Douglas Goodin

University of California, San Francisco | UCSF · Department of Neurology

Background and Objectives Prospective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televi...

OBJECTIVE To explore the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and to define the limits of this nature based on the statistical uncertainties regarding the various epidemiological observations that have been made. BACKGROUND Certain parameters of MS-epidemiology can be directly observed (e.g., the risk of MS...

Objective A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive dise...

Objective To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans. Background Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex ( MHC ) have been known for decades. For example, the haplotypes HLA-...

Background To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes ( CEHs ) of the MHC and three non- MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A . Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susce...

Objective To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases. Background Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS pati...

Aortic disease such as aortitis, aneurysms, or coarctation, and aortic surgery may lead to spinal cord ischemia, cerebral ischemia, and peripheral neuropathy. These complications are discussed in the present chapter, as is their pathogenesis. Specific conditions are then reviewed, including syphilitic aortitis, Takayasu and giant cell arteritis, di...

OBJECTIVE: To explore the nature and basis of environmental and genetic susceptibility to multiple sclerosis (MS). BACKGROUND Susceptibility to multiple sclerosis (MS) is complex but clearly involves both environmental events and genetic factors. Certain epidemiological observations regarding MS (e.g., proportion of women among MS patients, populat...

Background In persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments. Objective The aim of this study was to develop and validate a scalable, electronic, unsupervised patient-...

BACKGROUND To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptib...

OBJECTIVE: To explore the nature of MS-susceptibility and, by extension, other complex-genetic diseases. BACKGROUND Basic-epidemiological parameters of MS (e.g., prevalence, recurrence-risks for siblings and twins, time-dependent changes in sex-ratio, etc.) are well-established. Moreover, >200 genetic-loci are unequivocally MS-associated, especiall...

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). Methods: Adults with MS/CIS in the UCSF-EPIC cohort study were included. LTL was measured on DNA samples by quantitative PCR and expressed as telomere to somatic DNA...

Supplementary Table S1a: Comparison of pyramidal, cerebellar and bowel/bladder functional scales at baseline between the silent progression sub‐group versus the other sub‐groups Supplementary Table S1b: Comparison of pyramidal, cerebellar and bowel/bladder functional scales at long‐term follow‐up between the silent progression sub‐group versus the...

Supplementary Table S5: Analysis of the influence of age‐adjusted baseline brain volumes on short term, one year confirmed and long‐term disability in participants with and without clinical relapses

Supplementary Table S3: Analysis of the influence of age‐adjusted baseline brain volume on long‐term disability.

Supplementary Table S7a Sensitivity analysis of the correlations of relapses with disability and radiographic findings excluding participants who remained CIS at last observation Supplementary Table S7b: Multivariate regression model of relative brain volume over time, excluding stable CIS subjects

Supplementary Table S2a: Multivariate regression of platform therapies on relative brain volume over time Supplementary Table S2b: Multivariate regression of escalation therapy on relative brain volume over time Supplementary Table S2c: Comparison of relative brain loss by treatment tier

Supplementary Table S4: Analysis of the influence of age‐adjusted baseline brain volumes on silent progression

Supplementary Table S6a: Analysis of the impact of brain MRI activity on long‐term disability in treated and untreated participants Supplementary Table S6b: Analysis of the impact of brain MRI activity on brain atrophy in treated and untreated participants

OBJECTIVE: To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes of the MHC and three non-MHC risk-loci nearby genes EOMES, ZFP36L1, CLEC16A. BACKGROUND: Defining “genetic-susceptibility” as having a non-zero probability of developing MS, both theoretical considerations and epidemi...

Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pre‐treatment era. Nonetheless, in our recently reported prospective cohort more than half of patients with relapsing MS accumulated significant new disabili...

Background: Long-term follow-up from the randomized trial of interferon beta-1b (IFNB-1b) permitted the assessment of different definitions of no evidence of disease activity (NEDA) for predicting long-term outcome in multiple sclerosis (MS). Objective: To examine the predictive validity of different NEDA definitions. Methods: Predictive valid...

Objective To determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility. Background Among the ~200 MS-susceptibility regions, which are known from genome-wide analyses of single nucleotide polymorphisms (SNPs), the MHC accounts for roughly a third of the curren...

