80 patients); 41% for sphingosine 1-phosphate receptor modulators (S1PRM, 16/39); and 100% for all other classes, including the no DMT group. Conclusion: Anti-CD20 therapies and S1PRMs reduce IgG response to SARS-CoV-2 vaccination; IgG response is preserved with other DMTs.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Biogen (Cambridge, MA, USA). Funding for writing and editorial support was provided by Biogen

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI

Deep learning; Disability; Structural MRIAprendizaje profundo; Discapacidad; Resonancia magnética estructuralAprenentatge profund; Discapacitat; Ressonància magnètica estructuralThe application of convolutional neural networks (CNNs) to MRI data has emerged as a promising approach to achieving unprecedented levels of accuracy when predicting the course of neurological conditions, including multiple sclerosis, by means of extracting image features not detectable through conventional methods. Additionally, the study of CNN-derived attention maps, which indicate the most relevant anatomical features for CNN-based decisions, has the potential to uncover key disease mechanisms leading to disability accumulation. From a cohort of patients prospectively followed up after a first demyelinating attack, we selected those with T1-weighted and T2-FLAIR brain MRI sequences available for image analysis and a clinical assessment performed within the following six months (N = 319). Patients were divided into two groups according to expanded disability status scale (EDSS) score: ≥3.0 and < 3.0. A 3D-CNN model predicted the class using whole-brain MRI scans as input. A comparison with a logistic regression (LR) model using volumetric measurements as explanatory variables and a validation of the CNN model on an independent dataset with similar characteristics (N = 440) were also performed. The layer-wise relevance propagation method was used to obtain individual attention maps. The CNN model achieved a mean accuracy of 79% and proved to be superior to the equivalent LR-model (77%). Additionally, the model was successfully validated in the independent external cohort without any re-training (accuracy = 71%). Attention-map analyses revealed the predominant role of frontotemporal cortex and cerebellum for CNN decisions, suggesting that the mechanisms leading to disability accrual exceed the mere presence of brain lesions or atrophy and probably involve how damage is distributed in the central nervous system.MS PATHS is funded by Biogen. This study has been possible thanks to a Junior Leader La Caixa Fellowship awarded to C. Tur (fellowship code is LCF/BQ/PI20/11760008) by “la Caixa” Foundation (ID 100010434). The salaries of C. Tur and Ll. Coll are covered by this award

Susceptibility, severity and immunological factors against SARSCoV- 2 infection in patients with Multiple Sclerosis

Considerant que els pacients amb esclerosi múltiple (EM) presenten un major risc de morbimortalitat secundari a infeccions i que aquest risc es troba incrementat en aquells amb tractament immunosupressors, quan la pandèmia de COVID-19 va començar va quedar palès que era crucial estudiar quins pacients amb EM presentaven major risc de COVID-19 i com influïa el tractament en aquest risc. A més a més, donat que la majoria de tractaments alteren la resposta immunitària humoral i/o cel·lular, aquesta resposta immunitària a la infecció o a la vacuna per SARS-CoV-2 es podria veure influenciada pels diferents tractaments. Per tot això, els objectius d'aquest estudi són els d'analitzar la incidència, la susceptibilitat i els factors de risc per a presentar un COVID-19 greu en pacients amb EM; el d'estudiar la resposta humoral i cel·lular després de la infecció i la vacunació en aquests pacients i el d'analitzar com s'ha modificat la pràctica clínica arran de la pandèmia. Amb aquest objectius en ment, vam dur a terme varis projectes de recerca. Durant la primera onada de la pandèmia, vam enviar una enquesta per correu electrònic a tots els nostres pacients per a detectar quins havien presentat la COVID-19, el que ens va permetre establir una incidència del COVID-19 en la nostra cohort del 6.3%. Addicionalment, vam trobar que els pacients