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Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β = −0.4882, P = 2.73 × 10−7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79–0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48–0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale = 0.8289, P = 3.52 × 10−8), the other in males (rs698805; βmale = −1.5395, P = 4.35 × 10−8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10−4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.

Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for the disease. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14 802 cases and 26 703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31 684) and brain (n = 1194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (Dataset 1: n = 73 cases and 97 controls; Dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (Dataset 1: n = 4 cases and 5 controls; Dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared with controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.

Immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) produce significant disability and often require maintenance treatment. There is a paucity of epidemiological data on these conditions in Australia.We undertook a prevalence study of CIDP and MMN in North Queensland and Tasmania, coinciding with a national census. Diagnoses were classified against the diagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society. Case ascertainment was undertaken via multiple methods, including survey of local neurologists across public and private clinics, search of neurophysiology, neurology and hospital databases, search of admitted hospital database collections using ICD codes and through immunoglobulin therapy prescription lists.The crude prevalence of CIDP was 5.00 per 100,000 (95% confidence interval [CI] 3.79-6.62) and the crude prevalence of MMN was 1.33 per 100,000 (95% CI 0.78-2.27). Prevalence was also investigated using National Blood Authority numbers of cases prescribed immunoglobulin therapy, indicating a CIDP prevalence of 5.72 per 100,000 (95% CI 4.41-7.43) and MMN prevalence of 1.94 per 100,000 (95% CI 1.24-3.03). There was no significant difference between these numbers and those calculated through access of patient records locally. There was no significant difference in prevalence between Tasmania and North Queensland for any category.This study updates the prevalence of CIDP and MMN in Australia. Understanding the distribution of CIDP and MMN patients and their need for treatment is essential for future resource planning and to enable monitoring and coordination of therapies such as immunoglobulin.

As of June 2009, 361 genome-wide association studies (GWAS) had been referenced by the HuGE database. GWAS require DNA from many thousands of individuals, relying on suitable DNA collections. We recently performed a multiple sclerosis (MS) GWAS where a substantial component of the cases (24%) had DNA derived from saliva. Genotyping was done on the Illumina genotyping platform using the Infinium Hap370CNV DUO microarray. Additionally, we genotyped 10 individuals in duplicate using both saliva- and blood-derived DNA. The performance of blood- versus saliva-derived DNA was compared using genotyping call rate, which reflects both the quantity and quality of genotyping per sample and the “GCScore,” an Illumina genotyping quality score, which is a measure of DNA quality. We also compared genotype calls and GCScores for the 10 sample pairs. Call rates were assessed for each sample individually. For the GWAS samples, we compared data according to source of DNA and center of origin. We observed high concordance in genotyping quality and quantity between the paired samples and minimal loss of quality and quantity of DNA in the saliva samples in the large GWAS sample, with the blood samples showing greater variation between centers of origin. This large data set highlights the usefulness of saliva DNA for genotyping, especially in high-density single-nucleotide polymorphism microarray studies such as GWAS. Cancer Epidemiol Biomarkers Prev; 19(3); 794–8

Supplementary Figures 1-5, Supplementary Tables 1-3, Full List of Authors and Affiliations from Saliva-Derived DNA Performs Well in Large-Scale, High-Density Single-Nucleotide Polymorphism Microarray Studies

Background: People with multiple sclerosis face significant employment-related challenges, with little known of the drivers of these outcomes. Objective: We examined prospective trajectories of employment-related outcomes up to 11 years following a first episode of central nervous system (CNS) demyelination (FCD). Methods: Participants were aged 18–59 years, at FCD, with at least two observations and were employed at study entry or anytime during follow-up ( n = 207). Outcomes were employment status (full-time, part-time and unemployed), average workhours per week and disability support pension (DSP; receiving/not receiving). We used group-based trajectory modelling to identify groups with common trajectories. Factors associated with trajectory membership were explored using log-multinomial regression. Results: Distinct trajectories were identified for employment (4), workhours (4) and DSP (2). Compared with stable full-time, female sex was strongly associated with being in the stable part-time trajectory (risk ratio (RR): 5.35; 95% confidence interval (CI) = 2.56–11.20; p Conclusion: These trajectories indicate substantial heterogeneity and the complex impact of MS on employment from its earliest timepoints. Understanding these trends could enable better targeting of interventions to facilitate workforce retention, particularly for females, those with a higher number of comorbidities, more frequent relapses and greater rate of disability accrual.

