Article Figures & Data
Figures
- Figure 1 Decile of 25(OH)D PGS and Measured 25(OH)D Levels in 935 People With MS From the JHU Cohort
25(OH)D PGS are derived from summary statistics in which the primary model was adjusted for BMI. The association between circulating 25(OH)D levels and 25(OH)D PGS are adjusted for also BMI among people with MS. We excluded individuals with measured levels exceeding 70 ng/mL, as previous studies suggest this threshold may be the physiologic limit of 25(OH)D derived from nonsupplemental sources. Similar results were obtained when applying a threshold of 100 ng/mL (not shown). 25[OH]D = 25-hydroxyvitamin D; PGS = polygenic score.
- Figure 2 Results for Continuous 25(OH)D PGS1 Clinical Outcomes for Individual Studies and the Pooled Estimate2 Across Studies
125(OH)D PGS are derived from summary statistics in which the primary model was adjusted for BMI. 2Effect estimates displayed are for a 1 SD increase in 25(OH)D PGS. They are adjusted for age, 5 ancestry PCs, MS DMT, disease duration, and the number of relapses in previous 3 years. The pooled effect estimate is results from a random effects meta-analysis. (A) The results for rate of EDSS progression (heterogeneity I2 = 0.00%; p het=0.45). (B) The results for annualized percent change T25FW (I2 = 0.0%; p het=0.91). (C) The results for annualized percent change 9HPT (I2 = 0.0%; p het=0.67). 25[OH]D = 25-hydroxyvitamin D; 9HPT = nine-hole peg test; EDSS = expanded disability status scale; PGS = polygenic score; T25FW = timed 25-foot walk; DMT = disease-modifying therapies; JHU = Johns Hopkins; IMID = immune-mediated inflammatory diseases.
- Figure 3 Results for Continuous 25(OH)D PGS1 and MRI Outcomes for Individual Studies and the Pooled Estimate2 Across Studies
125(OH)D PGS are derived from summary statistics in which the primary model was adjusted for BMI. 2Effect estimates displayed are for a 1 SD increase in 25(OH)D PGS. 2Effect estimates displayed are for a 1 SD increase in 25(OH)D PGS. They are adjusted for age, 5 ancestry PCs, MS DMT, disease duration, and the number of relapses in previous 3 years. The pooled effect estimate is results from a random effects meta-analysis. (A) The results for annualized percent change in BPF (Heterogeneity I2 = 66.0%; p het=0.09). (B) The results for annualized percent change in lesion volume (I2 = 0.0%; p het=0.78). (C) Relative rate for new lesions (I2 = 38.8%; p het=0.20). 25[OH]D = 25-hydroxyvitamin D; BPF = brain parenchymal fraction; DMT = disease-modifying therapies; JHU = Johns Hopkins; PGS = polygenic score.
Tables
- Eleni S. Vasileiou, MD*,
- Chen Hu, MS*,
- Charles N. Bernstein, MD,
- Fred Lublin, MD,
- Jerry S. Wolinsky, MD,
- Gary R. Cutter, PhD,
- Elias S. Sotirchos, MD,
- Kaarina Kowalec, PhD,
- Amber Salter, PhD,
- Shiv Saidha, MBBCh, MD, MRCPI,
- Ellen M. Mowry, MD, MCR,
- Peter A. Calabresi, MD,
- Ruth Ann Marrie, MD, PhD and
- Kathryn C. Fitzgerald, ScD
- From the Department of Neurology (E.S.V., C.H., E.S.S., S.S., E.M.M., P.A.C., K.C.F.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Internal Medicine (C.N.B.), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Neurology (F.L.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neurology (J.S.W.), McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth); Department of Biostatistics (G.R.C.), University of Alabama at Birmingham; College of Pharmacy (K.K.), Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Medical Epidemiology and Biostatistics (K.K.), Karolinska Institute, Solna, Sweden; Department of Neurology (A.S.), University of Texas Southwestern, Dallas; and Department of Community Health Sciences (R.A.M.), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
- Correspondence
Dr. Fitzgerald fitzgerald{at}jhmi.edu
Abstract
Background and Objectives Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS.
Methods We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10−8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10−5) and applying Mendelian randomization (MR) rather than using PGS.
Results Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87–1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87–1.28), change in T25FW (per 1SD: 0.07%; 95% CI: −0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: −0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR.
Discussion Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.
Glossary
- 25[OH]D=
- 25-hydroxyvitamin D;
- BMI=
- body mass index;
- BPF=
- brain parenchymal fraction;
- DMT=
- disease modifying therapies;
- EDSS=
- Expanded disability status scale;
- EMR=
- electronic medical record;
- FLAIR=
- fluid-attenuated inversion recovery;
- GA=
- glatiramer acetate;
- GCIPL=
- ganglion cell inner plexiform layer;
- GMF=
- gray matter fraction;
- GWAS=
- genome-wide association studies;
- IMID=
- immune-mediated inflammatory diseases;
- INFB=
- interferon beta-1a;
- JHU=
- Johns Hopkins;
- LD=
- linkage disequilibrium;
- MR=
- Mendelian randomization;
- MSFC=
- MS Functional Composite;
- OCT=
- Optical coherence tomography;
- PC=
- principal components;
- PGS=
- polygenic score;
- TE=
- echo time;
- TI=
- inversion time;
- WMF=
- white matter fraction
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder of the CNS.1,2 Disease course in people with MS typically follows a pattern of intermittent inflammatory disease activity that evolves into a state in which progressive neurologic deficits accumulate.3 Notably, disease course in people with MS is highly variable, and contributors to this variability remain poorly understood.4
Observations of higher MS risk in individuals with low vitamin D intake or low circulating 25-hydroxyvitamin D (25[OH]D) levels, and the results implicating a potential worse MS prognosis in individuals with low 25(OH)D levels suggest that vitamin D may contribute to MS disease processes.5,-,8 Small experimental vitamin D supplementation studies have also reported a beneficial role of supplementation on immunologic, radiologic, and clinical outcomes. However, the results from larger scale randomized clinical trials to date have been less clear.9,-,18
Genome-wide association studies (GWAS) have identified multiple loci associated with circulating 25[OH]D levels and suggest that a significant proportion of variation in 25(OH)D levels can be explained by common genetic variation.19,20 Resultant measures of polygenic inheritance of 25(OH)D can then be summarized using a polygenic score (PGS), which represent the sum of the number of alleles contributing to 25(OH)D levels possessed by a given individual weighted by their effect size on 25(OH)D levels.21 Such scores then can not only be used to predict a given person's 25(OH)D levels but also serve as a proxy for measured 25(OH)D levels, potentially minimizing confounding (e.g., geographical location, dietary intake, vitamin D supplementation) and reverse causation in the study of vitamin D levels and disease outcomes.22,23 PGS may also provide some insight into the expected level (rather than observed as with measured 25[OH]D levels) of vitamin D. Notably, studies using a PGS approach have consistently identified an association of vitamin D with MS susceptibility.24,-,26 In contrast, studies relating vitamin D-associated PGS to disease prognosis in MS are scarce.27 Although a possible association between genetically determined 25(OH)D levels and relapse risk was noted in a Belgian cohort of people with MS (PwMS), this study involved a single center and did not consider other clinical outcomes or objective imaging outcomes such as the rate of new lesion development, which has a strong body of support from observational studies.28 Thus, to address this gap, we explored whether genetically determined 25(OH)D levels are associated with disease outcomes in a large, multinational study of PwMS considering multiple radiologic and clinical outcomes. We hypothesized that genetically predicted higher 25(OH)D levels would be associated with better MS outcomes over time.
Methods
Standard Protocol Approvals, Registrations, and Patient Consents
The studies used in this manuscript were approved by all clinic or cohort-specific local Institutional Review Boards. All study participants provided written informed consent.
Study Population and Inclusion Criteria
In this multicenter study, 3 well-characterized cohorts of MS participants were included.
The CombiRx trial was a 3-arm double-blind placebo-controlled phase III clinical trial conducted in the United State with a 2:1:1 randomization scheme of combination therapy (interferon beta-1a [INFB] plus glatiramer acetate [GA]) vs single therapy (INFB or GA). The trial design and primary findings have been described in detail elsewhere.29 Briefly, eligible participants were treatment-naïve PwMS (McDonald 2005 revised criteria)30 with ≥2 clinical relapses or ≥1 clinically identified relapse with subsequent radiologic activity within 2 years before study onset. Participants were followed for 3 years as a part of the trial and had an option to enter the extension study in which follow-up continued for up to 7 years.
The Johns Hopkins (JHU) cohort included participants with a confirmed MS diagnosis who receive clinical care at the JHU MS center in Baltimore, Maryland. Participants are followed approximately biannually and complete functional assessments for research in a clinical care setting. Information on current 25(OH)D levels was available for a subset of the cohort using values obtained clinically.