més joves, amb una EM de més llarga evolució, que vivien a Barcelona ciutat i que havien estat amb contacte amb una persona infectada presentaven un risc més alt de COVID-19. En la nostre cohort, l'edat va ser l'únic factor independent que es va relacionar amb la severitat del COVID-19. Cap tractament va augmentar la susceptibilitat o la severitat del COVID-19. Seguidament, vam avaluar la resposta immunològica humoral i cel·lular al SARS-CoV-2 dels pacients amb EM que havien presentat COVID-19. La resposta humoral es trobava disminuïda en els pacients tractats amb anti-CD20s i augmentada en aquells amb sexe masculí. Per contra, la resposta cel·lular es trobava disminuïda en pacients amb formes progressives de la malaltia. Quan les vacunes contra el SARS-CoV-2 van estar disponibles, vam realitzar l'estudi de resposta humoral i cel·lular després de la vacunació amb col·laboració de la unitat de neuroimmunologia i EM de l'hospital universitari de Girona Doctor Trueta/ Santa Caterina. Vam detectar que la resposta humoral es troba reduïda en els pacients tractats amb moduladors del receptors de la esfingosina 1-fosfats (SP1RM) o amb anti-CD20s. En aquests darrers, la resposta humoral augmentava quan més temps hagués passat entre la vacuna i la darrera infusió. A més a més, també vam detectar que una major durada del tractament disminuïa la resposta humoral post-vacunal. La resposta cel·lular després de la vacuna estava disminuïda en aquells pacients amb SP1RM i majors de 50 anys. Finalment, vam avaluar com la pandèmia va impactar la practica clínica en el nostre centre mesurant el nombre de visites i ressonàncies magnètiques realitzades i el nombre i tipus de prescripció de tractaments fetes durant l'any 2020 i comparant-los amb els anys previs. Vam trobar que durant la pandèmia tant les visites com l'activitat radiològica es va mantenir però es va disminuir el nombre de prescripcions i es va modificar el patró de prescripció de fàrmacs d'alta eficàcia. Concretament, es va disminuir la prescripció d'anti-CD20s i es va augmentar la de natalizumab.Considerando que los pacientes con esclerosis múltiple (EM) presenta un mayor riesgo de morbimortalidad secundaria a infecciones y que este riesgo se encuentra incrementado en aquellos con tratamientos inmunosupresores, cuando la pandemia de COVID-19 inició se puso de manifiesto que era crucial estudiar cuales eran los pacientes con EM que presentaban una mayor riesgo de COVID-10 y como influía el tratamiento en este riesgo. Además, dado que la mayoría de estos pacientes alteran la respuesta inmunitaria humoral y/o celular, esta respuesta a inmunitaria a la infección o vacuna por SARS-CoV-2 se podría ver influenciada por los diferentes tratamiento. Por ello, los objetivos de este estudio son los de analizar la incidencia, la susceptibilidad y los factores de riesgo para presentar un COVID-19 grave en pacientes con EM; el estudiar la respuesta humoral i celular después de la infección y la vacunación en estos pacientes y el de analizar como se ha modificado la práctica clínica a raíz de la pandemia. Con estos objetivos en mente, realizamos varios proyectos de investigación. Durante la primera ola de la pandemia, enviamos una encuesta por correo electrónico a todos nuestros pacientes para detectar cuales habían presentado la COVID-19, lo que nos permitió establecer una incidencia de COVID-19 en nuestro cohorte del 6.3%. Adicionalmente, encontramos que aquellos pacientes más jóvenes, con una EM de larga evolución, que vivían en Barcelona ciudad y los que habían estado en contacto con una persona infectada presentaban un riesgo más alta de COVID-19. En nuestra cohorte, la edad fue el único factor independiente que se relacionó con la severidad del COVID-19. Ningún tratamiento aumentó la susceptibilidad o la severidad del COVID-19. Seguidamente, evaluamos la respuesta inmunológica humoral y celular al SARS-CoV-2 de los pacientes con EM que habían presentado un COVID-19. La respuesta humoral se encontraba disminuida en los pacientes tratados con anti-CD20s y aumentada en aquellos con sexo masculino. Por el contrario, la respuesta celular se encontraba disminuida en aquellos pacientes con formas progresivas de la enfermedad. Cuando