This section develops the mathematical model for understanding the dynamics of haplotype conversion and selection as they relate to the MHC. This is the model used in the Text to estimate the values of these two parameters from the WTCCC and EPIC data. (PDF)

Conserved extended haplotypes (CEHs) in the WTCCC, the EPIC, and in other populations. This includes an estimate of the overlap (in % of the total number of CEHs) of each ethnicity with the CEHs from another ethnicity. (XLSX)

This section considers the wide-spread occurrence of high frequency CEHs in different human populations and also how the WTCCC population differs from certain other populations of the world. (PDF)

This section includes the data for Figures (A–C). (PDF)

Variations in the frequency of the 25 most common CEHs in different geographic regions participating in the WTCCC and in the EPIC. (XLSX)

Common extended haplotypes (CEHs) in the EPIC population. (DOCX)

Background: Electronic medical records (EMR) data are increasingly used in research, but no studies have yet evaluated similarity between EMR and research-quality data and between characteristics of an EMR multiple sclerosis (MS) population and known natural MS history. Objectives: To (1) identify MS patients in an EMR system and extract clinica...

Establishing the relative efficacy and safety of the different disease modifying therapies (DMTs) in multiple sclerosis (MS) is critical to the choice of agent that clinicians recommend for individual MS patients. The best evidence for the relative efficacy of the different DMTs comes from head-to-head randomized clinical trials (RCTs). Understandi...

MS-pathogenesis involves both genetic-susceptibility and environmental determinants. Three (or more) sequential environmental-factors are implicated. The first acts near birth, the second acts during childhood/adolescence, and the third acts subsequently. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem particularl...

Supporting Information

Objectives: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and MRI data used in clinical trials have long-term prognostic value. Methods: This is a prospective study of 517 actively managed MS patients enrolled at a single center. Results: More...

Early experience in MS generated concerns that interferon beta treatment might provoke onset or worsening of depression. The objective of the study was to compare depression incidence in relapsing–remitting MS patients receiving interferon beta-1b (IFNB-1b) or glatiramer acetate (GA) in the BEYOND trial. 891/897 (99 %) of English, French, Spanish a...

Background Epidemiological observations regarding certain population-wide parameters (e.g., disease-prevalence, recurrence-risk in relatives, gender predilections, and the distribution of common genetic-variants) place important constraints on the possibilities for the genetic-basis underlying susceptibility to multiple sclerosis (MS). Methods Usin...

The pathogenesis of multiple sclerosis (MS) involves both genetic-susceptibility and, at least, three sequential environmental-events. The first environmental-event is a maternal-factor, which acts near birth. The second acts subsequently but prior to approximately age 15 years and the third acts long after these first two events have already taken...

Patient-Reported Expanded Disability Status Scale (PREDSS) tools are an attractive alternative to the Expanded Disability Status Scale (EDSS) during long term or geographically challenging studies, or in pressured clinical service environments. Objectives: because the studies reporting these tools have used different metrics to compare the PREDSS...

Importance Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS.Objective To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-...

Multiple sclerosis (MS) is a recurrent inflammatory disease of the central nervous system, which ultimately causes substantial disability in many patients. A key clinical feature of this disease is the occurrence of relapses, consisting of episodes of neurological dysfunction followed by periods of remission. This review considers in detail the imp...

Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the CNS that requires long-term treatment. The identification of patient characteristics that can help predict disease outcomes could improve care for patients with MS. The objective of this study is to identify predictors of disease activity in patients from the BEYOND...

Genome-wide association studies (GWAS), using single nucleotide polymorphisms (SNPs), have yielded 110 non-human leucocyte antigen genomic regions that are associated with multiple sclerosis (MS). Despite this large number of associations, however, only 28% of MS-heritability can currently be explained. Here we compare the use of multi-SNP-haplotyp...

In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging technique...

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine – i.e. the application of informati...

Timely individualized treatment is essential to improving relapsing-remitting multiple sclerosis (RRMS) patient health outcomes, yet little is known about how patients make treatment decisions. We sought to evaluate RRMS patient preferences for risks and benefits of treatment. Fifty patients with RRMS completed conjoint analysis surveys with 16 hyp...

Objective: In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we...

Understanding patient preferences facilitates shared decision-making and focuses on patient-centered outcomes. Little is known about relapsing remitting multiple sclerosis (RRMS) patient preferences for disease modifying therapies (DMTs). We use choice based conjoint (CBC) analysis to calculate patient preferences for risk/benefit trade-offs for hy...

Background: Information on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascu...

Genome-wide association studies (GWAS) identify disease-associations for single-nucleotide-polymorphisms (SNPs) from scattered genomic-locations. However, SNPs frequently reside on several different SNP-haplotypes, only some of which may be disease-associated. This circumstance lowers the observed odds-ratio for disease-association. Here we develop...

