Common and low Frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients

Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome

We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS). The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation. A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation. In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation

Genome-wide survey of SNP variation uncovers the genetic structure of cattle breeds

status: publishe

Multiple Sclerosis MSBase registry: using real-world data to define MS outcomes and optimise treatment strategies

© 2016 Dr. Timothy Denis SpelmanMultiple sclerosis (MS) is a progressive, chronic and inflammatory demyelinating disease of the central nervous system that represents a significant social and economic burden to sufferers and the community. Whilst primary evidence from clinical trials supports the short-term efficacy and safety of MS-specific treatments, the typical 12 or 24-month trial period captures only a small proportion of a patients overall MS experience which can span decades. A considerable challenge to MS epidemiology and treatment research involves developing and adapting statistical techniques for separating out genuine signals from the considerable noise which often characterises data collected from patients with a complex, long-term disease such as MS. Analysis of appropriately powered, longitudinal real world databases is central to providing novel insights into both the biological mechanisms of disease and better targeting and management of treatment for a debilitating and chronic disease for which there is presently no cure. This thesis details a range of novel applications and adaptations of a variety of statistical techniques for analysing real world MS outcomes using the international MSBase registry of multiple sclerosis and comparing a range of competing treatment strategies for which there currently exists limited precedent data to guide decision making in clinical practice. A series of analytical themes ranging from global epidemiology through to the derivation of personalised risk prediction tools and conduct of propensity-score matched head-to-head treatment and management comparisons are presented and these illustrate the flexibility and utility of a large, global registry data source. Amongst the various analyses presented herein, this report presents a novel use of trigonometric regression modelling to demonstrate for the first time that there is a latitude-dependent relationship between seasonal ultraviolet radiation (UVR) trough and relapse frequency peak independent of location-specific UVR levels, with latitudes further from the equator associated with shorter gaps. This modelling exercise further confirms prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extends this observation, again for the first time, to the southern hemisphere. An analysis of the, to date, largest ever studied seen-from-onset MS cohort is also presented, culminating in the derivation of a series of empirically grounded prognostic nomograms for personalised risk assessment of conversion to clinically definite MS in clinical practice. Finally a variety of propensity score matching methods are tested and applied to a series of head-to-head treatment comparisons and decision points, including initiation, switch and discontinunation triggers, to return relatively unbiased estimation of comparative treatment efficacy in clinically relevant scenarios using non-randomly assigned observational data

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

BACKGROUND: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses. OBJECTIVE: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP). METHODS: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a "roving" system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score. RESULTS: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively). CONCLUSION: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Background: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses. Objective: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri®Observational Program (TOP). Methods: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score. Results: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively). Conclusion: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease

Panamania. Vocal score

Presented by the Hasty Pudding Club, 1913. Harvard University