las vacunas contra el SARS-CoV-2 estuvieron disponibles, realizamos el estudio de la respuesta humoral y celular después de la vacunación en colaboración de la unidad de neuroinmunología y EM del hospital universitario de Girona Doctor Trueta/ Santa Caterina. Detectamos que la respuesta humoral se encuentra reducida en los pacientes tratados con modulares de los receptores de la esfingosina 1-fosfats (SP1RM) o con anti-CD20s. En estos últimos, la respuesta humoral aumentaba cuanto más tiempo hubiera pasado entre la vacuna y la última infusión. Además, también detectamos que una mayor duración del tratamiento disminuida la respuesta humoral post-vacunal. La respuesta celular después de la vacuna estaba disminuida en aquellos pacientes con SP1RM y mayores de 50 años. Finalmente, evaluamos como la pandemia impactó en la práctica clínica de nuestro centro midiendo el número de visitas y resonancias magnéticas realizadas y el número y tipo de prescripción de tratamiento realizadas durante el año 2002 y comparándolos con los años previos. Encontramos que durante la pandemia tanto las visitas como la actividad radiológica se mantuvo pero el número de prescripciones disminuyó y se modificó el patrón de prescripciones de fármacos de alta eficacia. Concretamente, se disminuyó la prescripción de anti-CD20s y aumentó la de natalizumab.Given that MS patients are at higher risk of morbimortality due to infection and that this risk is increased in those under immunosuppressant treatments, when the COVID-19 pandemic started it was crucial to study which MS patients where at higher risk of COVID-19 and how DMT influenced in this risk. Additionally, as most MS treatments alter humoral and/or cellular immunity, these immunological responses to SARS-CoV-2 infection and vaccination may be modified by the different treatments. Therefore, the aim of this study is to analyze the incidence, susceptibility and severity risk factors for COVID-19 in MS patients, their humoral and cellular response to SARS-CoV-2 infection and vaccination and the modification in the clinical practice caused by the pandemic. With these objectives in mind, several research proposals were considered. First, we sent an online survey to all our patients to detect those who have had COVID-19, allowing us to estimate an incidence of COVID-19 of 6.3% in our cohort. Additionally, we found that younger patients, with a longer disease duration, living in Barcelona city and who had had contact with an infected person presented a higher risk of COVID-19. In our cohort, age was the only independent factor related to severity. No DMT was related to an increased risk of COVID-19 susceptibility or severity. Next, we evaluated the humoral and cellular immunological response of MS patients who had presented COVID-19. After COVID-19, humoral response decreased in in anti-CD20s-treated patients and increased in male patients, whereas progressive forms decreased cellular response. When SARS-CoV-2 vaccines were available, we performed a humoral and cellular immunological response study after vaccination in collaboration with the Neuroimmunology and MS unit of the Doctor Trueta/Santa Caterina University Hospital of Girona. We detected that humoral response was reduced in SP1RM-treated and anti-CD20s-treated patients. In the later, the humoral response rate increased the longer the interval between last infusion and vaccination. A longer treatment duration also decreased humoral response to vaccines. The cellular response after vaccination was also blunted by SP1RM treatment and in patients over 50 years of age. Finally, we evaluated how the pandemic impacted the clinical practice in our center by analyzing the number of clinical visits, the number of magnetic resonance imaging studies and the number and type of treatment prescriptions during the year 2020 compared to 2019. We found that, during the pandemic, the clinical and radiological activity of our center were maintained but the number of treatment prescriptions was reduced, and the pattern modified. Specifically, there was a change in the high efficacy prescription pattern where anti-CD20s therapy prescription was diminished while natalizumab prescription increased