The Immune-Mediated Inflammatory Diseases (IMIDs) Winnipeg cohort,31 included participants with MS, rheumatoid arthritis, inflammatory bowel disease, or a lifetime diagnosis of depression or anxiety disorder without an IMID residing in Winnipeg, Manitoba, Canada who were aged 18 years or older, able to provide consent, and had an adequate knowledge of English to complete questionnaires and interviews. Participants were enrolled from November 2014 through July 2016 and followed prospectively approximately annually over a 3-year period.
From these 3 cohorts, we included in our study participants with available genotyping who were of European ancestry.
Genotyping Information and Calculation of 25(OH)D PGS
For each cohort, blood samples from eligible participants underwent DNA extraction and subsequent genotyping using genome-wide Illumina genotyping chips: (CombiRx: HumanOmni1-Quad chip; IMID: Global Screening Array v2; JHU: Multi-Ethnic Global Array [MEGA]). After genotyping, we implemented an established quality control procedure for GWAS by excluding individuals with low genotyping success rates, related individuals, and those with excess heterozygosity. We also excluded individuals of non-European ancestry as identified using principal components (PCs) analysis (>2SD from PC1, PC2) mapping study populations on to the 1,000 Genomes population. We excluded variants with minor allele frequencies >0.05, missing genotype rates >0.05, and those with evidence of deviation from Hardy Weinberg equilibrium (p < 0.001). For each cohort, genotype imputation was applied using the Haplotype Reference Consortium as deployed on the Michigan Imputation Server and filtered for allele frequency (0.05–0.95) and imputation quality scores (imputation quality scores >0.70).32
To derive 25(OH) PGS, we used summary statistics from a large-scale meta-analysis combining a study linking genetic variants to 25(OH)D levels conducted in the UK Biobank and SUNLIGHT Consortium in 485,762 individuals (for body mass index [BMI]-adjusted analyses) and in the UK Biobank in 416,560 individuals (for BMI unadjusted analyses).20,33 Summary statistics from these studies were used to create the 25(OH)D PGSs for this study using Polygenic Risk Score software for Biobank-Scale Data (PGSice-2) with a p-value threshold of 5e-8, and linkage disequilibrium (LD) clumping (r2 < 0.10 in 250-kb window) and proxy R2 threshold of 0.80. Our primary analyses used the 25(OH)D PGS adjusted for BMI (as this was the original 25(OH)D GWAS with the larger sample size); sensitivity analyses considered the unadjusted 25(OH)D PGS. Sensitivity analyses also considered PGS using a p value threshold of 5e-05; some previous research suggests that this threshold may provide increased power when considering PGS and outcomes.34,35
Clinical Assessment, Data Collection, and Outcomes
Sociodemographic and clinical characteristics, disease-modifying therapies (DMTs), and concomitant medications were available for all participants through a combination of designated study visits, questionnaires, or the electronic medical record (EMR) depending on the cohort. A summary of available outcomes and associated sample size for each outcome considered across cohorts is provided in eTable 1 (http://links.lww.com/NXI/A766).
CombiRx
Participants underwent clinical assessments including Expanded Disability Status Scale (EDSS) and MSultiple Sclerosis Functional Composite (MSFC) examinations at baseline, and every 3 months until month 36, then every 6 months thereafter.29,36 MRIs were obtained at baseline, months 6, 12, 24, and 36, then annually thereafter. For relapses, we considered both protocol-defined relapses (PDE) and nonprotocol-defined relapse (NPDE). PDEs were defined as the development of new symptoms or worsening of old symptoms, lasting ≥24 hours in the absence of fever, preceded by 30 days of stability, and associated with changes in the EDSS score confirmed by the examining physician within 7 days of onset. NPDE were defined as relapses, which met these criteria but were not confirmed within 7 days of onset. For MRIs, brain volume was estimated using a standardized protocol that included 7 scan series; all MRIs obtained in CombiRx used Siemens, General Electric or Phillips scanners at 1.5 or 3T. Semiautomated processing was applied to estimate enhancing lesion volume, the strictly T2 hyperintense and T1 hypointense lesion volumes, total normal appearing white matter, gray matter and CSF (CSF) volumes, and normalized by the sum of all segmented values. We also considered a combined unique lesion activity, defined as the sum of the number of new enhancing lesions, new nonenhancing T2 lesions, and enlarged nonenhancing T2 lesions observed after enrollment.
JHU
Serum 25(OH)D levels were available for a subset of the cohort and were collected as a part of routine clinical monitoring. Disability status was determined by Neurostatus-certified raters for EDSS scores and was collected as a part of an on-going longitudinal observational study. Other clinical characteristics including the use of DMTs were also available. Similarly, information regarding walking speed, manual dexterity, and cognitive status was derived using the timed 25-foot walk, nine-hole peg, and the paced auditory serial addition (PASAT-3) tests of the MSFC, also collected as a part of on-going study visits. For neuroimaging, participant MRIs are acquired as a part of clinical care and are generally obtained for monitoring purposes. Each is obtained on any Siemens 3T Scanner after a standardized protocol. Two 3-D sagittal, whole-brain sequences are used: 1) fluid-attenuated inversion recovery (FLAIR; acquired resolution: 1 × 1 × 1mm; echo time [TE]: 392 ms; repetition time: 5,000 ms; inversion time [TI]: 1,800 ms) and 2) magnetization-prepared rapid gradient-echo (MPRAGE; acquired resolution: 1 × 1 × 1mm; TE: 2.96 ms; TR: 2,300 ms; TI: 900ms). Images are reviewed by neuroradiology to ensure correct sequence use, complete brain coverage, and adequate image quality. Quantitative MRI measures are derived from brain MRIs as part of a collaboration with the MS Partners Advancing Technology and Health Solutions (MS PATHS) network.37 Volumetric measures include brain parenchymal fraction (BPF), gray matter fraction (GMF), white matter fraction (WMF), and T2 lesion volume. These values are automatically calculated from MS PATHS MRIs via a software prototype developed jointly by Biogen and Siemens (MS PATHS Image Evaluation or MSPie).37 BPF is a normalized measure of whole brain volume that is calculated via a combined approach to segmentation of the brain parenchyma and total intracranial volume in the 3D FLAIR and 3D T1 images. The algorithm removes nonbrain tissue to create a total intracranial volume mask and then performs tissue classification incorporating partial volume effects using a Bayesian “mixel” model.38 In analyses of a scan-rescan substudy of MS-PATHS including 3 MS-PATHS sites at which 30 PwMS underwent 4 MRIs on 2 different Siemens 3T MRI scanners within 1 week, BPF estimated by MSPie exhibited excellent reproducibility, with a mean coefficient of variation of 0.18%. New T2 lesions are segmented automatically based on 3D FLAIR and 3D T1 images using a Bayesian partial volume estimation algorithm.
In addition, longitudinal retinal imaging data were available as a part of a long-term observational study. Optical coherence tomography (OCT) scans were acquired annually or biannually using CIRRUS HD-OCT device (model 5000; Carl Zeiss Meditec, Dublin, CA). Macular scans were obtained with the Macular Cube 512 x 128 protocol by experienced technicians, in accordance with the quality control criteria for (O) obvious problems, (S) poor signal strength, (C) centration of scan, (A) algorithm failure, (R) retinal pathology other than MS related, (I) illumination and (B) beam placement (OSCAR-IB), as described in detail elsewhere.39,40 Ganglion cell and inner plexus layer (GCIPL) thickness was quantified using a validated in-house segmentation algorithm.41 We focused on GCIPL thinning in this study, as changes in these layers are a highly sensitive marker reflecting global CNS neurodegeneration and disease progression in MS that may capture subtler changes than clinical outcomes.42,-,44 All scans underwent rigorous quality assurance evaluation by experienced raters to confirm the accuracy of segmentation boundaries and identify the presence of incidental pathologies impactful on retinal measures. Only scans with adequate quality were considered. Individuals with other known neurologic or ophthalmologic disorders, glaucoma, or refractive errors exceeding ±6 diopters were excluded. OCT methods and the results presented in this study were in accordance with the Advised Protocol for OCT Study Terminology and Elements criteria.45
IMID
Clinical and MS characteristics including the use of DMTs were collected at baseline and approximately annually thereafter. Likewise, functional assessments including the EDSS and MSFC components for timed 25-foot walk and 9-hole peg test scores were available approximately annually for each participant; the PASAT-3 was not obtained as a part of the IMID study protocol.
Statistical Analysis
Descriptive analyses characterized baseline demographic, clinical, and radiologic characteristics for each cohort. We first assessed the association between 25(OH)D PGS and circulating 25(OH)D levels in the JHU cohort to ensure that 25(OH)D PGS were a reasonable surrogate for 25(OH)D levels. For this analysis, we residual-adjusted 25(OH)D levels for BMI and the use of vitamin D supplements using generalized estimating equations to incorporate multiple circulating levels per person. Furthermore, because supplementation use was obtained from the EMR and could potentially be misclassified, we also excluded individuals with circulating levels exceeding 70 ng/mL. This threshold may constitute the physiologic maximum blood level of 25(OH)D, and some studies suggest people with MS may have a suboptimal response to supplementation (e.g., a person with MS may have a lower circulating level, despite use of supplements).46 Sensitivity analyses also considered 100 ng/mL as the physiologic threshold.47
Linear mixed effects models assessed the association between 25(OH)D PGS with the following continuous outcomes (1) clinical: EDSS, timed 25-foot walk, nine-hole peg, and PASAT-3 and (2) radiologic outcomes: T2 lesion volume, BPF, GMF, WMF, and GCIPL thickness. Models included subject-specific random intercepts and slopes (and eye-specific random slope for GCIPL analyses) to account for repeated measures. For analyses of 25(OH)D PGS and new lesions, we applied negative binomial regression models, and for relapses, we used an Andersen-Gill model for recurrent events. In secondary EDSS-based analyses, we defined disability progression as (1) EDSS increase by 1.5 points if baseline EDSS was zero, (2) increase in EDSS by 1 point if baseline EDSS was between 1 and 5.5, and (3) 0.5 point increase in EDSS if baseline EDSS was above 5.5, as previously described.48 We then assessed time to disability progression using a Cox proportional hazards model. Model fit and assumptions were verified using tests appropriate for the model in question.
We conducted all analyses in each individual cohort and pooled studies using random effects meta-analysis and calculated I2 statistics and associated tests of heterogeneity. For each study and outcome, we considered 25(OH)D PGS as a linear variable and categorically, using cohort-specific quartiles. We tested for trend by modeling the quartile variable as a linear covariate.49 We fit 3 series of models: model A, adjusted for age (continuous), sex, MS DMT (categorical), and genetic ancestry (as first 5 PC; continuous); model B, adjusted for model A covariates and the number of relapses in the previous 3 years and disease duration (both continuous); and a supplementary model C, adjusted for model B covariates and the use of vitamin D supplements and use of a medication associated with changes to vitamin D status (both binary covariates). These medications included corticosteroids, anticonvulsants, antidepressants, neuropathic pain medication, statins, and weight loss medication (e.g., orlistat).
We performed several sensitivity analyses assessing the consistency of our findings. First, we repeated all analyses using 25(OH)D PGS without adjusting for BMI. Second, we relaxed the p-value threshold to compute the 25(OH)D PGS to 5e-5 and repeated all analyses. Other analyses for relapse in the CombiRx data set were stratified by type of relapse (protocol defined exacerbation [PDE] and nonprotocol defined exacerbation [NPDE]). In addition, because some analyses are pooling results with only 2 studies (see eTable 1, http://links.lww.com/NXI/A766), we also performed sensitivity analyses applying Bayesian random effects meta-analysis with half-normal priors with a specified SD of 0.5; a previous analysis suggested these modeling parameters in the context of pooling 2 studies.50 We also performed sensitivity analyses to confirm consistent results were observed when applying Mendelian randomization (MR); this approach was previously applied in a study linking 25(OH)D and relapse hazard.28 To select instrumental variables (IVs) for 25(OH)D, we used the set of summary statistics for 25(OH)D used to create 25(OH)D PGS for our primary analyses and we aligned alleles to ensure directionality of effect estimates was maintained.20 We clumped 25(OH)D variants using a p-value threshold of 5e-8, distance of 10,000 kilobases, and LD of 0.001. For IVs not genotyped explicitly in the outcome cohort, we selected a proxy variant in LD (with R2 ≥ 0.9) with the variant of interest. Proxy variants were also included for palindromic IVs. For primary MR analyses, we applied multiplicative random effects inverse variance (IVW) to estimate the effects of 25(OH)D IVs on relapse risk and rate of new lesion development. We selected these outcomes as a relatively large body of observational evidence implicates a potential link between higher 25(OH)D and a lower rate of new lesion development and a previous study linked genetic liability to 25(OH)D and relapse risk. Secondary analyses calculated radial IVW with modified second order weights, MR-Egger, and weighted median-based effect estimates.51,-,53 Cochran Q test and I2 statistic were calculated to assess heterogeneity. We removed potential outlying variants identified using the modified weights from the radial IVW estimate. Pleiotropy was also assessed by testing whether the intercept obtained from the MR Egger analyses differed from 0. MR analyses were implemented using the TwoSampleMR package (v.0.5.6).53,-,55 Last, sensitivity analyses considered measured 25(OH)D levels available from the JHU cohort and their association with the rate of new lesion development (e.g., to confirm that the results do not merely reflect that the PGS explains an insufficient amount of variation in 25[OH]D levels). For this analysis, we regressed new lesions on the average 25(OH)D levels in the 5 years before the first MRI using similarly adjusted negative binomial regression models.
All statistical analyses were conducted using R programming (R version 4.1.0). Statistical significance was defined as p < 0.05.
Data Availability
Components of the IMID data set may be made accessible to qualified investigators with the appropriate ethical approvals and data use agreements upon request.
Results
Study Population and Baseline Characteristics
Table 1 describes demographic and clinical characteristics of included cohorts. Overall, 1924 participants were included in this study (from JHU: n = 1,152; from CombiRx: n = 575; from IMID: n = 197). The average age of the participants at first visit varied across cohorts (JHU: 44.1 years, SD [SD]:12.2; CombiRx: 40.9 [12.5], IMID: 50.4 [12.7]). The cohorts also varied about disease duration, with JHU and IMID participants having longer disease duration. Across all cohorts, participants were largely female (1,425; 74.1%) and had relapsing remitting MS (n = 1,670; 87%). Cohort-specific subpopulations contributing to individual outcomes of interest are included in eTable 1 (http://links.lww.com/NXI/A766).
25(OH)D PGS Scores and Circulating 25(OH)D Levels
Initial analyses assessed the association between continuous 25(OH)D PGS with circulating 25(OH)D levels in 935 participants in whom clinical values were available (n = 935). The subgroup of participants with measured 25(OH)D levels was generally similar to the overall JHU cohort regarding age, sex, BMI, and MS characteristics (eTable 2, http://links.lww.com/NXI/A766). 25(OH)D PGS was strongly associated with circulating 25(OH)D levels; each 1 SD increase in 25(OH)D PGS was associated with a 3.08% increase in circulating 25(OH)D level (95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%) (Figure 1).
25(OH)D PGS are derived from summary statistics in which the primary model was adjusted for BMI. The association between circulating 25(OH)D levels and 25(OH)D PGS are adjusted for also BMI among people with MS. We excluded individuals with measured levels exceeding 70 ng/mL, as previous studies suggest this threshold may be the physiologic limit of 25(OH)D derived from nonsupplemental sources. Similar results were obtained when applying a threshold of 100 ng/mL (not shown). 25[OH]D = 25-hydroxyvitamin D; PGS = polygenic score.
25(OH)D PGS Scores and Clinical Outcomes
The pooled results for analyses examining the association between quartiles of 25(OH)D PGS and clinical outcomes are presented in Table 2. We did not observe an association between 25(OH)D PGS and any clinical outcomes (EDSS progression, relapse, MSFC), and the results were consistent for all models considered (eTable 3, http://links.lww.com/NXI/A766). In models considering continuous 25(OH)D PGS, we similarly did not observe any association between 25(OH)D PGS and outcomes in any cohort or overall (Figure 2). Although we did note some potential heterogeneity for analyses of EDSS progression, formal tests were not significant and could be related to relatively few progression events in JHU and IMID cohorts.
125(OH)D PGS are derived from summary statistics in which the primary model was adjusted for BMI. 2Effect estimates displayed are for a 1 SD increase in 25(OH)D PGS. They are adjusted for age, 5 ancestry PCs, MS DMT, disease duration, and the number of relapses in previous 3 years. The pooled effect estimate is results from a random effects meta-analysis. (A) The results for rate of EDSS progression (heterogeneity I2 = 0.00%; p het=0.45). (B) The results for annualized percent change T25FW (I2 = 0.0%; p het=0.91). (C) The results for annualized percent change 9HPT (I2 = 0.0%; p het=0.67). 25[OH]D = 25-hydroxyvitamin D; 9HPT = nine-hole peg test; EDSS = expanded disability status scale; PGS = polygenic score; T25FW = timed 25-foot walk; DMT = disease-modifying therapies; JHU = Johns Hopkins; IMID = immune-mediated inflammatory diseases.
