A Risk Score for Predicting Multiple Sclerosis.

Ruth Dobson,Declan Chard,Klaus Schmierer,Bhavana Solanky,Paul Smith,Joanne Topping,Gavin Giovannoni,Sreeram Ramagopalan,Orhan Aktas

doi:10.1371/journal.pone.0164992

Abstract

ObjectiveMultiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible. Siblings of people with MS have an increased risk of both MS and demonstrating asymptomatic changes in keeping with MS. We set out to develop an MS risk score integrating both genetic and environmental risk factors. We used this score to identify siblings at extremes of MS risk and attempted to validate the score using brain MRI.Methods78 probands with MS, 121 of their unaffected siblings and 103 healthy controls were studied. Personal history was taken, and serological and genetic analysis using the illumina immunochip was performed. Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. Scores were initially calculated using log odds ratio from the HLA-DRB1*1501 allele only, secondly using data from all MS-associated SNPs identified in the 2011 GWAS. Subjects with extreme risk scores underwent validation studies. MRI was performed on selected individuals.ResultsThere was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p<0.0005). Unaffected siblings had a risk score intermediate to people with MS and controls (p<0.0005). The best performing risk score generated an AUC of 0.82 (95%CI 0.75–0.88).InterpretationsThe risk score demonstrates an AUC on the threshold for clinical utility. Our score enables the identification of a high-risk sibling group to inform pre-symptomatic longitudinal studies.

Highlights

No single factor appears to precipitate the development of multiple sclerosis (MS); a complex interplay of risk factors provides overall risk [1]
There was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p
The MS risk score reported here demonstrates performance characteristics at the threshold accepted for clinical utility

Summary

Introduction

No single factor appears to precipitate the development of multiple sclerosis (MS); a complex interplay of risk factors provides overall risk [1]. Epidemiological data implicates both genetic and environmental factors in disease development. Identifying and studying asymptomatic individuals at high risk of MS provides a powerful opportunity to understand the MS causal cascade. As the MS therapeutic armamentarium increases, the importance of early treatment in influencing long-term outcomes has been realised. Identification of MS risk provides the opportunity to prevent fixed disability. Development of a predictive tool has the potential to inform longitudinal studies, enriching trial populations with those at high risk of disease

Methods

Results

Conclusion