Background and ObjectivesLongitudinal cognitive trajectories in multiple sclerosis are heterogeneous and difficult to measure. We aimed to identify discrete longitudinal reaction time trajectories in relapsing-remitting multiple sclerosis using a computerized cognitive battery and to assess the association between trajectories of reaction time and disability progression.MethodsAll participants serially completed computerized reaction time tasks measuring psychomotor speed, visual attention, and working memory. Participants completed at least 3 testing sessions over a minimum of 180 days. Longitudinal reaction times were modeled with latent class mixed models to identify groups of individuals sharing similar latent characteristics. Optimal models were validated for consistency and baseline associations with class membership tested using multinomial logistic regression. Interclass differences in the probability of reaction time worsening and the probability of 6-month confirmed disability progression were assessed with survival analysis.ResultsA total of 460 people with relapsing-remitting multiple sclerosis were included in the analysis. For each task of the MSReactor battery, the optimal model comprised 3 latent classes. All MSReactor tasks could identify a group with high probability of reaction time slowing. The visual attention and working memory tasks could identify a group of participants who were 3.7 and 2.6 times more likely to experience a 6-month confirmed disability progression, respectively. Participants could be classified into predicted cognitive trajectories after just 5 tests with 64% to 89% accuracy.DiscussionLatent class modeling of longitudinal cognitive data collected by a computerized battery identified patients with worsening reaction times and increased risk of disability progression. Slower baseline reaction time, age, and disability increased assignment into this trajectory. Monitoring of cognition in clinical practice with computerized tests may enable detection of cognitive change trajectories and people with relapsing-remitting multiple sclerosis at risk of disability progression.

An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well established, but whether this reflects a shared genetic aetiology, and whether consistent genetic relationships exist between MS and the two predominant IBD subtypes, ulcerative colitis (UC) and Crohn’s disease (CD), remains unclear. Here, we use large-scale genome-wide association study summary data to investigate the shared genetic architecture between MS and IBD overall and UC and CD independently. We find a significantly greater genetic correlation between MS and UC than between MS and CD, and identify three SNPs shared between MS and IBD (rs13428812), UC (rs116555563) and CD (rs13428812, rs9977672) in cross-trait meta-analyses. We find suggestive evidence for a causal effect of MS on UC and IBD using Mendelian randomization, but no or weak and inconsistent evidence for a causal effect of IBD or UC on MS. We observe largely consistent patterns of tissue-specific heritability enrichment for MS and IBDs in lung, spleen, whole blood and small intestine, and identify cell-type-specific enrichment for MS and IBDs in CD4+ T cells in lung and CD8+ cytotoxic T cells in lung and spleen. Our study sheds light on the biological basis of comorbidity between MS and IBD., An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but a genetic link is unclear. Here, the authors investigate the shared genetic architecture between MS and IBD to shed light on the biological basis of comorbidity.

Background Health state utilities (HSU) are a health-related quality-of-life (HRQoL) input for cost-utility analyses used for resource allocation decisions, including medication reimbursement. New Zealand (NZ) guidelines recommend the EQ-5D instruments; however, the EQ-5D-5L may not sufficiently capture psychosocial health. We evaluated HRQoL among people with multiple sclerosis (MS) in NZ using the EQ-5D-5L and assessed the instrument’s discriminatory sensitivity for a NZ MS cohort. Methods Participants were recruited from the NZ MS Prevalence Study. Participants self-completed a 45-min online survey that included the EQ-5D-5L/EQ-VAS. Disability severity was classified using the Expanded Disability Status Scale (EDSS) to categorise participant disability as mild (EDSS: 0–3.5), moderate (EDSS: 4.0–6.0) and severe (EDSS: 6.5–9.5). Anxiety/depression were also measured using the Hospital Anxiety and Depression Score (HADS). In the absence of an EQ-5D-5L NZ tariff, HSUs were derived using an Australian tariff. We evaluated associations between HSUs and participant characteristics with linear regression models. Results 254 participants entered the study. Mean age was 55.2 years, 79.5% were female. Mean (SD) EQ-5D-5L HSU was 0.58 (0.33). Mean (SD) HSUs for disability categories were: mild 0.80 ± 0.17, moderate 0.57 ± 0.21 and severe 0.14 ± 0.32. Twelve percent reported HSU = 1.0 (i.e., no problems in any domain). Participants who had never used a disease-modifying therapy reported a lower mean HSU. Multivariable modelling found that the HADS anxiety score was not associated with EQ-5D-5L. Conclusions HRQoL for people with MS in NZ was lower than comparable countries, including Australia. We suggest a comparison with other generic tools that may have improved sensitivity to mental health.