25(OH)D PGS Scores and Imaging Outcomes
Table 3 presents the pooled analysis assessing the association between imaging outcomes and quartiles of 25(OH)D PGS. Similar to clinical outcomes, we did not detect an association between 25(OH)D PGS and any MRI outcome. For example, individuals in the top quartile of 25(OH)D PGS did not have a slower rate of new lesion development relative to individuals in the bottom quartile in either multivariable model considered (model B: pooled rate ratio (RR): 0.98; 95% CI: 0.63, 1.51; model B: pooled RR: 0.99; 95% CI: 0.63, 1.58). The results were similar when we evaluated continuous measures of 25(OH)D PGS (Figure 3). Last, when inner retinal layer atrophy was evaluated as a surrogate of disease progression individuals with available OCT data, rates of retinal atrophy did not substantially differ across 25(OH)D PGS quartiles during pooled cohort analysis (Table 4).
125(OH)D PGS are derived from summary statistics in which the primary model was adjusted for BMI. 2Effect estimates displayed are for a 1 SD increase in 25(OH)D PGS. 2Effect estimates displayed are for a 1 SD increase in 25(OH)D PGS. They are adjusted for age, 5 ancestry PCs, MS DMT, disease duration, and the number of relapses in previous 3 years. The pooled effect estimate is results from a random effects meta-analysis. (A) The results for annualized percent change in BPF (Heterogeneity I2 = 66.0%; p het=0.09). (B) The results for annualized percent change in lesion volume (I2 = 0.0%; p het=0.78). (C) Relative rate for new lesions (I2 = 38.8%; p het=0.20). 25[OH]D = 25-hydroxyvitamin D; BPF = brain parenchymal fraction; DMT = disease-modifying therapies; JHU = Johns Hopkins; PGS = polygenic score.
Sensitivity Analyses
The results were also similar when we used a 25(OH)D PGS that was not adjusted for BMI (eFigures 1 and 2, http://links.lww.com/NXI/A766) and when we considered 25(OH)D PGS derived using a p value threshold of 5e-05 to compute the PGS (instead of 5e-08; eFigures 3 and 4); no associations were observed between 25(OH)D PGS and clinical or imaging outcomes. The results were similar when we modeled EDSS progression using survival analysis (pooled n = 1,066; 287 progression events) or in stratified analyses by relapse type. We also observed no association between 25(OH)D and relapse risk or new lesion formation when applying MR (eTable 4; eFigures 5). The results were also similar when we applied Bayesian meta-analysis methods to pool results.
As a last step, and in accordance with current standards in the field, we assessed the association between serum 25(OH)D levels and radiologic disease activity as an extra layer of validation of the presented findings. Although there was a substantial correlation between circulating 25(OH)D levels and 25(OH)D PGS, we did not find an association between circulating 25(OH)D levels and rate of new lesions (n = 208 with MRI and 25[OH]D levels; per 1SD increase in circulating 25(OH)D: 1.04; 95% CI: 0.76, 1.44).
Discussion
In this large binational study, we observed a strong association between 25(OH)D PGS and circulating 25(OH)D levels, but 25(OH)D PGS did not relate to the clinical outcomes in MS including relapses, disability progression, or imaging outcomes including measures of change in brain or T2 lesion volume and development of new lesions. These results were consistent in analyses considering continuous 25(OH)D PGS, as well as in analyses using quartiles, and analyses where we derived Mendelian randomization estimators.
Having low circulating 25(OH)D levels is an established risk factor for developing MS, where strong observational evidence links low vitamin D intake or low 25(OH)D levels and subsequent risk of MS.6,7,56 Previous Mendelian randomization (MR) studies have also found a strong association between genetically determined 25(OH)D levels and risk of MS.24,-,26 For example, a two-sample MR study incorporating summary information from large-scale genome-wide association studies (GWAS) for MS and 25(OH)D levels implicated low 25(OH)D levels as a causal risk factor for MS. These results are similar to a follow-up analysis in which summary statistics from GWAS for 25(OH)D were derived from larger populations and the most up to date GWAS of MS.57
Several observational studies and small clinical trials have reported a link between low 25(OH)D levels and adverse disease outcomes in MS, as well as suggested a potential favorable effect of vitamin D supplementation on MS disease activity.9,11,13,14 Small experimental vitamin D supplementation studies have reported a beneficial role of supplementation on immunologic, radiologic, and clinical outcomes. However, the results from larger scale randomized clinical trials to date have been less clear, with some positive findings in subgroups or for secondary outcomes but not for the primary outcomes of relapse rate or no evidence of disease activity.9,-,12,14 Notably, each trial included varying supplementation dosages, different disease-modifying therapies as adjunctive therapies, and diverse primary outcomes, all of which could have contributed to differences in the downstream results and conclusions. As a result, equipoise persists as to whether vitamin D supplementation confers any benefit about MS outcomes including relapse risk and new lesion formation. Our results add to this body of evidence suggesting a lack of benefit of modulation of 25(OH)D levels for improving MS outcomes.
Limited studies have examined disease heterogeneity in MS using PGS. In a study by Vandebergh et al.,58 the “response to vitamin D” pathway was identified by Gene Ontology as affecting susceptibility to relapses. In a more recent study, 25(OH)D-related genetic variants were identified by GWAS (using similar studies as in the current report) and 2 sample Mendelian Randomization (MR) was applied to link 25(OH)D with relapse risk in a cohort of 506 PwMS. The authors reported a protective effect of 25(OH)D PGS regarding relapse hazard.28 In our study, an association between 25(OH)D PGS and clinical relapses was not observed, although we included a larger sample size and more diverse set of MS outcomes. This remained true when numerous other clinical and radiologic outcomes were considered as potentially more sensitive proxies of disease activity. Reasons for this discrepancy could be related to the different regions (Europe vs the US and Canada) for which the study population was derived. Although we restricted to individuals with European ancestry, its possible different distributions of underlying contributors to vitamin D status (e.g., obesity) could contribute. We also did not have relapse (the primary outcome in Vandebergh et al.58) in all cohorts, although relapse in our study was derived using a rigorously collected clinical trial cohort. Notably, we also did not apply an identical set of methods in that we considered 25(OH)D PGS instead of MR in our primary analysis; the PGS approach is expected to be more powerful (although has a higher probability of false positives). Here, we applied both techniques and observed a lack of association using both PGS and MR and included other notable outcomes such as the rate of new lesion development which have been noted in previous large observational studies. Brain and retinal imaging data were also included as surrogates for disability because they have been shown to be highly linked with clinical disease progression and long-term MS prognosis.59 We did not find an association between 25(OH)D PGS and any radiographic measures, including change in GCIPL. GCIPL thinning is a highly sensitive marker reflecting global CNS neurodegeneration and disease progression in MS, with the potential to more readily capture subtle changes than clinical outcomes.42,60 Thus, our findings were consistent across a spectrum of clinical and radiographic outcomes.
Our study has some important strengths. The data were obtained from geographically diverse populations with a broad range of clinical presentations and disease durations, enhancing our capacity to quantify the impact of 25(OH)D PGS and replicate our finding in 3 clinically distinct populations. The large total number of participants, long follow-up period, and detailed characterization of each group allowed us to assess the effect of vitamin D on disease heterogeneity after accounting for numerous known clinical and comorbid confounding factors. Nonetheless, the study does have some notable limitations. Namely, the availability of clinical and imaging data were variable across cohorts and outcomes, which could contribute to excess heterogeneity in pooled estimates, although it is worth noting that the I2 were generally low. Data on supplementation and use of medications for some of the cohorts were derived from the EMR and could be vulnerable to misclassification or inaccuracy. We also lacked circulating 25(OH)D levels across cohorts to verify 25(OH)D PGS were consistently associated with measured levels in all cohorts. Notably, the R2 from the model linking circulating 25(OH)D was lower than previous reports in other populations, which could have also contributed to the null results. It is possible underlying differences between the populations (e.g., about environmental or lifestyle factors) in the previous study and in our study may play a role. Genotyped participants were of predominantly European genetic ancestry; therefore, the observed results may not be applicable to more racially and ethnically diverse cohorts. We applied this restriction as similarly sized large multiethnic GWAS for 25(OH)D levels were not available. Horizontal pleiotropy, that is, that the PGS of interest may affect traits that influence the outcome other than the exposure (25[OH]D) of interest is also a potential concern. Although the results were consistent when we applied MR and in sensitivity tests assessing this potential bias, the potential for pleiotropy cannot be eliminated entirely. Furthermore, by design, the 25(OH)D PGS is a time-fixed exposure when 25(OH)D levels vary over the life-course. It is possible that there may be a specific time window in which modulation of 25(OH)D levels would be impactful; this limitation also applies to analyses using MR. Last, low 25(OH)D levels are associated with a higher risk of developing MS; thus, among patients with MS, the distribution of 25(OH)D or 25(OH)PRGS may be truncated, possibly limiting the potential to observe associations with outcomes.
