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Figure 1.
Study Design and Quantile-Quantile Plot
Study Design and Quantile-Quantile Plot

A, Detailed characterization of Genes and Environment in Multiple Sclerosis (GEMS) participants at extremes of the risk profile. GERSMS indicates Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility; MRI, magnetic resonance imaging; and OCT, optical coherence tomography. B, For a given outcome, the expected P values (−log10 [P value]) are shown on the x-axis, and the observed P values (−log10 [P value]) are shown on the y-axis. The expected P values assume a null distribution, with no difference between higher- and lower-risk participants. The corresponding dark and light gray areas indicate the extreme ranges of the quantile-quantile plots as generated by chance, at a threshold of P = .10 and P = .05, respectively. When the distribution of the observed P values for measured outcomes was taken as a whole, the overall difference between the higher- and lower-risk participants was unlikely to have occurred by chance (P = .01 by omnibus test). See the Methods section and eMethods in the Supplement for details.

aVibration sensitivity testing device measurement from the worse of the 2 sides.

Figure 2.
Representative 3-T Brain Magnetic Resonance Imaging Scans
Representative 3-T Brain Magnetic Resonance Imaging Scans

Images are from a neurologically asymptomatic participant meeting the 2010 McDonald magnetic resonance imaging criteria for dissemination in space. A, Lesions typical of multiple sclerosis are seen in the periventricular region on the sagittal T2-weighted, fluid-attenuated inversion recovery sequence. B, The lesions are hypointense on the corresponding T1-weighted sequence. C and D, A lesion’s central blood vessel is appreciated on the T2*-weighted sequence.

Figure 3.
Plots of Vibration Sensitivity Comparing Higher-Risk (n = 20) and Lower-Risk (n = 27) Asymptomatic Women Participants
Plots of Vibration Sensitivity Comparing Higher-Risk (n = 20) and Lower-Risk (n = 27) Asymptomatic Women Participants

A, The x-axis shows the higher-risk and lower-risk subgroups according to the Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility (GERSMS), namely, women with GERSMS at the top 10% (High) and bottom 10% (Low). The y-axis shows vibration sensitivity in vibration units (vu), which are the amplitudes of vibration and are proportional to the square of applied voltage. The vibration sensitivity threshold was quantified separately in the left and right great toe, and an average measure was calculated. A higher vu value indicates higher threshold for detecting vibration and thus worse vibration sensitivity. The P value represents the univariate comparison between the higher-risk and lower-risk subgroups. B, A participant with the highest GERSMS in the study, who was subsequently diagnosed as having MS after the detailed testing, is shown in the larger orange bubble. The x-axis shows the vibration sensitivity as the average measurement of both great toes. The y-axis shows the vibration sensitivity as the measurement from the worse side. The 2 Vibratron II (Physitemp Instruments, Inc) measurements do not perfectly correlate in this participant. Higher-risk women are shown in the orange bubbles. Lower-risk women are shown in the blue bubbles.

Table 1.  
Neuroimaging and Clinical Evaluation of the Neurologically Asymptomatic Women From the Genes and Environment in Multiple Sclerosis (GEMS) Study Cohort of First-Degree Family Members
Neuroimaging and Clinical Evaluation of the Neurologically Asymptomatic Women From the Genes and Environment in Multiple Sclerosis (GEMS) Study Cohort of First-Degree Family Members
Table 2.  
Evaluation of Vibration Sensitivity in a Subset of 47 Neurologically Asymptomatic Women From the Genes and Environment in Multiple Sclerosis (GEMS) Study Cohort of First-Degree Family Members
Evaluation of Vibration Sensitivity in a Subset of 47 Neurologically Asymptomatic Women From the Genes and Environment in Multiple Sclerosis (GEMS) Study Cohort of First-Degree Family Members
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Original Investigation
March 2017

Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members

Author Affiliations
  • 1Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2Harvard Medical School, Boston, Massachusetts
  • 3Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  • 4Program in Translational Neurology and Neuroinflammation, Pittsburgh Institute of Neurodegenerative Diseases and Institute of Multiple Sclerosis Care and Research, Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 5Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland
 

Copyright 2017 American Medical Association. All Rights Reserved.

JAMA Neurol. 2017;74(3):293-300. doi:10.1001/jamaneurol.2016.5056
Key Points

Question  Is there early evidence of dysfunction in individuals at risk for multiple sclerosis (MS)?

Findings  In this cohort study, we performed neuroimaging and quantitative measures of neurological function in 100 neurologically asymptomatic first-degree relatives with MS. Asymptomatic women deemed at higher risk of developing MS by our risk algorithm (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility) exhibited a greater burden of MS-like findings and diminished neurological function than women at lower risk, with impaired vibration perception in the distal lower extremities being the most pronounced result.

Meaning  Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS and deserve further monitoring.

Abstract

Importance  Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS).

Objective  To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.

Design, Setting, and Participants  The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant’s risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual’s genetic burden and environmental exposures. The study dates were August 2012 to July 2015.

Main Outcomes and Measures  Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.

Results  This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.

Conclusions and Relevance  Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.

Trial Registration  clinicaltrials.gov Identifier: NCT01353547

Introduction

Subclinical inflammatory demyelination and neurodegeneration have been postulated to precede symptom onset in multiple sclerosis (MS).1 This concept is supported by the observation that 34% of neurologically asymptomatic individuals with incidentally discovered brain lesions consistent with MS (radiologically isolated syndrome [RIS]) develop clinical MS within 5 years.2,3 The time frame of the underlying disease process preceding symptom onset is unknown.4 Furthermore, the lack of primary prevention strategies for MS in high-risk populations, such as family members,1 remains an unmet challenge.5

We aim to examine the sequence of events leading to the onset of MS. To accomplish our long-term goal of identifying targets for prevention strategies and the optimal timing for their deployment, we launched a multicenter, prospective cohort study of first-degree relatives of people with MS, the Genes and Environment in Multiple Sclerosis (GEMS) project.6 Within family members with MS, we showed that an aggregate estimate of MS risk (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) incorporating an individual’s genetic burden7-9 and environmental exposures10,11 informs MS risk beyond family history. Indeed, participants in the upper strata of the GERSMS distribution had the greatest probability of having clinical MS.6

In the present study, we investigated early evidence of the disease in asymptomatic family members whose risk profiles for MS susceptibility are at the extreme ends of the spectrum. We hypothesized that neurologically asymptomatic, higher-risk individuals are more likely to manifest subtle inflammatory demyelination or neurodegeneration, the 2 cardinal pathological features of MS. Given the wide range of possible manifestations in MS, we obtained standard and quantitative clinical assessments as well as qualitative and quantitative neuroimaging measures.

Methods
Overall Study Design

The inclusion criteria for the GEMS project are (1) age between 18 and 50 years at enrollment and (2) at least 1 first-degree family member (ie, parent, full sibling, or child) diagnosed as having MS (Figure 1A). The GEMS project study design, including calculation of the GERSMS for individualized risk stratification, has been described earlier6 (eMethods in the Supplement). The institutional review boards of all participating sites (Partners HealthCare, National Institutes of Health, and University of Pittsburgh) approved the study. All participants provided written informed consent.

Study Design for Deep Phenotyping

One hundred neurologically asymptomatic GEMS study participants traveled to the National Institutes of Health between August 2012 and July 2015, from various locations across the United States, for detailed neuroimaging, laboratory, and neurological examination (Figure 1A). The eMethods in the Supplement describes participant selection criteria and the battery of standard and quantitative neurological evaluations, including vibration sensitivity testing with a device (Vibratron II; Physitemp Instruments, Inc), as well as optical coherence tomography and magnetic resonance imaging (MRI). Each participant completed a single study visit. Examiners (S.U.S., A.B., M.K.S., J.O., I.C.M.C., and D.S.R.) were unaware of each participant’s risk score.

Statistical Analysis

For unadjusted comparison between higher- and lower-risk participants, we used χ2 and Fisher exact tests for categorical variables, independent-sample 2-tailed t tests for continuous variables with normal distribution, and Wilcoxon rank sum tests for continuous variables with nonnormal distribution. The continuous outcomes from a vibration sensitivity testing device were analyzed using linear regression models. Analyses were performed using SAS (version 9.3; SAS Institute Inc), JMP (Pro 12.2.0; SAS Institute), or R (R Foundation12,13).

The eMethods in the Supplement provides details on the omnibus test (Figure 1B) of the hypothesis that the χ2 statistic calculated from a Fisher combined probability test (combining the P values of all phenotypes) was higher in the observed data than chance. The 90% and 95% CIs (corresponding to a threshold of P = .10 and P = .05) were derived empirically by randomly assigning participants to the higher- or lower-risk group and repeating the analysis 10 000 times. For phenotypes in which we took right- and left-sided measurements (eg, vibration sensitivity testing device), we used the measurement from the worse side to avoid inclusion of highly correlated phenotypes.

Results

One hundred participants (mean [SD] age, 35.1 [8.7] years) of self-reported European ancestry from the GEMS study cohort who were neurologically asymptomatic at the time of testing underwent detailed examination. They included 41 higher-risk participants (40 women [98%]) from the top 10% and 59 lower-risk participants (25 women [42%]) from the bottom 10% of the GERSMS distribution (eTable 1A in the Supplement). Because women have a higher participation rate in the GEMS project overall and because female sex is a risk factor in the GERSMS,6 there was a significantly greater representation of women in the higher-risk group (P < .001), also previously reported.6 To meaningfully compare the 2 risk groups without attributing any potential difference primarily to the role of sex, we restricted subsequent analyses to women (among 65 women, 40 were at higher risk and 25 were at lower risk) (eTable 1B in the Supplement). In comparing the demographic characteristics and clinical history of the women, we observed a suggestion of higher body mass index (P = .046) and greater weight (P = .01) in the higher-risk group, but the difference was not statistically significant after adjusting for multiple testing. Higher-risk and lower-risk women had no difference in age, height, cigarette smoking exposure, 25-hydroxyvitamin D level, or history of infectious mononucleosis or migraine. No participant reported a history of diabetes.

Qualitative and Quantitative Neuroimaging Measures

To investigate evidence of MS on brain MRI in neurologically asymptomatic individuals (Table 1), we predefined the primary outcome measure of the study as the presence of T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space (DIS).14 Among the 65 women, 5 (8%) (4 at higher risk and 1 at lower risk [P = .64]) met the primary outcome, consistent with prior MRI findings of MS-type lesions in asymptomatic family members.18,19

We examined additional MRI measures as secondary outcomes (Table 1). Among the 65 women, 3 (5%) met 2016 proposed consensus MRI criteria for MS diagnosis,15 while 2 (3%) met criteria for RIS2 and 4 (6%) exhibited single foci of leptomeningeal enhancement.20 Fourteen participants (22% of the 65 women) (12 at higher risk and 2 at lower risk) had at least 40% of T2-weighted brain lesions with a perivenous appearance16,17; 3 of these participants also met the 2010 McDonald MRI criteria for DIS (Figure 2). One of those 3 women, and no other participant, also had a focal upper cervical spinal cord lesion. Therefore, a subset of the first-degree family members of people with MS harbor a variety of neuroimaging features associated with MS.

After adjusting for the testing of multiple hypotheses, there was no difference between the 2 subgroups in the secondary neuroimaging outcomes, including normalized whole and regional (thalamus, total gray matter, and total white matter) brain volume and the mean upper cervical spinal cord cross-sectional area (Table 1). The optical coherence tomography analysis likewise showed no significant retinal nerve fiber layer thickness and total macular volume differences between the 2 groups.

Quantitative Neurological Measures

To investigate subtle subclinical dysfunction in neurologically asymptomatic participants, we measured the following quantitative outcomes known to correlate with physical and cognitive disability in MS: Expanded Disability Status Scale,21 timed 25-ft walk,22 Nine-Hole Peg Test,22 Paced Auditory Serial Addition Test,22 Symbol Digit Modalities Test,23,24 and Timed Up and Go25,26 (Table 1), as well as high-contrast and low-contrast visual acuity (eTable 2 in the Supplement). After considering the testing burden of multiple hypotheses, we did not identify differences between higher-risk and lower-risk women. However, higher-risk women were slower in completing the Timed Up and Go task, a test of motor and balance function, than lower-risk women (P = .03, adjusted for body weight).

Measures of Vibration Sensitivity

As part of the standard neurological examination, we observed impaired vibratory sensation in the distal lower extremities as measured by the 128-Hz tuning fork test. This clinical observation during the early phase of the study led to subsequent incorporation of 2 additional measures of vibration sensitivity into the study protocol, the Rydel-Seiffer graduated tuning fork27,28 and a vibration sensitivity testing device.29-32 Of the 65 women, 47 (27 at higher risk and 20 at lower risk) completed vibration testing using all 3 modalities, a subgroup that had demographic and clinical characteristics similar to the overall cohort of women (eTable 1B in the Supplement).

We chose the vibration sensitivity testing device results as the primary outcome because this device provides the most objective quantitative measurement of vibration sensation in MS.30-32 Because we measured vibration sensitivity in the left and right distal lower extremity (specifically, the great toe), we compared the vibration sensitivity threshold between higher-risk and lower-risk participants using the vibration unit value from the worse side33 (ie, higher value) and the average value of the 2 sides. In univariate analysis, we found evidence of poorer vibration sensitivity (ie, higher threshold for perceiving vibration) in the distal lower extremity of the higher-risk women when comparing the worse side of the distal lower extremity (P = 2 × 10−4) or the average value between the 2 sides (P = 2 × 10−4) (Table 2 and Figure 3).

Because vibration perception is under the potential influence of several factors, we included age at the time of testing and height as covariates in a multivariable analysis. Current cigarette smoking status was used to stratify participants, such that there was no current smoker among the lower-risk participants who underwent vibration sensitivity testing (eTable 1B in the Supplement). Given that the study was completed over 3 years, we further included the test date (in ordinal format) as a covariate and as a control for batch effect. In the multivariable analysis, evidence of poorer vibration sensitivity in higher-risk women persisted when comparing the worse vibration value (P = .008) and the average value (P = .02) (Table 2). We observed the same finding when current smoking status was also included in the analysis (P = .003 for worse vibration value and P = .008 for average vibration value).

We observed a consistent trend when comparing the vibration sensitivity testing device results with the other modalities, the 128-Hz tuning fork test (proportion of participants reporting duration ≤25 seconds) and the Rydel-Seiffer graduated tuning fork (median duration) (eTable 2 in the Supplement). Specifically, among the women, we found that lower threshold for vibration sensitivity by a vibration sensitivity testing device was correlated with shorter duration on the 128-Hz tuning fork test (Spearman coefficient, −0.33; P = .02); the 128-Hz tuning fork test and Rydel-Seiffer graduated tuning fork measures were also correlated (Spearman coefficient, 0.38; P = .01) (eFigure in the Supplement).

One woman who was neurologically asymptomatic at the study visit subsequently developed symptoms of tingling in the fingers and was diagnosed as having MS 14 months after enrollment into the GEMS project and 2 months after completing the National Institutes of Health study visit. This individual had the highest risk score within the entire GEMS study cohort. She exhibited evidence of impaired vibration sensitivity on all 3 modalities, the 128-Hz tuning fork test (14 seconds bilaterally), Rydel-Seiffer graduated tuning fork (7 out of 8 bilaterally), and vibration sensitivity testing device (2.28 vibration units on the right and 3.25 vibration units on the left) (Figure 3B). In addition, her brain MRI met the primary MRI outcome, consistent with the 2010 McDonald MRI criteria for DIS (Figure 2A and B) and all secondary MRI outcomes, including perivenous brain lesions (Figure 2C and D) and spinal cord lesions.

Global Assessment of the Burden of Potential Neurological Dysfunction

Given the wide spectrum of neurological dysfunction seen in patients with MS at symptom onset, we investigated a large number of clinical and neuroimaging outcomes in this cohort of at-risk individuals (eResults and eTable 3 in the Supplement). To globally assess the burden of neurological dysfunction in these family members, we performed an omnibus test to assess for overall differences between the higher-risk and lower-risk participants when considering all of the measured outcomes, many of which have suggestive associations (Figure 1B). When the distribution of the observed P values for these outcomes was taken as a whole, the overall difference between the 2 groups of participants was greater than expected by chance (P = .01), as calculated with permutation tests. For a given outcome, we expect the difference between higher- and lower-risk participants to be beyond chance if the observed probability is outside the confidence interval and further to the right. This is the case for vibration sensitivity testing device measurements from the worse of the 2 sides, which is the great toe on the side with the higher vibration unit or worse vibration sensitivity. It is also the case for vibration sensitivity testing device measurement in the left and right great toes as well as the average of the 2 sides. For the vibration sensitivity testing device measurement from the worse side, we also compared the observed P value (univariate: P=.0002; multivariable: P=.008) to the set of minimum P values, as taken across all measured outcomes, generated from the 10 000 randomly sampled permutations (10 000 minimum P values), and found an empirical P value of .002, suggesting that the P value for this phenotype remains significant after adjusting for multiple testing.

Discussion

Herein, we report the detailed investigation of early evidence of MS-related findings and dysfunction in a subset of participants in the GEMS project, a large prospective cohort study of first-degree family members. Our major finding is that neurologically asymptomatic women deemed to be at higher risk of developing MS by our risk algorithm (GERSMS) exhibited a greater burden of potential neurological dysfunction than women at lower risk, with impaired vibration perception in the distal lower extremities being the most pronounced result. In addition, 8% (5 of 65) of all the women studied in detail met the primary neuroimaging outcome of having brain T2-weighted hyperintense lesions consistent with the 2010 McDonald MRI criteria for DIS, higher than one would expect to find in the general population. The presence of these findings and of other MS-type changes, including central veins in T2-weighted hyperintense lesions, focal leptomeningeal enhancement, and a spinal cord lesion, suggests that a subset of family members have an asymptomatic disease process and deserve further monitoring.

Below, we discuss our findings in the context of prior literature, speculate on their broader significance, and mention the limitations of the present study. The intriguing neuroimaging findings from this study are consistent with prior reports concerning the frequency of MS-like white matter lesions on brain MRI among asymptomatic first-degree relatives (ranging from 4%-10%)19 and the frequency of RIS among healthy family members (3%).18 There were substantial differences in study design, population characteristics, MRI protocol, and predefined outcomes between our study and these earlier studies. Determining the optimal management of first-degree relatives with MS-type findings was not our aim; an ongoing RIS trial34 should provide information to guide treatment decisions.

Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain. Such changes could derive from focal lesions in the dorsal columns of the spinal cord, but we cannot rule out the possibility of abnormal myelin structure or early degeneration of long axonal tracts or subcortical structures, such as the thalami. Regardless of etiology, our results underscore the importance of using sensitive tools to detect subtle neurological changes early in the MS disease process.

Our results also suggest that the present study was underpowered to detect a difference in neuroimaging outcomes between higher-risk and lower-risk women. Because, to our knowledge, the GEMS project is the first prospective study of populations at risk for MS and because this investigation is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, there was limited information regarding the sample size required to detect early or subtle evidence of MS when we launched the GEMS project in 2010. The sample size calculation for the primary brain MRI outcome was initially estimated by extrapolating results from people with MS and healthy control individuals.35 Because of the limited information available for power calculation, we planned to investigate 100 participants for this study. In retrospect, given our observations, we had excellent statistical power (99%) to detect a difference in vibration sensitivity but modest power (12%) to detect a difference in the primary MRI outcome of having brain lesions consistent with the 2010 McDonald MRI criteria for DIS (eTable 4 in the Supplement). Based on the primary neuroimaging outcome (Table 1 and eTable 5 in the Supplement), we can estimate that a study comparing 283 higher-risk and 283 lower-risk female participants will be needed to attain statistical significance. Therefore, these family members with carefully characterized baseline phenotypes provide crucial insights for the future direction of the GEMS project and other similar studies. Specifically, we plan to confirm the finding of change in vibration sensitivity with a follow-up study.