Background: Disease-modifying therapies (DMTs) are used to treat people with relapsing-onset multiple sclerosis (ROMS), but our knowledge is largely limited to their short-term effects. Objective: To determine (1) the impact of national-level DMT subsidy policy on DMT use and health outcomes in people with MS (PwMS) and (2) the long-term effects of DMT on disability and quality of life (QoL; 5-level EQ-5D version (EQ-5D-5L) utility value). Methods: This observational cohort study compared Australian and New Zealand populations with different levels of DMT availability 10–20 years post-ROMS diagnosis. Between-country differences were assessed using standardised differences. Associations were assessed with multivariable linear regression models. Results: We recruited 328 Australians and 256 New Zealanders. The Australian cohort had longer DMT treatment duration, greater proportion of disease course treated and shorter duration between diagnosis and starting DMT. The Australian cohort had lower median Expanded Disability Status Scale (EDSS) (3.5 vs 4.0) and Multiple Sclerosis Severity Score (MSSS) (3.05 vs 3.71) and higher QoL (0.71 vs 0.65). In multivariable models, between-country differences in disability and QoL were largely attributed to differential use of DMT. Conclusions: This study provides evidence for the impact of national-level DMT policy on disability outcomes in PwMS. Where DMTs are more accessible, PwMS experienced less disability progression and improved QoL 10–20 years post-diagnosis.

Background and ObjectivesTo longitudinally investigate patients with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), quantifying timing and location of sensory involvements in motor onset patients, along with clinicohistopathologic and electrophysiologic findings to ascertain differences in patients with and without monoclonal gammopathy of uncertain significance (MGUS).MethodsPatients with MADSAM seen at Mayo Clinic and tested for monoclonal gammopathy and ganglioside antibodies were retrospectively reviewed (January 1, 2007–December 31, 2018).ResultsOf 76 patients with MADSAM, 53% had pure motor, 16% pure sensory, 30% sensorimotor, and 1% cranial nerve onsets. Motor-onset patients were initially diagnosed with multifocal motor neuropathy (MMN). MGUS occurred in 25% (89% immunoglobulin M [IgM] subtype), associating with ganglioside autoantibodies (p < 0.001) and higher IgM titers (p < 0.04). Median time to sensory involvements (confirmed by electrophysiology) in motor onset patients was 18 months (range 6–180). Compared to initial motor nerve involvements, subsequent sensory findings were within the same territory in 35% (14/40), outside in 20% (8/40), or both in 45% (18/40). Brachial and lumbosacral plexus MRI was abnormal in 87% (34/39) and 84% (21/25), respectively, identifying hypertrophy and increased T2 signal predominantly in brachial plexus trunks (64%), divisions (69%), and cords (69%), and intrapelvic sciatic (64%) and femoral (44%) nerves. Proximal fascicular nerve biopsies (n = 9) more frequently demonstrated onion-bulb pathology (p = 0.001) and endoneurial inflammation (p = 0.01) than distal biopsies (n = 17). MRI and biopsy findings were similar among patient subgroups. Initial Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores were higher in patients with MGUS relative to without (p = 0.02). Long-term treatment responsiveness by INCAT score reduction ≥1 or motor Neuropathy Impairment Score (mNIS) >8-point reduction occurred in 75% (49/65) irrespective of MGUS or motor onsets. Most required ongoing immunotherapy (86%). Patients with MGUS more commonly required dual-agent immunotherapy for stability (p = 0.02).DiscussionPure motor onsets are the most common MADSAM presentation. Long-term follow-up, repeat electrophysiology, and nerve pathology help distinguish motor onset MADSAM from MMN. Better long-term immunotherapy responsiveness occurs in motor onset MADSAM compared to MMN reports. Patients with MGUS commonly require dual immunotherapy.Classification of EvidenceThis study provides Class II evidence that most clinical, electrophysiologic, and histopathologic findings were similar between patients with MADSAM with and without MGUS.