Aortic disease such as aortitis, aneurysms, or coarctation, and aortic surgery may lead to spinal cord ischemia, cerebral ischemia, and peripheral neuropathy. These complications are discussed in the present chapter, as is their pathogenesis. Specific conditions are then reviewed, including syphilitic aortitis, Takayasu and giant cell arteritis, di...

Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we ra...

The purpose of studying the epidemiology of multiple sclerosis (MS) is twofold. First, it is important to understand clearly the natural history of the illness in order to assist patients in making decisions about their future with respect to issues such as family planning, the importance of securing lifelong healthcare, their ability to get and ma...

Glucorticorticoids have both anti-inflammatory and immunosuppressive properties and both synthetic and natural glucocorticoid medications have been used to treat a number of inflammatory and autoimmune conditions, including the management of acute multiple sclerosis (MS) attacks. Many of the studies supporting the use of this approach to MS treatme...

Mortality in patients with multiple sclerosis (MS) is significantly increased compared with the general population. Many questions concerning survival in MS are still unanswered due to the difficulty of comparing information collected at different times and in different geographic areas. The increasing incidence of MS, the improvement in care of th...

Importance: High serum levels of interleukin 17F (IL-17F) at baseline have been associated with suboptimal response to interferon beta in patients with relapsing-remitting multiple sclerosis. Objective: To further investigate the role of IL-17F in predicting treatment response to interferon beta-1b in patients with relapsing-remitting multiple s...

The modern era of the therapy for multiple sclerosis began in the 1990s with introduction of interferon beta and glatiramer acetate. Now 20 years since the introduction of these disease modifying therapies, several alternatives have become available. Although, in many cases, these new agents seem especially effective, there is little head-to-head t...

Making only the assumption that twins are representative of the population from which they are drawn, we here develop a simple mathematical model (using widely available epidemiological information) that sheds considerable light on the pathogenesis of complex human diseases. Specifically, for the case of multiple sclerosis (MS), we demonstrate that...

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Compared with controls, multiple sclerosis (MS) patients die, on average, 7-14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46-47% in the two groups who received active therapy during the RCT. To determine whether th...

To the Editor: Dr Shirani and colleagues¹ suggested that interferon beta treatment was not associated with a reduction in progression of long-term disability in patients with multiple sclerosis (MS). In contrast, long-term follow-up of a randomized controlled trial of interferon beta-1b reported a 60% to 70% reduction in long-term disability² and a...

Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs. Blood samples from 125 IFNB-1b-treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three y...

In reply We thank Hanwell and Kimball¹ for their interest in our case report.² Recently, the Institute of Medicine recommended that individuals aged 51 to 70 years (our patient's age bracket) have a daily intake level of 1200 mg of calcium and 600 IU of vitamin D.³ It also suggested tolerable daily upper intake levels of 2000 mg and 4000 IU for cal...

To determine whether retinal axonal loss is detectable in patients with a clinically isolated syndrome (CIS), a first clinical demyelinating attack suggestive of multiple sclerosis (MS), and examine patterns of retinal axonal loss across MS disease subtypes. Spectral-domain Optical Coherence Tomography was performed in 541 patients with MS, includi...

To evaluate whether spinal cord intraoperative monitoring (IOM) with somatosensory and transcranial electrical motor evoked potentials (EPs) predict adverse surgical outcomes. A panel of experts reviewed the results of a comprehensive literature search and identified published studies relevant to the clinical question. These studies were classified...

To describe a patient with multiple sclerosis (MS) who developed severe hypercalcemia, attributed to the additive effect of 5500 IU of cholecalciferol and 2020 mg of calcium daily. Case report. University hospital. A 58-year-old woman with MS and osteoporosis presenting with acute-onset tremors and confusion. Serum calcium and 25-hydroxyvitamin D l...

Evaluating the long term benefit of therapy in multiple sclerosis (MS) is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established. In a patient cohort from the pivotal interferon β-1b trial, the value of clinical...

To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 d...

Percentage of the time that different weighting schemes were selected in the 2,000 samples selected using bootstrap methods (see text for details). The “optimal” weighting scheme (bTN4SN2) was chosen in 52% of the time. However, the next most commonly selected weighting schemes (bTN4SN3, eTN4SN3, eTN4SN4, and bTN1SN3) are similar to the bTN4SN2 sch...

The on-therapy event-rate (annualized attack-rate) in clinical trials since the completion of the original IFNβ-1b (Betaseron®) trial2, 3