Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis

The Expanded Disability Status Scale (EDSS) is the current ‘gold standard’ for monitoring disease severity in multiple sclerosis (MS). The EDSS is a physician-based assessment. A patient-related surrogate for the EDSS may be useful in remotely capturing information. Eighty-one patients (EDSS range 0–8) having EDSS as part of clinical trials were recruited. All patients carried out the web-based survey with minimal assistance. Full EDSS scores were available for 78 patients. The EDSS scores were compared to those generated by the online survey using analysis of variance, matched pair test, Pearson’s coefficient, weighted kappa coefficient, and the intra-class correlation coefficient. The internet-based EDSS scores showed good correlation with the physician-measured assessment (Pearson’s coefficient = 0.85). Weighted kappa for full agreement was 0.647. Full agreement was observed in 20 patient

Inflammatory Activity on Natalizumab Predicts Short-term but not Long-term Disability in Multiple Sclerosis

BACKGROUND: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis. OBJECTIVE: To study this association in those receiving natalizumab. METHODS: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline. RESULTS: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3. CONCLUSIONS: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability

Crossing the death valley to transfer environmental decision support systems to the water market

Environmental decision support systems (EDSSs) are attractive tools to cope with the complexity of environmental global challenges. Several thoughtful reviews have analyzed EDSSs to identify the key challenges and best practices for their development. One of the major criticisms is that a wide and generalized use of deployed EDSSs has not been observed. The paper briefly describes and compares four case studies of EDSSs applied to the water domain, where the key aspects involved in the initial conception and the use and transfer evolution that determine the final success or failure of these tools (i.e., market uptake) are identified. Those aspects that contribute to bridging the gap between the EDSS science and the EDSS market are highlighted in the manuscript. Experience suggests that the construction of a successful EDSS should focus significant efforts on crossing the death-valley toward a general use implementation by society (the market) rather than on development.The authors would like to thank the Catalan Water Agency (Agència Catalana de l’Aigua), Besòs River Basin Regional Administration (Consorci per la Defensa de la Conca del Riu Besòs), SISLtech, and Spanish Ministry of Science and Innovation for providing funding (CTM2012-38314-C02-01 and CTM2015-66892-R). LEQUIA, KEMLG, and ICRA were recognized as consolidated research groups by the Catalan Government under the codes 2014-SGR-1168, 2013-SGR-1304 and 2014-SGR-291.Peer ReviewedPostprint (published version

Treating Systematic Errors in Multiple Sclerosis Data

Multiple sclerosis (MS) is characterized by high variability between patients and, more importantly here, within an individual over time. This makes categorization and prognosis difficult. Moreover, it is unclear to what degree this intra-individual variation reflects the long-term course of irreversible disability and what is attributable to short-term processes such as relapses, to interrater variability and to measurement error. Any investigation and prediction of the medium or long term evolution of irreversible disability in individual patients is therefore confronted with the problem of systematic error in addition to random fluctuations. The approach described in this article aims to assist in detecting relapses in disease curves and in identifying the underlying disease course. To this end neurological knowledge was transformed into simple rules which were then implemented into computer algorithms for pre-editing disease curves. Based on simulations it is shown that pre-editing time series of disability measured with the Expanded Disability Status Scale (EDSS) can lead to more robust and less biased estimates for important disease characteristics, such as baseline EDSS and time to reach certain EDSS levels or sustained progression

A longitudinal study of abnormalities on MRI and disability from multiple sclerosis

Background: In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability. Methods: Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke's Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability). Results: Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61). Conclusions: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment

User-driven design of decision support systems for polycentric environmental resources management

Open and decentralized technologies such as the Internet provide increasing opportunities to create knowledge and deliver computer-based decision support for multiple types of users across scales. However, environmental decision support systems/tools (henceforth EDSS) are often strongly science-driven and assuming single types of decision makers, and hence poorly suited for more decentralized and polycentric decision making contexts. In such contexts, EDSS need to be tailored to meet diverse user requirements to ensure that it provides useful (relevant), usable (intuitive), and exchangeable (institutionally unobstructed) information for decision support for different types of actors. To address these issues, we present a participatory framework for designing EDSS that emphasizes a more complete understanding of the decision making structures and iterative design of the user interface. We illustrate the application of the framework through a case study within the context of water-stressed upstream/downstream communities in Lima, Peru

Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-C omparison Study

Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48 and 43, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years

Changing EDSS progression in placebo cohorts in relapsing MS: A systematic review and meta-regression

Background: Recent systematic reviews of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS) revealed a decrease in placebo annualized relapse rates (ARR) over the past two decades. Furthermore, regression to the mean effects were observed in ARR and MRI lesion counts. It is unclear whether disease progression measured by the expanded disability status scale (EDSS) exhibits similar features. Methods: A systematic review of RCTs in RMS was conducted extracting data on EDSS and baseline characteristics. The logarithmic odds of disease progression were modelled to investigate time trends. Random-effects models were used to account for between-study variability; all investigated models included trial duration as a predictor to correct for unequal study durations. Meta-regressions were conducted to assess the prognostic value of a number of baseline variables. Results: The systematic literature search identified 39 studies, including a total of 19,714 patients. The proportion of patients in placebo controls experiencing a disease progression decreased over the years (p<0.001). Meta regression identified associated covariates including the size of the study and its duration that in part explained the time trend. Progression probabilities tended to be lower in the second year compared to the first year with a reduction of 24% in progression probability from year 1 to year 2 (p=0.014). Conclusion: EDSS disease progression exhibits similar behaviour over time as the ARR and point to changes in trial characteristics over the years, questioning comparisons between historical and recent trials.Comment: 17 pages, 2 figure

Bayesian P-Splines to investigate the impact of covariates on Multiple Sclerosis clinical course

This paper aims at proposing suitable statistical tools to address heterogeneity in repeated measures, within a Multiple Sclerosis (MS) longitudinal study. Indeed, due to unobservable sources of heterogeneity, modelling the effect of covariates on MS severity evolves as a very difficult feature. Bayesian P-Splines are suggested for modelling non linear smooth effects of covariates within generalized additive models. Thus, based on a pooled MS data set, we show how extending Bayesian P-splines to mixed effects models (Lang and Brezger, 2001), represents an attractive statistical approach to investigate the role of prognostic factors in affecting individual change in disability

The multiple sclerosis risk sharing scheme monitoring study - early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis ( MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed