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Background and Objectives: This survey study aimed to (1) identify patient/family research priorities in pediatric-onset multiple sclerosis (POMS), and (2) delineate optimized methods for research study/clinical trials design, engagement, and implementation., Methods: Participants were as follows: (1) parents of a child (<18 years) with POMS enrolled in a national registry, (2) adolescents (13-17 years) with POMS in the registry, and (3) adults (18-40 years) with POMS receiving care at a registry affiliated clinic. Of 293 eligible participants, 192 completed surveys., Results: Experiences with health care and medications were generally positive but there remain areas of priority improvement. Incentives to participate in clinical trials included medications previously tested and in pill form, bloodwork/study visits required ⩾ every 3 months, cognitive testing ⩽1 hour, compensation for travel and time, ability to continue current multiple sclerosis (MS) medication, option to take study medication if on placebo, and individualized study feedback. Priorities for clinical research were (1) psychosocial impact, (2) cognitive/academic impact, (3) environmental risk, and (4) nutrition., Conclusions: Results highlighted the importance of a holistic approach to study design and a focus on the impact of disease on daily life to best engage patients and families in POMS clinical trials and research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.C. has received compensation for consulting from Banner Life Sciences*, Biogen, Bristol Myers Squibb, Janssen, Genentech, Novartis Pharmaceuticals, Octave Bioscience, Sandoz, Siemens, TG Therapeutics*, UCB Biopharma, and Vida Ventures*. He has received compensation for speaking engagements from Prime Education, LLC*. He has received research support from the National Institutes of Health, National MS Society, US Department of Defense, Sumaira Foundation, Brainstorm Cell Therapeutics, Bristol Myers Squibb, Genentech, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Massachusetts Life Sciences Center, Novartis Pharmaceuticals, Octave Bioscience, Sanofi Genzyme, Tiziana Life Sciences, and Wesley Clover International. All activities and funding have occurred within the past 24 months (*relationship has since ended), and disclosures do not conflict with the work being presented.

Background: Understanding nutrition's role in multiple sclerosis (MS) can guide recommendations and intervention-based studies., Objective: Evaluate the association between nutrition and pediatric-onset MS outcomes., Methods: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase., Results: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07-1.86), and risk of T2 progression by 40% (1.40, 1.12-1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60-0.95), 45% (0.55, 0.32-0.96), and 15% (0.84, 0.74-0.96), respectively. No associations were found with EDSS., Conclusion: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS., Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs)., Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p  < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction ( p  < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction ( p  = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58)., Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown., Objective: To test whether genes harboring rare variants associated with adult-onset MS risk ( PRF1, PRKRA, NLRP8 , and HDAC7 ) and 52 major histocompatibility complex (MHC) genes are associated with POMS., Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk., Results: After correction for multiple comparisons, one adult-onset MS gene ( PRF1, p = 2.70 × 10 -3 ) and two MHC genes ( BRD2, p = 5.89 × 10 -5 and AGER, p = 7.96 × 10 -5 ) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501., Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER . These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls., Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores., Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores ( p s > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p  = 0.83); Cogstate Brief Battery (26% vs. 32%, p  = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite ( p  = 0.03), Symbol Digit Modalities Test ( p  = 0.02), Rey Auditory Verbal Learning Test ( p  = 0.01), and Cogstate choice reaction time ( p  < 0.001)., Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure., Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86 , and HLA - DRB1*15 , the strongest genetic variant associated with POMS., Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC's Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86 , and the presence of DRB1*15:01 ( DRB1*15 ) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother's education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated., Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69-3.59 and 1.95, 95% CI: 1.32-2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15 , with a RERI of 2.21 (95% CI: 0.83-3.59) and an AP of 0.56 (95% CI: 0.33-0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14-3.06) and an AP of 0.37 (95% CI: 0.001-0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype., Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene-environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

Background: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS., Objective: To screen for cognitive impairment early in the course of POMS and analyze predictive factors., Methods: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free., Results: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing ( n  = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT., Conclusion: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children., Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard., Results: Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n  = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = -17.5, -4.5, p  = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p  = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p  = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively., Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology., Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS., Methods: Cases with onset <18 years ( n  = 569) and controls ( n  = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n  = 7588)., Results: HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta  = 2.95, p  < 2.0 × 10 -16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p  < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg  = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta  = 2.77, 95% confidence interval: 2.33, 3.32, p  < 2.0 × 10 -16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02 ., Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.

Background: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease., Objective: To determine the association between dietary factors and MS in children., Methods: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed., Results: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01)., Conclusion: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.