University of California, San Diego

Author Of 2 Presentations

Microbiome Late Breaking Abstracts

LB01.05 - Network analysis identifies gut bacteria associated with multiple sclerosis relapse among pediatric-onset patients

Abstract

Background

Commensal gut microbes are known to affect host immune function and may be modifiable. Recent work suggests gut microbiota composition contributes to onset of MS; however, little is known about its contribution to MS disease activity.

Objectives

Estimate the association between gut microbiota and subsequent disease activity among individuals with pediatric-onset MS (pedMS) from the U.S. Network of Pediatric MS Centers.

Methods

Stool samples were collected from cases (MS symptom onset <18 years) and profiled using 16S rRNA sequencing of the V4 region. Amplicon sequence variants (ASVs) were identified using the Divisive Amplicon Denoising Algorithm-2 (DADA2). ASVs present in <20% of samples were removed. ASV clusters (modules) were identified using weighted genetic correlation network analysis (WGCNA) and sparCC transformation of ASV abundance. Cox proportional hazard recurrent event models were used to examine the relationship between individual ASVs and then ASV clusters, adjusted for age, sex, and disease modifying therapy (DMT) use.

Results

Of 53 pedMS cases, 72% were girls. At stool sample collection, the mean age was 15.5 years (SD: 2.7) and disease duration was 1.1 years (SD: 1.0). Less than half (45%) had one relapse and 30% had >1 relapse over the subsequent mean follow-up of 2.5 years (SD:1.3). Over this time, 91% used a DMT. Among 270 individual ASVs included in the analyses, 20 were nominally significant (p<0.05), e.g. the presence of Blautia stercoris was associated with higher relapse risk (hazard ratio [HR]=2.50; 95% confidence interval [CI]=1.43, 4.37). WGCNA identified 6 ASV modules. Higher values of one module’s eigengene was significantly (false discovery rate q<0.2) associated with higher relapse risk (HR=1.23, 95% CI=1.02, 1.50). Four ASVs nominally associated with higher relapse risk were in this module. These included Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

Conclusions

We found that a high relative abundance of a gut microbiota species within the Blautia genus, and its interconnected variants, was associated with a higher relapse risk in pedMS cases. While our study represents the largest of its kind in MS, findings need to be replicated. However, Blautia stercoris has been linked to disease activity in other immune-mediated diseases such as systemic lupus erythematosus.

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Pediatric MS Oral Presentation

PS04.04 - Evidence for an interaction between ozone pollution and HLA-DRB1*15 alleles in pediatric multiple sclerosis

Abstract

Background

We previously reported a relationship between air pollutants and increased risk of pediatric MS (ped-MS). Environmental risk factor research in ped-MS offers the advantage of shorter duration between exposure and disease onset. Ozone, an air pollutant, is a major global health hazard thought to have a role in MS pathoetiology. Identifying gene-environment interactions advances the understanding of biological processes at play in MS susceptibility.

Objectives

We sought to examine the interaction between ozone pollution and DRB1*15 status as the main genetic variant associated with MS susceptibility.

Methods

Cases and controls enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers were analysed. County-level modeled ozone data were acquired from the CDC’s Environmental Tracking Network air pollution database. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS were assessed by logistic regression. Interaction between tertiles of ozone level and presence of DRB1*15 alleles on odds of ped-MS was evaluated. Models were adjusted for sex, race, ethnicity, age, second-hand smoke exposure, and mother’s education. Additive interaction was estimated using relative risk due to interaction (RERI) and attributable proportion of disease were calculated.

Results

355 ped-MS cases and 565 controls contributed to the analyses. Ozone levels were associated with MS with an odds ratio (OR) of 2.35 (95%CI 1.57–3.51) and 2.21 (95%CI 1.48–3.32) in the upper two tertiles, respectively, compared with the lowest tertile. DRB1 status was also independently associated with MS (OR 1.99; 95%CI 1.43–2.78). There was a significant additive interaction between ozone and DRB1, with a RERI of 2.74 (95%CI 0.50–4.98) and 2.43 (95%CI 0.36–4.5) in the upper two tertiles, respectively. Approximately 60% of the ped-MS risk in those with HLA-DRB1*15 haplotype and high ozone exposure was attributable to the interaction between these risk factors.

Conclusions

Our data revealed additive interaction between higher exposure to ozone and DRB1 alleles on ped-MS susceptibility. Further evaluation of additional genetic variants that might play a role in ozone-induced ped-MS is underway to provide mechanistic insight.

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Moderator Of 1 Session

Parallel Session Sat, Sep 12, 2020
Session Type
Parallel Session
Date
Sat, Sep 12, 2020
Time (ET)
12:45 - 14:15

Author Of 6 Presentations

Disease Modifying Therapies – Mechanism of Action Poster Presentation

LB1174 - Patient and healthcare professional perspectives of immune dynamics and MS disease-modifying therapies mode of action throughout COVID-19 pandemic   (ID 1766)

Speakers
Presentation Number
LB1174
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) modulate or deplete immune cells, including T and B cells. Healthcare professionals (HCPs) and patients consider many factors when selecting a DMT in a shared decision model, including efficacy, frequency/route of administration and safety. Patient understanding of mechanisms of action (MoA), and DMT effects on the dynamics and function of the immune system may be challenging to understand and further influenced by the COVID-19 pandemic, including risk interpretation and administration preferences.