BACKGROUND: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. METHODS: Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. RESULTS: There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Māori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000. CONCLUSION: The prevalence of NMOSD in the Māori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.

Background Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the central nervous system which results in disability over time and reduced quality of life. To increase the sensitivity of the EQ-5D-5L for psychosocial health, four bolt-on items from the AQoL-8D were used to create the nine-item EQ-5D-5L-Psychosocial. We aimed to externally validate the EQ-5D-5L-Psychosocial in a large cohort of people with MS (pwMS) and explore the discriminatory power of the new instrument with EQ-5D-5L/AQoL-8D. Methods A large representative sample from the Australian MS Longitudinal Study completed the AQoL-8D and EQ-5D-5L (including EQ VAS) and both instruments health state utilities (HSUs) were scored using Australian tariffs. Sociodemographic/clinical data were also collected. External validity of EQ-5D-5L-Psychosocial scoring algorithm was assessed with mean absolute errors (MAE) and Spearman’s correlation coefficient. Discriminatory sensitivity was assessed with an examination of ceiling/floor effects, and disability severity classifications. Results Among 1683 participants (mean age: 58.6 years; 80% female), over half (55%) had moderate or severe disability. MAE (0.063) and the distribution of the prediction error were similar to the original development study. Mean (± standard deviation) HSUs were EQ-5D-5L: 0.58 ± 0.32, EQ-5D-5L-Psychosocial 0.62 ± 0.29, and AQoL-8D: 0.63 ± 0.20. N = 157 (10%) scored perfect health (i.e. HSU = 1.0) on the EQ-5D-5L, but reported a mean HSU of 0.90 on the alternative instruments. The Sleep bolt-on dimension was particularly important for pwMS. Conclusions The EQ-5D-5L-Psychosocial is more sensitive than the EQ-5D-5L in pwMS whose HSUs approach those reflecting full health. When respondent burden is taken into account, the EQ-5D-5L-Psychosocial is preferential to the AQoL-8D. We suggest a larger confirmatory study comparing all prevalent multi-attribute utility instruments for pwMS.

Among immune-mediated neuropathies, clinical-electrophysiological overlap exists between multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and multifocal motor neuropathy (MMN). Divergent immune pathogenesis, immunotherapy response, and prognosis exist between these two disorders. MRI reports have not shown distinction of these disorders, but biopsy confirmation is lacking in earlier reports. MADSAM nerves are hypertrophic with onion bulbs, inflammation, and edema, whereas MMN findings are limited to multifocal axonal atrophy.To understand if plexus MRI can distinguish MADSAM from MMN among pathologically (nerve biopsy) confirmed cases.Retrospective chart review and blinded plexus MRI review of biopsy-confirmed MADSAM and MMN cases at Mayo Clinic.Nine brachial plexuses (MADSAM-5, MMN-4) and 6 lumbosacral plexuses (MADSAM-4, MMN-2) had fascicular biopsies of varied nerves. Median follow-up in MADSAM was 93 months (range: 7-180) and 27 (range: 12-109) in MMN (p = 0.34). MRI hypertrophy occurred solely in MADSAM (89%, 8/9) with T2-hyperintensity in both. There was no correlation between time to imaging for hypertrophy, symptom onset age, or motor neuropathy impairments (mNIS). At last follow-up, on diverse immunotherapies mNIS improved in MADSAM (median - 4, range: -22 to 0), whereas MMN worsened (median 3, range: 0 to 6, p = 0.03) on largely IVIG.Nerve hypertrophy on plexus MRI helps distinguish MMN from MADSAM, where better immunotherapy treatment outcomes were observed. These findings are consistent with the immune pathogenesis seen on biopsies. Radiologic distinction is possible independent of time to imaging and extent of motor deficits, suggesting MRI is helpful in patients with uncertain clinical-electrophysiologic diagnosis, especially motor-onset MADSAM.