Although 25(OH)D PGS were highly associated with circulating 25(OH)D levels, 25(OH)D was not associated with measures of clinical or radiographic disease progression in people with MS. This finding is largely in-line with larger randomized clinical trials on vitamin D supplementation and raises questions about the plausibility of a treatment effect of vitamin D in established MS. Future research is warranted to understand whether similar findings exist in more racially and ethnically representative populations.
Study Funding
1K01MH121582-01; TA-1805-31,136; THC-135234; W81XWH2010566; MH123724.
Disclosure
Dr. Vasileiou reports no disclosures; Ms. Hu reports no disclosures; Dr. Bernstein reports no disclosures; Dr. Wolinsky received compensation for consulting, scientific advisory boards, or other activities with Avotres, Brainstorm Cell Therapeutics, Cleveland Clinic Foundation, EMD Serono, Inmagene, Novartis/Sandoz, Roche/Genentech, Sanofi Genzyme, University of Alabama. Royalties are received for out licensed monoclonal antibodies through UTHealth to Millipore (Chemicon International) Corporation; Dr. Lublin reports receiving reseach funding from Novartis, Actelion, Biogen, Sanofi, Brainstorm Cell Therapeutics, and has served as a consultant or on an advisory board or DSMB for Biogen, EMD Serono, Novartis, Teva, Actelion/Janssen, Sanofi/Genzyme, Acorda, Roche/Genentech, MedImmune/Viela Bio/Horizon Therapeutics, Receptos/Celgene/BMS, TG Therapeutics, Medday, Atara Biotherapeutics, Mapi Pharma, Apitope, Orion Biotechnology, Brainstorm Cell Therapeutics, Jazz Pharmaceuticals, GW Pharma, Mylan, Immunic, Population Council, Avotres, Neurogene, Banner Life Sciences, Labcorp, Entelexo Biotherapeutics, Neuralight, SetPoint Medical. He also has stock options Avotres and Neuralight, and has received non-promotional speaking fees from Sanofi; Dr. Cutter reports serving on data and safety monitoring boards for AstraZeneca, Avexis, Biolinerx, Brainstorm Cell Therapeutics, Bristol-Myers Squibb–Celgene, CSL Behring, Galmed, GreenValley Pharma, Mapi, Merck, Merck–Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Orphazyme, Sanofi, Reata, Teva Pharmaceuticals, VielaBio, Vivus, the National Heart, Lung, and Blood Institute (Protocol Review Committee), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric Pharmacology Research Unit oversight committee); consulting or advisory boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel, MedDay, MedImmune, Neurogenesis, Novartis, Osmotica, Perception Neurosciences, Recursion–Cerexis, Rekover, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham, Birmingham, AL, USA; and is president of Pythagoras, a private consulting company located in Birmingham, AL, USA; Dr. Sotirchos has served on scientific advisory boards for Horizon Therapeutics, Viela Bio, Alexion and Genentech, and has received speaker fees from Alexion, Viela Bio and Biogen; Dr. Salter reports no disclosures; Dr. Kowalec reports no disclosures; Dr. Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology, and has served on scientific advisory boards for Biogen, Genentech Corporation, TG therapeutics & Bristol Myers Squibb, and he has received consulting fees from Carl Zeiss Meditec and Novartis, and he is the PI of investigator-initiated studies funded by Genentech Corporation and Biogen, and he has previously received support from the Race to Erase MS foundation, and has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer, and he was also the site investigator of a trial sponsored by MedDay Pharmaceuticals; Dr. Mowry reports research support from Biogen, Teva and Genentech, and royalties for editorial duties from UpToDate; Dr. Calabresi has received consulting fees from Disarm, Nervgen, and Biogen, and is PI on grants to JHU from Genentech, Principia, Biogen and Annexon; Dr. Marrie reports no disclosures; Dr. Fitzgerald reports no disclosures.
Acknowledgment
This study was supported in part by the NIH (1K01MH121582-01 to K.C. Fitzgerald) and the National Multiple Sclerosis Society (TA-1805-31136 to K.C. Fitzgerald). The IMID study was funded by the Canadian Institutes of Health Research (THC-135234), Crohn's and Colitis Canada, Research Manitoba, and the Waugh Family Chair in Multiple Sclerosis (to R.A. Marrie), with genotyping supported by the CMSC, the University of Manitoba, and by the Department of Defense Congressionally Directed Medical Research Program, through the Multiple Sclerosis Research Program under Award No. W81XWH2010566 (PI: Kowalec). C.N. Bernstein is supported in part by the Bingham Chair in Gastroenterology. K. Kowalec is supported by the NIMH (MH123724) and the University of Manitoba. The authors acknowledge Shared Health and Health Sciences Centre Winnipeg. The authors acknowledge the use of the Genome QC/Genome QC Innovation Centre/Genome Canada for genotyping facilities for the IMID study.
Appendix Authors
Footnotes
↵* These authors contributed equally to this work.
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article
The Article Processing Charge was funded by the authors.
Submitted and externally peer reviewed. The handling editor was Friedemann Paul, MD.
- Received July 17, 2022.
- Accepted in final form September 26, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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Research Support, Academic Entities:ACTIVE*Title: UAB-UCSD O'Brien Center for Acute Kidney Injury ResearchMajor Goals: Acute kidney injury (AKI) is a major cause for morbidity and mortality in hospitalized patients and is being increasingly recognized as a cause for chronic kidney disease. AKI doubles the length of stay in the hospital, increasing health care resources. The UAB-UCSD O'Brien Center has brought together a team of investigators to serve unmet needs of our investigator base and to fill the gaps in knowledge in the field of AKI and AKI-related research.*Status of Support: Active Project Number: P30 DK079337Name of PD/PI: Agarwal, Anupam*Source of Support: NIDDKD*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 8/1/2018-7/31/2023*Total Award Amount (including Indirect Costs): $1,136,699*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)4. 20220.88 calendar5. 20230.15 calendar*Overlap: There is no scientific or budgetary overlap*Title: The Exercise and Physical Activity Collaborative Team (ExPACT): a Proposed MoTrPAC Clinical CenterMajor Goals: The goals are to help lead the NIH Common Fund initiative Molecular Transducers of Physical Activity Consortium (MoTrPAC) by serving as one of six adult clinical centers conducting a large-scale, randomized, controlled trial (RCT) of resistance vs. endurance exercise training vs. no-exercise control. The RCT will be complemented by molecular acute response studies in RCT participants as well as highly trained athletes; all with the goal of generating molecular maps that reveal potential underpinnings of exercise-induced health benefits.*Status of Support: Active Project Number: U01 AR071133Name of PD/PI: Trappe, S; Bufford, T; Goodpaster, B Name of Individual: Cutter, Gary R. Commons ID: CUTTERG*Source of Support: NIAMS*Primary Place of Performance: Ball State University Project/Proposal Start and End Date: 12/06/2016 - 11/30/2022*Total Award Amount (including Indirect Costs): $13,450,506*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)6. 20222.88 calendar*Overlap: There is no scientific or budgetary overlap*Title: Host Immune Responses to Chlamydia trachomatis Candidate Vaccine Antigens and their Association with Clinical Correlates of Protective Immunity in WomenMajor Goals: The purpose of the study is to evaluate systemic and mucosal cellular and humoral immune responses induced by promising chlamydia vaccine candidate antigens and to assess association of the immune responses with clinical correlates of protection against chlamydia in women.*Status of Support: Active Project Number: R01 AI148359Name of PD/PI: Geisler, William Michael*Source of Support: NIAID*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 5/11/2020-4/30/2025*Total Award Amount (including Indirect Costs): $3,201,254*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)2. 20220.30 calendar3. 20230.30 calendar4. 20240.30 calendar5. 20250.30 calendar*Overlap: There is no scientific or budgetary overlap*Title: Slow Wave Sleep as a Biomarker of Rehabilitation-Induced Cognitive Improvement in Parkinson's DiseaseMajor Goals: This study will investigate deep sleep as a marker of rehabilitation-induced improvement in cognition in Parkinsons disease to guide selection of the optimal exercise prescription for individuals with Parkinson's disease.*Status of Support: Active Project Number: R01 HD100670 Name of Individual: Cutter, Gary R. Commons ID: CUTTERGName of PD/PI: Amara, Amy Willis*Source of Support: NICHD*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 4/1/2021 - 3/31/2026*Total Award Amount (including Indirect Costs): $ 3,043,715*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)2. 20230.29 calendar3. 20240.60 calendar4. 20250.60 calendar5. 