Objectives

To assess the involvement of patients in MS treatment selection and the importance for patient understanding of MoA using a patient narrative approach, and to design a preliminary qualitative survey to inform future studies.

Methods

A preliminary qualitative survey was developed to explore factors most important to patients when considering DMTs, including patient understanding of immunological aspects of MS, MoAs, preferences regarding route of administration and provision of MS clinical information. Perspectives were sought from HCPs and patients on how this dialog has changed during the COVID-19 pandemic. The survey was distributed by email to 3 patients and 1 caregiver.

Results

Results are based on survey results and email correspondence from two adults with RMS, and an adolescent with pediatric MS and her caregiver. Overall, respondents felt they understood the general role of the immune system in MS and the role of DMTs but had poorer understanding of B and T cell functions and the impact of DMTs and their MoAs. Safety and efficacy were equally the most important variables when considering a new DMT. Face-to-face discussions between patients and HCPs were preferred to noninteractive materials; HCP authors (3 neurologists and 1 MS physician assistant) agreed that more face-to-face clinic time for dialog is needed. Patient independence was a key factor in preferences for methods of administration. Respondents reported an increase in MoA conversations in light of COVID-19.

Conclusions

While safety and efficacy are important in patients’ considerations of DMTs, there is a clear need to increase understanding of MoAs when starting or switching DMTs; immunological knowledge has become increasingly important during the COVID-19 pandemic. The preliminary qualitative survey can be used to inform future studies of what is needed to improve communication on DMT MoAs.

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Clinical Outcome Measures Poster Presentation

P0091 - Improving patient outcomes through a comprehensive care management platform (MOVING MS) (ID 364)

Speakers
Presentation Number
P0091
Presentation Topic
Clinical Outcome Measures

Abstract

Background

When standard of care neurology visits are 6 months apart, there can often be gaps in care and missed opportunities to improve patient function; the result is poor follow-up for care management or low medication adherence. MS care can be comprehensively approached with a human-tech platform that supports symptom and medication tracking, nursing interventions, laboratory monitoring for subclinical disease activity and curated MRI reports to ensure accurate data at return visits.

Objectives

To test the Octave integrated MS care platform for efficacy in reducing unplanned healthcare utilization (UHU) and improving patient and physician satisfaction.

Methods

This prospective, randomized study with a within-subjects, waitlist-control trial design aims to reduce UHU costs and increase patient and physician satisfaction with their MS care. Secondary endpoints include determining the feasibility of the human-tech service, blood-based disease activity tests and enhanced MRI reports. Approximately 80 participants will be randomized to a case or waitlist group. Case subjects will have access to the platform for all 12 months of enrollment; waitlist subjects will have access for the second 6 months of enrollment. The platform includes medication and symptom tracking, check-ins every 2 weeks with an MS-certified nurse and curated physician/MRI reports. UHU will be qualified by events captured in the EHR and monetary value assigned to these events. Satisfaction will be measured through participant and physician questionnaires. Subject’s blood tests will be correlated to symptomology and MRI findings to assess subclinical disease activity.

Results

UHU was created by Octave and is a composite metric of unplanned office visits and communication by phone or e-message, weighted by expense per interaction as collected in the EHR. Our analysis aims to quantify the UHU difference between 1) case vs. control samples over the first 6 months of the study, and 2) waitlist control patients for the first vs. second 6 months of the study. Satisfaction will be measured between case and control groups using a Likert scale and quantified with a 2-sample t-test.

Conclusions

This trial aims to improve MS disease management, reduce UHU and increase patient/physician satisfaction through a mobile platform intervention, using a waitlist design.

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Imaging Poster Presentation

P0583 - High throughput lesion evaluation and quality control for incorporating quantitative imaging metrics into clinical practice (ID 1502)

Speakers
Presentation Number
P0583
Presentation Topic
Imaging

Abstract

Background

Automated multiple sclerosis lesion counts and volumes are poised to be salient clinical biomarkers of disease progression; however, algorithmic variability and low expert agreement prevents widespread adoption in clinical practice. Because every method has a non-negligible error rate, visual quality control (QC) is required before a clinical decision can be made. QC is a bottleneck to the use of automated lesion count and volume metrics in the clinic. A method is needed to 1) quickly evaluate experts and non-experts to understand and resolve disagreements, and 2) quickly QC the output of automated lesion segmentation methods.

Objectives

To evaluate the feasibility of a web application called braindr (Keshavan et al., 2019) for high-throughput QC of automated lesion segmentation by measuring the 1) intra-rater reliability, 2) the inter-rater reliability, and 3) to characterize the types of lesions that are disagreed upon.