Limitations

Our findings have several limitations. First, we restricted analyses to women because inclusion of sex in the individualized risk score for MS susceptibility resulted in unequal representation of women in the 2 groups. The excess of women participating in the overall GEMS project was consistent with the sex discrepancy in clinical study participation, possibly heightened by public understanding of the increased risk of MS among women.6 We are working to increase men’s participation in the GEMS project. Second, the cross-sectional assessment does not allow for definitive conclusions regarding the sequence of events over time. To address this issue, we plan to perform longitudinal assessment in individuals in whom we have baseline measurements. Third, vibration sensitivity thresholds, as quantified by a vibration sensitivity testing device, were generally within the normal range (as presented in the package insert of the device) for both risk groups. Large-scale normative data relevant to the demographics of the study population were unavailable when this study was performed. As such, we have begun to quantify vibration sensitivity in healthy volunteers. Fourth, we selected a slightly older cohort of participants for this study (mean age, 35.1 years) because we initially aimed to identify participants with RIS. With findings from this study that inform the risk model, we plan to pursue a prospective investigation in younger individuals in part to determine the mean age at which RIS develops. Fifth, we selected the qualitative and quantitative clinical and neuroimaging measures that were deployed in this study primarily based on their usefulness in studies of patients with MS and healthy controls. Although we expected low sensitivity in detecting early evidence of MS in neurologically asymptomatic first-degree family members using these measures, they inform important baseline information in the larger prospective study. Therefore, our study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.

Conclusions

Higher-risk asymptomatic family members of people with MS are more likely to have early subclinical manifestations of MS. Findings from this prospective cohort study underscore the importance of early detection in individuals at higher risk for MS.

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Article Information

Corresponding Author: Daniel S. Reich, MD, PhD, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Diseases and Stroke, 10 Center Dr, MSC 1400, Bldg 10, Room 5C103, Bethesda, MD 20892 (reichds@ninds.nih.gov).

Accepted for Publication: October 19, 2016.

Published Online: January 17, 2017. doi:10.1001/jamaneurol.2016.5056

Author Contributions: Drs De Jager and Reich had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Xia and Ms Steele contributed equally as first authors. Drs De Jager and Reich contributed equally as senior and last authors.

Study concept and design: Xia, Chibnik, Cortese, De Jager, Reich.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Xia, Steele, Chibnik, De Jager, Reich.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Xia, Steele, White, Price, Chibnik, De Jager.

Obtained funding: Xia, De Jager, Reich.

Administrative, technical, or material support: Xia, Steele, Clarkson, Nair, Dewey, De Jager.

Study supervision: Xia, Nair, Cortese.

Conflict of Interest Disclosures: Dr Xia reported being the recipient of a Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology. Ms Steele reported being the recipient of a Multiple Sclerosis Workforce of the Future Scholarship from The Consortium of Multiple Sclerosis Centers. Dr Schindler reported being the recipient of a Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology. Ms Price reported being supported by the National Institute of Neurological Disorders and Stroke Summer Program. Dr De Jager reported being the recipient of a Harry Weaver Neuroscience Scholar Award from the National Multiple Sclerosis Society. No other disclosures were reported.

Funding/Support: This study was supported by the National Institutes of Health and the National Multiple Sclerosis Society. The Genes and Environment in Multiple Sclerosis (GEMS) project is supported by grant RG-5003-A-2 from the National Multiple Sclerosis Society (Dr DeJager), by grant K08-NS079493 from the National Institute of Neurological Disorders and Stroke (Dr Xia), and by the National Institute of Neurological Disorders and Stroke Division of Intramural Research (Dr Reich).

Role of the Funder/Sponsor: The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all of the study participants for being part of the Genes and Environment in Multiple Sclerosis (GEMS) project. We thank the staff of the National Institute of Neurological Disorders and Stroke Neuroimmunology Clinic for expert evaluation of the study participants. We thank the National Institute of Mental Health Functional MRI Core Facility for supporting the magnetic resonance imaging scans.

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