20261.20 calendar*Overlap: There is no scientific or budgetary overlap*Title: Childhood Follow-Up Study of Obesity and Neurodevelopment After Perinatal Exposure to Adjunctive Azithromycin Prophylaxis for Cesarean DeliveryMajor Goals: Cesarean delivery, the most common major surgical procedure in the US, is the strongest risk factor for maternal infection (a top 3 cause of death during childbirth). Adjunctive azithromycin compared to standard antibiotic prophylaxis alone is proven (through our large C/SOAP trial and other studies) to be highly effective in preventing infection after cesarean - with authorities now recommending consideration of its use while calling for more information on long-term health outcomes after exposure at birth. We propose a US multi-center long-term follow-up study of children from the parent C/SOAP trial at age 7 (6-9) years to evaluate childhood obesity/growth and neurodevelopment after perinatal exposure to adjunctive azithromycin (complementing our NICHD grant evaluating pulmonary and gastrointestinal health scored at the 6th percentile); findings from this study will be used to inform and strengthen national and global health care policy regarding the safety of adjunctive azithromycin to reduce maternal infection after cesarean delivery.*Status of Support: Active Project Number: R01 HD102962Name of PD/PI: Subramaniam, Akila*Source of Support: NICHD*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 7/20/2020-6/30/2025*Total Award Amount (including Indirect Costs): $ 3,343,613*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)2. 20220.12 calendar3. 20230.12 calendar4. 20240.12 calendar Name of Individual: Cutter, Gary R. Commons ID: CUTTERGYear (YYYY)Person Months (##.##)5. 20250.12 calendar*Overlap: There is no scientific or budgetary overlap*Title: Pregnancy as a Window to the Future: Outcomes of Antihypertensive Therapy and Superimposed Preeclampsia in Pregnant Women with Mild Chronic Hypertension (CHAP Maternal Follow-Up Study)Major Goals: This follow-up study of the well-characterized CHAP cohort will define the impact of preeclampsia and antihypertensive treatment during pregnancy on long-term risk for maternal cardiovascular outcomes and assess the predictive role of factors included in the ASCVD risk score for women aged <40 years. These results will help identify optimal blood pressure preventive strategies to enhance the long-term health of reproductive-aged women with CHTN*Status of Support: Active Project Number: R01 HL120338Name of PD/PI: Tita, Alan Thevenet N.*Source of Support: NHLBI*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 9/1/2021 - 8/31/2026*Total Award Amount (including Indirect Costs): $10,527,329*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)1. 20220.48 calendar2. 20230.60 calendar3. 20240.60 calendar4. 20250.60 calendar5. 20260.60 calendar*Overlap: There is no scientific or budgetary overlap*Title: Rare Disease Network for Myasthenia GravisMajor Goals: We propose development of the Myasthenia Gravis Clinical Research Consortium (MGNet) to coordinate investigators in collection of detailed clinical information and biological specimen along with performance of pilot investigations of a therapeutic and biomarker discovery. We link our efforts to a program to develop new investigators in myasthenia gravis.This is all done with the purpose of enhancing performance clinical trials and care of patients to one day find a cure for myasthenia gravis.*Status of Support: Active Project Number:Name of PD/PI: Kaminski, Henry J*Source of Support: NIH Name of Individual: Cutter, Gary R. Commons ID: CUTTERG*Primary Place of Performance: George Washington University Project/Proposal Start and End Date: 9/1/2019-5/31/2024*Total Award Amount (including Indirect Costs): $ 321,265*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)3. 20220.22 calendar4. 20230.30 calendar5. 20240.30 calendar*Overlap: There is no scientific or budgetary overlap*Title: 2/2 Video Telehealth Pulmonary Rehabilitation to Reduce Hospital Readmission in Chronic Obstructive Pulmonary Disease (Tele-COPD)Major Goals: Twenty percent of patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) are readmitted within 30 days of discharge. Pulmonary rehabilitation is associated with a reduction in hospitalization in patients with COPD, but significant barriers in availability and access limit its use. We propose a multicenter randomized controlled trial that will test whether a video telehealth pulmonary rehabilitation intervention that overcomes these barriers will reduce hospital readmissions, improve quality of life, and be cost- effective.*Status of Support: Active Project Number: U24 HL155807Name of PD/PI: Aban, Inmaculada*Source of Support: NHLBI*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 9/1/2021 - 7/31/2027*Total Award Amount (including Indirect Costs): $ 1,844,073*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)1. 20220.53 calendar2. 20230.60 calendar3. 20240.60 calendar4. 20250.60 calendar5. 20260.60 calendar6. 20270.60 calendar*Overlap: There is no scientific or budgetary overlap Name of Individual: Cutter, Gary R. Commons ID: CUTTERG*Title: Premature Infants Receiving Cord Milking or Delayed Cord Clamping (PREMOD)Major Goals: Delayed cord clamping reduces overall bleeding in the brain of premature infants, but not the most severe types. Milking the umbilical cord, a method used to transfer blood from the placenta into the baby before the umbilical cord is clamped, may provide additional blood volume to the brain and other vital organs thereby reducing bleeding in the brain and improving long-term outcomes in premature babies. This study will determine whether umbilical cord milking reduces bleeding in the brain or death in premature newborns delivered by Cesarean section compared to delaying clamping of the umbilical cord.*Status of Support: Active Project Number:Name of PD/PI: Szychowski, Jeffery M*Source of Support: NIH*Primary Place of Performance: Sharp Healthcare Foundation Project/Proposal Start and End Date: 4/1/2019-3/31/2023*Total Award Amount (including Indirect Costs): $ 547,855*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)4. 20230.12 calendar*Overlap: The scientific overlap is only in the potential for babies that require resuscitation, they could potentially be eligible for the OptiStart trial if the site participates in both trials, but the scientific question is different and there is no budgetary overlap*Title: Preventing Epilepsy Using Vigabatrin in Infants with Tuberous Sclerosis Complex Major Goals: This study focuses on the developmental impact of early vigabatrin treatments ininfants with Tuberous Sclerosis Complex who are at risk of developing epilepsy. Also, the study aims to determine the effectiveness of early vigabatrin treatment in clinical seizure prevention and its impact on the development of drug resistant epilepsy at 24 months of age. This is the first seizure prevention trial in patients with TSC in the United States.*Status of Support: Active Project Number: U01 NS092595 Name of PD/PI: Bebin*Source of Support: NINDS*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 06/01/2016 05/31/2022*Total Award Amount (including Indirect Costs): $ 1,235,496*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)6. 20220.06 calendar Name of Individual: Cutter, Gary R. Commons ID: CUTTERG*Overlap: There is no scientific or budgetary overlapPENDING*Title: Myasthenia Gravis Patient Registry Work Order #15 Major Goals:*Status of Support: Pending Project Number:Name of PD/PI: Aban, Inmaculada B*Source of Support: MGFA*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 9/1/2021-9/30/2023*Total Award Amount (including Indirect Costs): $137,817*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)2. 20230.30 calendar*Overlap: There is no scientific or budgetary overlap*Title: Transferring Speed of Processing Gains to Everyday Cognitive Tasks after StrokeMajor Goals: The goal is to test in adults with chronic cognitive impairment after stroke whether a set of behavioral techniques, adapted from CI Movement therapy, for transferring therapeutic gains from the treatment to everyday setting enhances the scope, size, and durability of gains in carrying out everyday tasks with important cognitive components observed after speed of cognitive processing training.*Status of Support: Pending Project Number: R01 AG070049 Name of PD/PI: Taub, Edward*Source of Support: NIA*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 9/5/2021 - 8/31/2025*Total Award Amount (including Indirect Costs): $2,245,294*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)Person Months (##.##)1. 20230.30 calendar2. 20240.30 calendar3. 20250.30 calendar*Overlap: There is no scientific or budgetary overlap Name of Individual: Cutter, Gary R. Commons ID: CUTTERG*Title: Endovascular vs. Surgical Arteriovenous Fistula OutcomesMajor Goals: Arteriovenous fistulas (AVFs) are the preferred type of vascular access for hemodialysis, and surgical creation of AVFs is the current gold standard, yet many surgical AVFs fail to mature for use. Endovascular AVF creation, a novel percutaneous (non-surgical) method to create a vascular access, was recently approved by the FDA. The goal of the proposed research is to establish a solid foundation for the design and conduct of a randomized clinical trial to compare the clinical and economic impact of endovascular AVFs and surgical AVFs.*Status of Support: Pending Project Number:Name of PD/PI: Al-Balas, Alian Ali*Source of Support: Southern Society for Clinical Investigation*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 07/01/2020-06/30/2025*Total Award Amount (including Indirect Costs): $930,946*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20210.6 calendar2. 20220.6 calendar3. 20230.6 calendar4. 20240.6 calendar5. 