Methods

3D T1 and FLAIR images from 32 subjects were registered, N4 bias field corrected, and z-scored. Subtraction images (Z_FLAIR-Z_T1) were thresholded at varying levels. A triplanar image of each resulting segmentation (called a potential lesion, PL) was generated, resulting in over 80,000 individual PL’s needing QC, which simulates a high-throughput scenario with a high error rate. Expert and non-expert raters were asked to pass or fail PLs based on the 2D triplanar image on the app. We measured variability between and within raters by calculating the intraclass correlation coefficients (ICC).

Results

1) Feasibility: 14,973 PLs were labelled by 5 raters. The raters were a neuroradiologist (MI), a general neurologist (BD), 2 experienced technicians (AK, KL), and 1 beginner (MB). 2) Intra-rater reliability (ICC(1,1)) : a) neuroradiologist: 0.97, b) beginner: 0.90, c) experienced techs: 0.87, 0.85, and d) neurologist: 0.84. 3) Inter-rater reliability for an average rating ICC(2,k) = 0.92, and individual ICC(2,1) = 0.74. 4) Disagreements occurred more frequently on PL’s in the brainstem, cerebellum, hippocampal, and basal ganglia.

Conclusions

We simultaneously evaluated raters, and QC’d lesions from an automated method using a quick, scalable, web application. This enables us to 1) improve expert agreement on lesion identification, 2) develop better quality education materials for experts and non-experts alike, 3) train new raters quickly, and 4) ensure the quality of the measurements at scale.

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Microbiome Poster Presentation

P0671 - Exploring the gut microbiome in multiple sclerosis via the international MS Microbiome Study (iMSMS) (ID 1532)

Abstract

Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

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Pediatric MS Poster Presentation

P1082 - Therapeutic Response in Pediatric Neuromyelitis Optics Spectrum Disorder (ID 1820)

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition which can led to significant disability. Approximately 4% of the NMOSD cases are pediatric onset. At present, there are limited studies that aim at guiding physicians in their treatment choices for NMOSD in children.

Objectives

To evaluate the effect of different disease modifying therapies (DMT) with respect to attack prevention in children with NMOSD.

Methods

Cohort study that included 12 clinical centers participating in the US Network of Pediatric MS Centers. Cases were validated for NMOSD diagnostic criteria and classified via serostatus as AQP4+, MOG+, or double-seronegative (DS). Clinical data, including demographics, attack details, type of initial DMT (rituximab, mycophenolate mofetil, azathioprine, IVIg) and neurological visit data were extracted from charts, centrally collected in a database, and analyzed. Treatment response in the three serostatus subgroups was evaluated. Effect of DMTs on annualized relapse rate (ARR) was assessed by negative binomial regression.

Results

111 pediatric patients with NMOSD were identified: 80 AQP4+, 10 MOG+, 14 double seronegative (DS), and 7 with unknown serostatus (94 females and 17 males; 48 white, 47 African American, 13 other races). Mean follow-up duration was 1.9 years (SD±2.2). About 6% of patients were treatment-naive. First-line DMTs varied by serostatus: in the AQP4+ subgroup 42% used rituximab, 16% mycophenolate mofetil, 16% azathioprine, and 8% IVIg. Among MOG+ patients, 13% received rituximab, 13% azathioprine, 13% mycophenolate, and 38% IVIg. Within the DS group, rituximab was used in 21% of cases, azathioprine in 7%, mycophenolate in 21%, and IVIg in 21%. In the unknown serogroup, 33% received rituximab, 17% azathioprine, 0% mycophenolate, and 33% IVIg. The ARR calculated in all the serogroups was 0.25 (95% CI 0.13-0.46) for rituximab, 0.73 (95% CI 0.27-2.00) for azathioprine, 0.40 (95% CI 0.18-0.89) for mycophenolate, and 0.56 (95% CI 0.26-1.20) for IVIg. In the AQP4+ subgroup, the patients started on rituximab showed an ARR of 0.25 (95% CI 0.13-0.48), those on azathioprine an ARR of 0.76 (95% CI 0.24-2.39), those on mycophenolate an ARR 0.43 (95% CI 0.17-1.07), and those on IVIg an ARR of 0.63 (95% CI 0.26-1.55).

Conclusions

This retrospective study showed that rituximab is associated with a lowered annual relapse rate in pediatric NMOSD and in particular in the AQP4+ subgroup.

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Invited Presentations Invited Abstracts

TC12.03 - Presentation 03 (ID 625)

Speakers
Authors
Presentation Number
TC12.03
Presentation Topic
Invited Presentations

Abstract

Abstract

N/A

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Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

TC12.03 - Presentation 03 (ID 625)

Speakers
Authors
Presentation Number
TC12.03
Presentation Topic
Invited Presentations

Abstract

Abstract

N/A

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Moderator Of 1 Session

Teaching Course Fri, Sep 11, 2020
Session Type
Teaching Course
Date
Fri, Sep 11, 2020

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

TC12.03 - Presentation 03 (ID 625)

Speakers
Authors
Presentation Number
TC12.03
Presentation Topic
Invited Presentations

Abstract

Abstract

N/A

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