Background: A comprehensive understanding of factors associated with multiple sclerosis (MS)-related work productivity loss will inform targeted interventions. We have previously shown the strong impact of symptom severity on MS-related work productivity loss. However, the effect of work difficulties, work self-efficacy and work psychological safety is yet to be well evaluated in this context. Objectives: This study evaluates the association between work difficulties, work self-efficacy and work psychological safety, and MS-related presenteeism, absenteeism and total work productivity loss. Methods: We analysed data from employed participants of the Australian MS Longitudinal Study (AMSLS) who took part in both the 2015 Medication and Disease Course survey, and 2015 Employment survey ( n = 744). Data were analysed using Cragg Hurdle regression models. Results: We found that low workplace self-esteem, interpersonal difficulties at work and work self-efficacy were associated with total work productivity loss. In a multivariable model, a 10-unit decrease in workplace self-esteem, increase in interpersonal difficulties at work and 5-unit increase in work self-efficacy were independently associated with a 3.75% increase, 2.89% increase and 3.36% reduction in total work productivity loss, respectively. When separating total work productivity loss in presenteeism and absenteeism, stronger effects were seen for presenteeism than absenteeism. Surprisingly, work psychological safety was not associated with MS-related work productivity loss. Conclusion: Work psychosocial well-being such as self-confidence at work, work self-efficacy and interpersonal difficulties at work are crucial factors governing work productivity in people with MS (PwMS). Multidisciplinary support team assistance of PwMS in symptom self-care, skills around effective communication about MS in the workplace, the psychological impact of work and the modification of work demands may positively influence the employment outcomes.

Background and purpose: This study was undertaken to identify clinically meaningful comorbidity patterns and their associations with the demographic/clinical characteristics of people with multiple sclerosis (MS). Methods: We conducted latent class analysis to identify clinically distinct comorbidity patterns in MS using the 15 most common comorbidities among 1518 Australian Multiple Sclerosis Longitudinal Study participants. The associations between demographic/clinical characteristics and comorbidity patterns were examined using log-binomial and multinomial logistic regression. Results: Five distinct comorbidity patterns were identified: "minimally diseased class" (30.8%), consisting of participants with no or one comorbidity; "metabolic class" (22.7%); "mental health-allergy class" (21.7%); "nonmetabolic class" (7.6%); and "severely diseased class" (7.0%), consisting of participants with higher prevalence of these comorbidities. The relative probabilities of being assigned to comorbidity classes compared to the minimally diseased class were significantly increased for participants who were older (metabolic: relative risk ratio [RRR] = 1.09, 95% confidence interval [CI] = 1.06-1.11; nonmetabolic: RRR = 1.07, 95% CI = 1.04-1.11; severely diseased: RRR = 1.04, 95% CI = 1.01-1.08), female (nonmetabolic: RRR = 5.35, 95% CI = 1.98-14.42; severely diseased: RRR = 2.21, 95% CI = 1.02-4.77), and obese (metabolic: RRR = 4.06, 95% CI = 2.45-6.72; mental health-allergy: RRR = 1.57, 95% CI = 1.00-2.46; severely diseased: RRR = 4.53, 95% CI = 2.21-9.29) and who had moderate disability (mental health-allergy: RRR = 2.32, 95% CI = 1.47-3.64; severely diseased: RRR = 2.65, 95% CI = 1.16-6.04). Conclusions: Comorbidity patterns exist in MS. Women, people who were older, people who were obese, and people who had higher disability levels were more likely to be in classes with higher levels of comorbidity. These findings may offer opportunities for designing more personalised approaches to comorbidity prevention and treatment.

Background: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. Objective: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. Methods: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. Results: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = −1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (β = 0.38, 95% CI = 0.04, 0.72, p = 0.03). Conclusion: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS.

Background/objectives: Associations between patterns of food intake and health in people with multiple sclerosis (MS) are of increasing global interest; however, Australian data are lacking. This study aimed to assess the dietary habits and associations with health outcomes of Australians with MS. Subjects/methods: This cross-sectional study used 2016 survey data from the Australian MS Longitudinal Study, including the Dietary Habits Questionnaire, Hospital Anxiety and Depression Scale, Assessment of Quality of Life, Fatigue Severity Scale, Patient-Determined Disease Steps Scale and 13 MS symptoms scales. Regression models were constructed using directed acyclic graphs. Results: Almost all (94.3%) of the 1490 participants reported making an effort to eating healthy with 21.2% following one or more specific diets, although often not strictly. Overall, 7.9% reported not eating meat, 8.1% reported not consuming dairy, and 4.0% consumed neither food group. A healthier diet score was associated with better mental, physical and total quality of life, and lower depression, and pain scores, and fewer cognition, vision and bowel symptoms. Higher reported fibre, fruit, vegetable and healthy fat scores were positively associated with most health outcomes. Conclusions: Healthier overall diet scores and higher fibre, fruit and vegetable scores were associated with better health outcomes in this sample of Australians adults with MS. However, the proportion of participants avoiding dairy and meat, or adhering to a specific MS diet was much lower than previously reported. Prospective dietary studies are needed to further understand whether dietary change is feasible and affects health outcomes over time.

Nutrient runoff from catchments that drain into the Great Barrier Reef (GBR) is a significant source of stress for this World Heritage Area. An alliance of collaborative on-ground water quality monitoring (Project 25) and technologically driven digital application development (Digiscape GBR) projects were formulated to provide data that highlighted the contribution of a network of Australian sugar cane farmers, amongst other sources, to nutrient runoff. This environmental data and subsequent information were extended to the farming community through scientist-led feedback sessions and the development of specialised digital technology (1622™WQ) that help build an understanding of the nutrient movements, in this case nitrogen, such that farmers might think about and eventually act to alter their fertilizer application practices. This paper reflects on a socio-environmental sustainability challenge that emerged during this case study, by utilising the nascent concept of digi-grasping. We highlight the importance of the entire agricultural knowledge and advice network being part of an innovation journey to increase the utility of digital agricultural technologies developed to increase overall sustainability. We develop the digi-MAST analytical framework, which explores modes of being and doing in the digital world, ranging from ‘the everyday mystery of the digital world (M)’, through digital ‘awareness (A)’, digitally ‘sparked’ being/s (S), and finally the ability of individuals and/or groups to ‘transform (T)’ utilising digital technologies and human imaginations. Our digi-MAST framework allows us to compare agricultural actors, in this case, to understand present modes of digi-grasping to help determine the resources and actions likely to be required to achieve impact from the development of various forms of digital technological research outputs.

Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR = 0.92, P = 2.4x10− 5; rs12211604: HR = 1.16, P = 3.2x10− 7; rs55858457: HR = 0.93, P = 3.7x10− 7; rs10271373: HR = 0.90, P = 1.1x10− 7; rs11256593: HR = 1.13, P = 5.1x10− 57; rs12588969: HR = 1.10, P = 2.1x10− 10; rs1465697: HR = 1.09, P = 1.7x10− 128) associated with worsening of disability; most of which are located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles provided a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

BackgroundSleep difficulties are common in people with multiple sclerosis (MS), but whether associations between poor sleep quality and quality of life are independent of MS symptoms, obesity and other MS-related factors remains unclear.MethodsCross-sectional analyses of data from the Australian MS Longitudinal Study (n=1717). Sleep was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and International Restless Legs Syndrome Study Group Rating Scale; health-related quality of life using the Assessment of Quality-of-Life 8-D.ResultsPoor sleep quality was common (67%), and more common than in community samples. Sleep measures clustered independently within MS symptoms. The clusters ‘fatigue and cognitive’, ‘feelings of anxiety and depression’, ‘pain and sensory’, were independently associated with poor sleep quality. Quality-of-Life utility scores were a clinically meaningful 0.19 units lower in those with poor sleep. Sleep quality, daytime sleepiness and restless leg syndrome were associated with reduced quality of life, independent of MS-related symptoms and body mass index.ConclusionPoor sleep quality is common in MS and was strongly associated with worse health-related quality of life, independent of other MS symptoms and did not cluster with other common MS symptoms. Improving sleep quality may substantially improve quality of life in people with MS.

BackgroundLittle is known about the comparative effectiveness of multiple sclerosis (MS) disease-modifying therapies (DMTs) on patient-reported outcomes in MS. We compared the effects of natalizumab to other DMTs in relation to MS symptom severity, quality of life, disability, disease progression and employment outcomes using real-world data.MethodsWe included 2817 observations in 2015, 2016 and 2017 from 1382 participants in the Australian MS Longitudinal Study. Information on treatment, health and employment outcomes was prospectively collected by questionnaires. Marginal structural models with interaction terms for DMT×time were used to compare natalizumab and other comparator treatment groups.ResultsNatalizumab was associated with improvements over time, or general trends of improvement, in the severity of many symptoms and work productivity loss. Compared with any other DMTs, natalizumab was associated with superior effects over time for 8 of 23 patient-reported outcomes, with similar directions of effect observed for another 6, demonstrating consistency. There were no differences in effect for spasticity, fatigue, pain, feelings of depression, disability, European quality of life five dimension index, presenteeism and work status. Natalizumab did not perform significantly worse over time compared with any other DMTs for any of the outcomes.ConclusionsNatalizumab was associated with superior outcomes over time for many patient-reported health and employment outcomes when compared with other DMTs in this large prospective cohort study. These findings may influence treatment selection in clinical practice and future treatment cost-effectiveness analyses.

Background: The symptoms that have the largest impact on health-related quality of life (HRQoL) in people with multiple sclerosis (MS) may vary by MS phenotype (relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)). Knowing these symptoms assists in symptom management. Objective: To examine the associations between 13 common MS symptoms and HRQoL in the total sample and stratified by MS phenotype. Method: The study included 1985 participants. HRQoL was measured with two multi-attribute utility instruments: assessment of quality of life with eight dimensions (AQoL-8D) and European quality of life with five dimensions and five levels for each dimension (EQ-5D-5L). Multivariable linear regression was used to identify the symptoms that had the largest impact on the HRQoLs. Results: Feelings of depression, pain, fatigue, and feelings of anxiety were most strongly associated with AQoL-8D and EQ-5D-5L. Walking difficulties additionally contributed to reduced EQ-5D-5L. The strongest single predictors in the multivariable analyses were feelings of depression or pain for AQoL-8D and walking difficulties for EQ-5D-5L, irrespective of MS phenotype. Conclusion: The strongest single predictors for the AQoL-8D and EQ-5D-5L were feelings of depression, pain and walking difficulties, irrespective of MS phenotype. Reducing these symptoms may have the largest impact on improving HRQoL in all MS phenotypes of people with MS.

Little is known about the change in prevalence of comorbidities during the disease course of people with multiple sclerosis (MS) and whether the prevalences vary by MS onset type. To calculate the change in prevalence of comorbidities between symptom onset and the time of study, to compare the prevalences of comorbidities with those in the Australian population at the time of study and to examine onset-type differences. Comorbidity data from 1518 participants of the Australian MS Longitudinal Study and Australian population comparator data (2014–2015 National Health Survey) were used. The change in prevalence between time points and prevalence ratios (PR) at the time of study (crude, age and sex adjusted, and stratified by onset type) was calculated. Comorbidities were common, and those with the largest increases in prevalence between MS symptom onset and the time of study were depression (+ 26.9%), anxiety (+ 23.1%), hypertension (+ 21.9%), elevated cholesterol (+ 16.3%), osteoarthritis (+ 17.1%), eye diseases (+ 11.6%), osteoporosis (+ 10.9%) and cancer (+ 10.3%). Compared to the general population and after age and sex adjustment, participants had a significantly higher prevalence for 14/19 comorbidities at the time of study. The associations were strongest for anaemia, cancer (both PR > 4.00), anxiety, depression, migraine (all PR > 3.00), psoriasis and epilepsy (both PR > 2.00). No significant differences were seen by onset type. Comorbidities are common at MS symptom onset and increase with MS duration. Having MS may thus contribute to accrual of comorbidities. This emphasises the importance of optimal screening for and management of comorbidities in early MS and throughout the disease course.