20250.6 calendar*Overlap: There is no scientific or budgetary overlap*Title: Optimization of Saturation Targets and Resuscitation Trial (OptiSTART)Major Goals: Multicenter randomized controlled trial to evaluate two different ranges of target goal saturations for preterm resuscitation in the delivery room*Status of Support: Pending Project Number: R01 HD104970 Name of PD/PI: Kapadia, Vishal*Source of Support: NICHD*Primary Place of Performance: University of Texas Southwestern Medical Center Project/Proposal Start and End Date: 4/1/2022 - 3/31/2027*Total Award Amount (including Indirect Costs): $ 2,928,922*Person Months (Calendar/Academic/Summer) per budget period. Name of Individual: Cutter, Gary R. Commons ID: CUTTERGYear (YYYY)`Person Months (##.##)1. 20230.12 calendar2. 20240.12 calendar3. 20250.12 calendar4. 20260.12 calendar5. 20270.12 calendar*Overlap: The scientific overlap is only in the potential for babies that require resuscitation, they could potentially be eligible for the PREMOD trial if the site participates in both trials, but the scientific question is different and there is no budgetary overlap*Title: Early Epilepsy Surgery in Tuberous Sclerosis ComplexMajor Goals: This study will determine if epilepsy surgery improves language and behavior in children with tuberous sclerosis complex that are not seizure free on medications. It will provide guidance for doctors and caregivers to understand how the timing of epilepsy surgery impacts language development and discover what contributes to decision making about which patients undergo surgery.*Status of Support: Pending Project Number:Name of PD/PI: Aban, Inmaculada B.*Source of Support: NIH*Primary Place of Performance: Stanford University Project/Proposal Start and End Date: 2/1/2022 - 1/31/2028*Total Award Amount (including Indirect Costs): 281,882*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.12 calendar2. 20240.3 calendar3. 20250.3 calendar4. 20260.6 calendar5. 20270.6 calendar6. 20280.6 calendar*Overlap: There is no scientific or budgetary overlap*Title: NB-UVB Phototherapy with Established Disease-Modifying-Therapies to Counteract Demyelination and Attenuate NeuroinflammationMajor Goals: The specific Aims are (1) Evaluate the efficacy of octal-interval-frequency (O.I.F.) NB-UVB phototherapy in attenuating EAE, (2) Determine the underlying mechanism of anti- inflammatory and anti-oxidative responses and, (3) Determine whether NB-UVB treatment promotes neuronal repair and/or slows progression of neuronal damage. The results from this pre-clinical study will provide the foundation for a Phase 2/Phase 3 clinical study in partnership with LumaVive that is expected to begin within two years from onset of this pre-clinical study. Name of Individual: Cutter, Gary R. Commons ID: CUTTERG*Status of Support: Pending Project Number:Name of PD/PI: Raman, Chander*Source of Support: NMSS*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 6/1/2021-6/1/2023*Total Award Amount (including Indirect Costs): $599,999*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20220.6 calendar2. 20230.6 calendar*Overlap: There is no scientific or budgetary overlap*Title: Intrathecal production of CXCL13: A prognostic biomarker in MS Major Goals:*Status of Support: Pending Project Number:Name of PD/PI: Pachner, Andrew*Source of Support: NIH*Primary Place of Performance: Dartmouth-Hitchcock Clinic Project/Proposal Start and End Date: 9/1/2022-8/31/2027*Total Award Amount (including Indirect Costs): $ 26,315*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.6 calendar2. 20240.6 calendar3. 20250.6 calendar4. 20260.6 calendar5. 20270.6 calendar*Overlap: There is no scientific or budgetary overlap*Title: Chemopreventive role of Melatonin and its Metabolites in UVB Induced CancerogenesisMajor Goals: We will establish melatonin as a potent chemo preventive natural product against UVB-induced photocarcenogenesis and determine if its metabolites are more potent in this activity. The in vivo testing will use a unique genetically altered mouse model of UVB-induced squamous and basal cell carcinomas, which faithfully recapitulates the pathogenesis of human Name of Individual: Cutter, Gary R. Commons ID: CUTTERGcancers. We will also elucidate the mechanisms of action, which will include melatonin/metabolites regulation of AhR and/or IL-17 and NRF2 signaling.*Status of Support: Pending Project Number:Name of PD/PI: Slominski, Andrzej Tadeusz*Source of Support: NIH*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 7/1/2022-6/30/2027*Total Award Amount (including Indirect Costs): $3,712,495*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.3 calendar2. 20240.3 calendar3. 20250.3 calendar4. 20260.3 calendar5. 20270.3 calendar*Overlap: There is no scientific or budgetary overlap*Title: Reducing Future Fractures and Improving Outcomes in People with Fragility FracturesMajor Goals: RESTORE aims to test whether a specialist-FLS service where patients are contacted by a patient navigator and referred to a bone health specialist (who is more likely to prescribe a bone medicine) is better than an FLS service where patient navigators encourage patients to engage with their outpatient primary care providers. We also aim to determine the influence of race, ethnicity, sex, poverty level, geographic region, and timing of entry into the trial after a fracture on the effectiveness of the two strategies to prevent another fracture.*Status of Support: Pending Project Number:Name of PD/PI: Saag, Kenneth G*Source of Support: PCORI*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 12/1/2022-11/30/2027*Total Award Amount (including Indirect Costs): $13,845,791*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.6 calendar2. 20240.6 calendar3. 20250.6 calendar4. 20260.6 calendar Name of Individual: Cutter, Gary R. Commons ID: CUTTERGYear (YYYY)`Person Months (##.##)5. 20270.9 calendar*Overlap: There is no scientific or budgetary overlap*Title: Technique to Enable Return-to-Work by Employees with Long COVID Brain FogMajor Goals: The goals are to (a) refocus a new cognitive rehabilitation therapy for persistent brain fog and cognitive impairment in adults with long COVID to target return-to-work in this population and (b) evaluate the feasibility and acceptability of the modified intervention.*Status of Support: Pending Project Number:Name of PD/PI: Uswatte, Gitendra*Source of Support: Administration for Community Living/DHHS*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 09/01/22-08/31/25*Total Award Amount (including Indirect Costs): $599,726*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.3 calendar2. 20240.3 calendar3. 20250.3 calendar*Overlap: There is no scientific or budgetary overlap*Title: A Therapy for Long COVID Brain Fog and Cognitive Impairment.Major Goals: The goal is to evaluate the efficacy of a new cognitive rehabilitation therapy for persistent brain fog and cognitive impairment in adults with long COVID. The new therapy combines cognitive speed of processing training with a set of behavioral change techniques, adapted from CI Movement therapy.*Status of Support: Pending Project Number:Name of PD/PI: Taub, Edward*Source of Support: NIH*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 09/01/2022 -08/31/2026*Total Award Amount (including Indirect Costs): $2,462,212*Person Months (Calendar/Academic/Summer) per budget period. Name of Individual: Cutter, Gary R. Commons ID: CUTTERGYear (YYYY)`Person Months (##.##)1. 20230.3 calendar2. 20240.3 calendar3. 20250.3 calendar4. 20260.3 calendar*Overlap: There is no scientific or budgetary overlap*Title: Neutrophil Dysregulation as a Critical Driver in the Pathogenesis of Multiple SclerosisMajor Goals: Multiple sclerosis (MS) is a chronic autoimmune disease caused by demyelination of neurons in the central nervous system (CNS). Neutrophils are implicated to play a major role in demyelination in mice with experimental autoimmune encephalitis (EAE). The overall goals of this proposal are to define the role of neutrophil subpopulations as driving mechanisms of MS, and to identify the mechanisms responsible for chronic neutrophilic activation in MS in order to reveal the specific checkpoints for intervention.*Status of Support: Pending Project Number:Name of PD/PI: Raman, Chander*Source of Support: NIH*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 09/01/2022-08/31/2027*Total Award Amount (including Indirect Costs): $ 3,681,085*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.6 calendar2. 20240.6 calendar3. 20250.6 calendar4. 20260.6 calendar5. 20270.6 calendar*Overlap: There is no scientific or budgetary overlap*Title: Improving COVID-19 Vaccine Uptake Among Racial and Ethnic Minority Groups with Rheumatic DiseasesMajor Goals: People with autoimmune rheumatic diseases (AIRDs) such as rheumatoid arthritis or systemic lupus erythematosus, especially those on immunosuppressive treatment, often experience poorer outcomes following COVID-19 infection. Individuals with AIRDs, including Black and Latinx persons, are concerned about side effects, may have limited awareness about the complexity of COVID-19 vaccination and timing of subsequent vaccine doses in the context of AIRD and/or immunosuppressive treatment, or may have barriers to obtaining a COVID-19 vaccine dose. This study aims to test whether a novel intervention using first-person narratives (i.e., storytelling) recounting personal experiences with the COVID-19 vaccination as well as patient navigation to provide logistics support for and reinforce safety and effectiveness of Name of Individual: Cutter, Gary R. Commons ID: CUTTERGCOVID-19 vaccination will result in an increase in vaccination uptake among Black and Latinx adults with AIRDs.