A topological data analysis based classification method for multiple measurements

HR was partly supported by a collaboration agreement between the University of Aberdeen and EPFL. WC was partially supported by VR 2014-04770 and Wallenberg AI, Autonomous System and Software Program (WASP) funded by Knut and Alice Wallenberg Foundation, Göran Gustafsson Stiftelse. JT is fully funded by the Wenner-Gren Foundation. JH is partially supported by VR K825930053. RR is partially supported by MultipleMS. The collaboration agreement between EPFL and University of Aberdeen played a role in the design of the neuron spiking analysis and in providing the data required, i.e. the neuronal network and the spiking activity. Open access funding provided by Karolinska Institute.Peer reviewedPublisher PD

A multiple sclerosis disease progression measure based on cumulative disability

BACKGROUND: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult. OBJECTIVE: The objective of this study is to create a severity metric that can reliably summarize a patient's disease course. METHODS: We developed the nARMSS - normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from -5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings. RESULTS: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908. CONCLUSION: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible

Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study

Background Timing of disease-modifying therapy affects clinical disability in multiple sclerosis, but it is not known whether patient reported outcomes are also affected. This study investigates the relationship between treatment timing and patient-reported symptoms and health-related quality of life. Methods This was a nationwide observational cohort study of adults with relapsing multiple sclerosis, with disease onset between 2001 and 2016, and commenced on disease-modifying treatment within 4 years from disease onset. Patients commencing treatment within 0–2 years were compared with patients commencing treatment at 2–4 years. Indication bias was mitigated by propensity matching. Outcomes were patient-reported symptoms and health-related quality of life as measured by the Multiple Sclerosis Impact Scale (MSIS-29) and EuroQol-5 Dimensions-3 Level (EQ-5D). The follow-up period was 4–10 years from disease onset. Results There were 2648 patients (69% female, median age 32.8) eligible for matching. Mean follow-up time was 3.7 years. Based on 780 matched patients, each year of treatment delay was associated with a worse MSIS physical score by 2.75 points (95% CI 1.29 to 4.20), and worse MSIS psychological score by 2.02 points (95% CI 0.03 to 3.78), in the adjusted models. Among 690 matched patients, earlier treatment start was not associated with EQ-5D score during the follow-up. Conclusions Earlier commencement of disease-modifying treatment was associated with better patient-reported physical symptoms when measured using a disease-specific metric; however, general quality of life was not affected. This indicates that other factors may inform patients’ overall quality of life

Multiple sclerosis and psychiatric disorders : comorbidity and sibling risk in a nationwide Swedish cohort

Background: Psychiatric disorders are known to be prevalent in Multiple Sclerosis (MS). Objective: To study comorbidity between MS and bipolar disorder, schizophrenia and depression in a nation-wide cohort and to determine whether shared genetic liability underlies the putative association. Methods: We identified ICD-diagnosed patients with MS (n=16,467), bipolar disorder (n=30,761), schizophrenia (n= 22,781) and depression (n=172,479) in the Swedish National Patient Register and identified their siblings in the Multi-Generation Register. The risk of MS was compared in psychiatric patients and in matched unexposed individuals. Shared familial risk between MS and psychiatric disorders was estimated by sibling comparison. Results: The risk of MS was increased in patients with bipolar disorder (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.6-2.2, p<0.0001) and depression (HR 1.9, 95% CI 1.7-2.0, p<0.0001). MS risk in schizophrenia was decreased (HR 0.6, 95% CI 0.4-0.9, p=0.005). The association between having a sibling with a psychiatric disorder and developing MS was not significant. Conclusion: We found a strong positive association between MS and bipolar disorder and depression that could not be explained by genetic liability. The unexpected negative association between MS and schizophrenia might be spurious or indicate possible protective mechanisms that warrant further exploration.Stockholm County CouncilThe Swedish Research CouncilKarolinska InstitutetAccepte

Association between clinic-level quality of care and patient-level outcomes in multiple sclerosis

Background: Multiple sclerosis (MS) quality of care guidelines are consensus-based. The effectiveness of the recommendations is unknown.// Objective: To determine whether clinic-level quality of care affects clinical and patient-reported outcomes.// Methods: This nationwide observational cohort study included patients with adult-onset MS in the Swedish MS registry with disease onset 2005–2015. Clinic-level quality of care was measured by four indicators: visit density, magnetic resonance imaging (MRI) density, mean time to commencement of disease-modifying therapy, and data completeness. Outcomes were Expanded Disability Status Scale (EDSS) and patient-reported symptoms measured by the Multiple Sclerosis Impact Scale (MSIS-29). Analyses were adjusted for individual patient characteristics and disease-modifying therapy exposure.// Results: In relapsing MS, all quality indicators benefitted EDSS and physical symptoms. Faster treatment, frequent visits, and higher data completeness benefitted psychological symptoms. After controlling for all indicators and individual treatment exposures, faster treatment remained independently associated with lower EDSS (−0.06, 95% confidence interval (CI): −0.01, −0.10) and more frequent visits were associated with milder physical symptoms (MSIS-29 physical score: −16.2%, 95% CI: −1.8%, −29.5%). Clinic-level quality of care did not affect any outcomes in progressive-onset disease.// Conclusion: Certain quality of care indicators correlated to disability and patient-reported outcomes in relapse-onset but not progressive-onset disease. Future guidelines should consider recommendations specific to disease course..

Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study

BACKGROUND: Spasticity is common among people with multiple sclerosis (MS), but there are few studies of spasticity treatment patterns. We aim to describe associations with spasticity treatment measured primarily by oral baclofen use. METHODS: This cohort study using Swedish registers included 1826 and 3519 people with incident and prevalent MS (pwIMS, pwPMS) respectively, followed from 2005 to 2014. Cox regression assessed factors associated with new baclofen prescriptions and its discontinuation. RESULTS: A total of 10% of pwIMS and 19% of pwPMS received baclofen, a drug prescribed specifically for spasticity in Sweden, of which many patients had relapsing-remitting course. Prescriptions occurred soon after MS diagnosis: pwIMS received baclofen typically within 6 months of diagnosis, and pwPMS within 3 years. Younger patients compared with older patients were three times more likely to receive baclofen with similar disability level measured using Expanded Disability Severity Scores (EDSS). Patients aged 18-44 years with EDSS 3.0-5.0 have an HR for baclofen use of 5.62 (95% CI 2.91 to 10.85) and EDSS 6+ have an HR of 15.41 (95% CI 7.07 to 33.58) compared with individuals with EDSS 0-2.5. In comparison, patients aged 45+ years with EDSS 3.0-5.0 have an HR of 2.05 (95% CI 1.10 to 3.82) and EDSS 6+ a hour 4.26 (95% CI 1.96 to 9.17). Baclofen discontinuation was high: 49% (95% CI 0.42 to 0.57) of pwIMS discontinued within 150 days of dispensation, 90% discontinued within 2 years including patients with progressive course or higher EDSS. Associations among pwPMS and sensitivity analyses including additional treatments were similar. CONCLUSIONS: Younger patients with MS are more likely to receive baclofen compared with older patients with MS. High rates of baclofen discontinuation highlight the need for more tolerable and efficacious spasticity treatments and monitoring of spasticity among people with MS

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

ObjectiveWe sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.MethodsWe conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.ResultsFindings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.ConclusionsThese results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors

Trajectories of disease-modifying therapies and associated sickness absence and disability pension among 1923 people with multiple sclerosis in Sweden

BACKGROUND: There is limited information on the trajectories of disease-modifying therapy (DMT) use and their association with sickness absence and/or disability pension (SADP) among people with multiple sclerosis (PwMS). The objective of the study was to identify trajectories of DMT use over 10 years among PwMS, identify sociodemographic and clinical factors associated with the trajectories, and to assess the association between identified trajectories and SADP days. METHODS: A longitudinal register-based study was conducted, on a prospective data set linked across six nationwide registers, assessing treatment courses of PwMS with DMTs for the 10 years following multiple sclerosis (MS) onset. The study included 1923 PwMS with MS onset in 2007-2010, when aged 19-56 years. In each 6-month-period, their treatment was categorized as before treatment, high-efficacy, non-high-efficacy, or no DMT. Sequence analysis was performed to identify sequences of the treatment categories and cluster them into different DMT trajectories. Cluster belonging, in relation to demographic and clinical characteristics, was assessed through log-multinomial regression analysis. The association of trajectories/cluster-belonging with SADP net days was assessed using generalized estimating equation (GEE) models. RESULTS: Cluster analyses identified 4 trajectories of DMT use: long-term non-high-efficacy DMTs (38.6%), escalation to high-efficacy DMTs (31.2%), delayed start and escalation to high-efficacy DMTs (15.4%), and discontinued/ no DMT (14.2%). Age, MS type, expanded disability status scale (EDSS) score and the number of DMT switches were associated with cluster belonging. The youngest age group (18-25) were more likely to be in the escalation to high-efficacy cluster. People with primary progressive MS were more likely to be in the delayed start or discontinued/ no DMT cluster. Higher EDSS scores were associated to being in the other three clusters than in the long-term non-high-efficacy DMTs cluster. Higher number of DMT switches were associated with being in the escalation to high-efficacy DMTs cluster but less likely to be in the delayed start or discontinued/ no DMT clusters. Descriptive analyses showed a trend of fewer mean SADP days among PwMS using non-high-efficacy DMT than the other clusters about 9 years after onset. PwMS in the escalation to high-efficacy and discontinued/no DMT clusters had more SADP days. PwMS in the delayed start and escalation to high-efficacy DMTs cluster, started with fewer SADP days which increased over time. SADP days adjusted through GEE models showed trends comparable with the descriptive analysis. CONCLUSION: This study described the long-term real-world trajectories of DMT use among PwMS in Sweden using sequence analysis and showed the association of the trajectories with SADP days as well as sociodemographic and clinical characteristics

Accurate classification of secondary progression in multiple sclerosis using a decision tree

BACKGROUND: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult. OBJECTIVE: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes. METHODS: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists. RESULTS: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data. CONCLUSION: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information

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)