Dataset Information

Using biomarkers to predict progression from clinically isolated syndrome to multiple sclerosis.

ABSTRACT:

Background

Detection of brain lesions disseminated in space and time by magnetic resonance imaging remains a cornerstone for the diagnosis of clinically definite multiple sclerosis. We have sought to determine if gene expression biomarkers could contribute to the clinical diagnosis of multiple sclerosis.

Methods

We employed expression levels of 30 genes in blood from 199 subjects with multiple sclerosis, 203 subjects with other neurologic disorders, and 114 healthy control subjects to train ratioscore and support vector machine algorithms. Blood samples were obtained from 46 subjects coincident with clinically isolated syndrome who progressed to clinically definite multiple sclerosis determined by conventional methods. Gene expression levels from these subjects were inputted into ratioscore and support vector machine algorithms to determine if these methods also predicted that these subjects would develop multiple sclerosis. Standard calculations of sensitivity and specificity were employed to determine accuracy of these predictions.

Results

Our results demonstrate that ratioscore and support vector machine methods employing input gene transcript levels in blood can accurately identify subjects with clinically isolated syndrome that will progress to multiple sclerosis.

Conclusions

We conclude these approaches may be useful to predict progression from clinically isolated syndrome to multiple sclerosis.

SUBMITTER: Tossberg JT

PROVIDER: S-EPMC3850501 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Publications

Using biomarkers to predict progression from clinically isolated syndrome to multiple sclerosis.

Tossberg John T JT Crooke Philip S PS Henderson Melodie A MA Sriram Subramaniam S Mrelashvili Davit D Vosslamber Saskia S Verweij Cor L CL Olsen Nancy J NJ Aune Thomas M TM

Journal of clinical bioinformatics 20131003 1

<h4>Background</h4>Detection of brain lesions disseminated in space and time by magnetic resonance imaging remains a cornerstone for the diagnosis of clinically definite multiple sclerosis. We have sought to determine if gene expression biomarkers could contribute to the clinical diagnosis of multiple sclerosis.<h4>Methods</h4>We employed expression levels of 30 genes in blood from 199 subjects with multiple sclerosis, 203 subjects with other neurologic disorders, and 114 healthy control subject ...[more]

PMID: 24088512

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Project description:Clinically isolated syndrome (CIS) is a first episode of neurological symptoms that may precede a diagnosis of multiple sclerosis (MS). Therefore, studying individuals with CIS may lead to breakthroughs in understanding the development and pathogenesis of MS. In this study, serum levels of immunoglobulin (Ig)G, IgA, IgM, and IgG1-4 were measured in 20 people with CIS and compared with those in 10 healthy controls (HC) and 8 people with MS. Serum Ig levels in individuals with CIS were compared with (a) the time to their conversion from CIS to MS, (b) serum levels of antibodies to Epstein-Barr virus, (c) frequencies of T regulatory (Treg), T follicular regulatory (Tfr), and B cell subsets, and (d) Treg/Tfr expression of Helios. Serum IgG, IgM, and IgG2 levels were significantly lower in people with CIS than HC, and IgG, IgM, and IgG1 levels were significantly lower in people with CIS than MS. After adjusting for age, sex, and serum 25(OH) vitamin D3 [25(OH)D] levels, CIS was associated with lower serum levels of IgG and IgG2 compared with HC (p = 0.001 and p < 0.001, respectively). People with MS had lower IgG2 levels (p < 0.001) and IgG2 proportions (%IgG; p = 0.007) compared with HC. After adjusting for age, sex, and 25(OH)D, these outcomes remained, in addition to lower serum IgA levels (p = 0.01) and increased IgG3 levels (p = 0.053) in people with MS compared with HC. Furthermore, serum from people with MS had increased proportions of IgG1 and IgG3 (p = 0.03 and p = 0.02, respectively), decreased proportions of IgG2 (p = 0.007), and greater ratios of "upstream" to "downstream" IgG subclasses (p = 0.001) compared with HC. Serum IgG3 proportions (%IgG) from people with CIS correlated with the frequency of plasmablasts in peripheral blood (p = 0.02). Expression of Helios by Treg and Tfr cell subsets from individuals with CIS correlated with levels of serum IgG2 and IgG4. IgG3 levels and proportions of IgG3 (%IgG) in serum at CIS diagnosis were inversely correlated with the time until conversion to MS (p = 0.018 and p < 0.001, respectively), suggesting they may be useful prognostic markers of individuals with CIS who rapidly convert to MS.

Project description:Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Dataset Information

Using biomarkers to predict progression from clinically isolated syndrome to multiple sclerosis.

Background

Methods

Results

Conclusions

Publications

Using biomarkers to predict progression from clinically isolated syndrome to multiple sclerosis.

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