*Status of Support: Pending Project Number:Name of PD/PI: Danila, Maria I*Source of Support: NIH*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 12/01/2022-11/30/2027*Total Award Amount (including Indirect Costs): $ 3,669,258*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.6 calendar2. 20240.6 calendar3. 20250.6 calendar4. 20260.6 calendar5. 20270.6 calendar*Overlap: There is no scientific or budgetary overlap*Title: Canonical and Non-Canonical Secosteroid Activation and Signaling Pathways in Immunomodulation of Multiple SclerosisMajor Goals: Vitamin D deficiency in MS is common and vitamin D has an essential function in regulating the immune system to counteract an autoimmunity, however, benefits of vitamin D supplementation have been mixed. We have discovered novel pathways of vitamin D activation with products that are non-calcemic and that can affect immune cells activities in unique ways. Using comprehensive and unbiased approaches, we will determine if any of these immune cell intrinsic pathways are defective in MS and whether CYP11A1 derivatives will affect functions of lymphocytes in control and MS patients with a long-term objective to utilize immunoregulatory and anti-oxidative properties of novel vitamin D derivatives in therapy of MS.*Status of Support: Pending Project Number:Name of PD/PI: Raman, Chander*Source of Support: NIAID*Primary Place of Performance: University of Alabama at Birmingham Project/Proposal Start and End Date: 10/01/2022-09/30/2027*Total Award Amount (including Indirect Costs): $ 3,697,405*Person Months (Calendar/Academic/Summer) per budget period.Year (YYYY)`Person Months (##.##)1. 20230.6 calendar Name of Individual: Cutter, Gary R. Commons ID: CUTTERGYear (YYYY)`Person Months (##.##)2. 20240.6 calendar3. 20250.6 calendar4. 20260.6 calendar5. 20270.6 calendar*Overlap: There is no scientific or budgetary overlapIn-KindNone*Overlap (summarized for each individual):I have reviewed my obligations and confirm that the aggregate effort on all currently active projects does not exceed 12 months. In the event that funding of pending grants leads to an effort level greater than 12 months, my effort will be reduced and the effort of other qualified personnel on the project will be increased.
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:None
License Fee Payments, Technology or Inventions:Consortium of MS Centers - Past President and Board Member - only expenses covered
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:Scientific advisory boards:1) Alexion 2) Horizon Therapeutics 3) Genentech 4) Viela Bio 5) Ad Scientiam
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:Speaker honoraria:1) Alexion 2) Viela Bio
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:National Institutes of Health (NIH) K23NS117883
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:1) National MS Society (NMSS) FP-1607-249992) National MS Society (NMSS) TA-1904-338343) Sumaira Foundation
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:None
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:None
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:(1) Commercial entity: Consulting with Emerald Lake Safety Ltd. (2017-2018).
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:None
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:(1) DSMB for Premature Infants Receiving Milking or Delayed Cord Clamping: PREMOD2(2) OSMB for Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis(3) DSMB for Ocrelizuamb for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease: CELLO(4) DSMB for Video Telehealth Pulmonary Rehabilitation to Reduce Hospital Readmission in Chronic Obstructive Pulmonary Disease: Tele-COPD
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:None
Patents:Circulation: Cardiovascular Imaging, Statistical Editor, 2018-2021Neurology, Editorial board member, 2021-2022
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:Gryphon Bio, LLC
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:(1) Department of Defense, Principal Investigator, 2021-2024
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:(1) Consortium of Multiple Sclerosis Centers (2) National Multiple Sclerosis Society (3) MS Society of Canada
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:Dr. Saidha has served on scientific advisory boards for TG Therapeutics, Novartis, Biogen, Bristol Myers Squibb, and Genentech.
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:None
Patents:I am a member of the editorial board of Multiple Sclerosis Journal and editor of Multiple Sclerosis Journal Experimental, Translational and Clinical
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:Consulting fees from Medical Logix for the development of CME programs in neurology, and has received equity compensation and consulting fee for consulting from JuneBrain LLC, a retinal imaging device developer. He has also consulted for Carl Zeiss Meditec and Novartis.
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:Dr. Saidha is the PI of investigator-initiated studies funded by Genentech Corporation, Biogen, and Novartis, is the site PI of a trial sponsored by Novartis, and was also the site investigator of a trial sponsored by MedDay Pharmaceuticals.
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:Dr. Saidha receives research funding from the National MS Society
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:DSMB member for NIAID
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:None
Patents:Editorial boards: Multiple Sclerosis Journal, 2020-
Publishing Royalties:NONE
Employment, Commercial Entity:UptoDate chapter editor
Consultancies:NONE
Speakers' Bureaus:1.BeCare Link LLC, 2022-
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:(1)Free glatiramer acetate for a clinical trial from Teva Neuroscience.(2)Research funding paid to my institution from Biogen and Genentech (for investigator-initiated studies).(3) Site PI of studies sponsored by Biogen and Genentech
Research Support, Academic Entities:(1)Department of Defense, W81XWH-16-1-0693, 9/2016-9/2022(2)National Institutes of Health, 1R01NR018851-01A1, 9/2020-6/2025
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:1. National Multiple Sclerosis Society. 2. Patient-Centered Outcomes Research Institute (PCORI)
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:1. DiSARM Therapeutics (now part of Lilly)2. Biogen3. Avidea Technologies
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:1. NMSS (travel only)2. Myelin Repair Foundation (honorarium)
Patents:Neurology Editorial Board 2007 to 2017Journal of Clinical Investigation Associate Editor-2017-2022Multiple Sclerosis Journal Editorial Board-present
Publishing Royalties:Report of invention filed for use of bryostatin in autoimmune disease.
Employment, Commercial Entity:Optical Coherence Tomography in Neurological Diseases (book)Royalties for being co-editor received from Cambridge Press.
Consultancies:NONE
Speakers' Bureaus:1. DiSARM Therapeutics (now Lilly)2. Biogen3. Avidea technologies4. Idorsia
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:We utilize OCT in the clinic and bill for patients not enrolled in research studies. I have been a co-author on papers outlining guidelines for use of OCT.
Research Support, Government Entities:1. Principia (expired 2021)2. Genentech (active)3. Myelin Repair Foundation (active)
Research Support, Academic Entities:NIH, NINDS R-01 NS041435 2020-2025 PINIH, NINDS R-01 NS082347 2018-2023 PIDoD, CDRMS W81XWH1910622 2019-2021 PI
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:National MS Society (NMSS) The role of complement C3 in retinal neuroprotection in EAENMSS, sNfL healthy control normative data
License Fee Payments, Technology or Inventions:1. Disarm Therapeutics 2. Avidea technologies (now Vaccitech)Katharine Whartenby, PhD (my wife)1. Shares of MyMD
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:None
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:None
Patents:Multiple Sclerosis Journal, Editorial BoardMultiple Sclerosis Journal-ETC, Co-Editor (ended Dec 2020)Neurology, Editorial Board (2022)
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:Roche Canada (no direct funding to me or my institution), Biogen (no direct funding to me or my institution)
Research Support, Academic Entities:Received support as principal investigator from theCanadian Institutes of Health Research (2010-2023), and Research Manitoba (2014-2022) and as co-investigator from US Department of Defense (2020-2023).
Research Support, Foundations and Societies:Waugh Family Chair in Multiple Sclerosis
Stock/Stock Options/Board of Directors Compensation:Received support as principal investigator from Multiple Sclerosis Society of Canada (2009-2025) and theNational Multiple Sclerosis Society (2013-2023), and as co-principal investigator from Multiple Sclerosis Scientific Foundation (2009-2021). Received support from Consortium of Multiple Sclerosis Centers (2004-2009, 2011-2014, 2016-2022), Crohn's and Colitis Canada (2014-2023), The Arthritis Society (2021-2023)
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:Data safety monitoring board for NIH-funded study.
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:None
Patents:Frontiers in Epidemiology Associate Editor
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NIH NIMH 1-K01MH121582-01, PI, 2019-2023
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:Career Transition Fellowship (TA-1805-31136) from the National MS Society
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE