The successes and challenges of harmonising juvenile idiopathic arthritis (JIA) datasets to create a large-scale JIA data resource

Background CLUSTER is a UK consortium focussed on precision medicine research in JIA/JIA-Uveitis. As part of this programme, a large-scale JIA data resource was created by harmonizing and pooling existing real-world studies. Here we present challenges and progress towards creation of this unique large JIA dataset. Methods Four real-world studies contributed data; two clinical datasets of JIA patients starting first-line methotrexate (MTX) or tumour necrosis factor inhibitors (TNFi) were created. Variables were selected based on a previously developed core dataset, and encrypted NHS numbers were used to identify children contributing similar data across multiple studies. Results Of 7013 records (from 5435 individuals), 2882 (1304 individuals) represented the same child across studies. The final datasets contain 2899 (MTX) and 2401 (TNFi) unique patients; 1018 are in both datasets. Missingness ranged from 10 to 60% and was not improved through harmonisation. Conclusions Combining data across studies has achieved dataset sizes rarely seen in JIA, invaluable to progressing research. Losing variable specificity and missingness, and their impact on future analyses requires further consideration

A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer Maps to Chromosome 4q32-34

Pancreatic cancer is the fifth leading cause of cancer death in the United States. Nearly every person diagnosed with pancreatic cancer will die from it, usually in <6 mo. Familial clustering of pancreatic cancers is commonly recognized, with an autosomal dominant inheritance pattern in ∼10% of all cases. However, the late age at disease onset and rapid demise of affected individuals markedly hamper collection of biological samples. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early onset and high penetrance. For the study of this family, we have developed an endoscopic surveillance program that allows the early detection of cancer and its precursor, before family members have died of the disease. In a genomewide screening of 373 microsatellite markers, we found significant linkage (maximum LOD score 4.56 in two-point analysis and 5.36 in three-point analysis) on chromosome 4q32-34, providing evidence for a major locus for pancreatic cancer

Excessive daytime sleepiness in multiple system atrophy (SLEEMSA study)

\u3cp\u3eBACKGROUND: Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known.\u3c/p\u3e\u3cp\u3eOBJECTIVE: To assess the frequency and associations of EDS in MSA.\u3c/p\u3e\u3cp\u3eDESIGN: Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease.\u3c/p\u3e\u3cp\u3eSETTING: Twelve tertiary referral centers.\u3c/p\u3e\u3cp\u3ePARTICIPANTS: Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex.\u3c/p\u3e\u3cp\u3eMAIN OUTCOME MEASURES: Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome.\u3c/p\u3e\u3cp\u3eRESULTS: Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P &lt; .001). Excessive daytime sleepiness (ESS score &gt;10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P &lt; .001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P &lt; .001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD.\u3c/p\u3e\u3cp\u3eCONCLUSIONS: More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes.\u3c/p\u3

Excessive Daytime Sleepiness in Multiple System Atrophy (SLEEMSA Study)

system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known. Objective: To assess the frequency and associations of EDS in MSA. Design: Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease. Setting: Twelve tertiary referral centers. Participants: Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex. Main Outcome Measures: Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome. Results: Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P 10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P <.001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P <.001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD. Conclusions: More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes. Arch Neurol. 2011; 68(2):223-23

Patient-reported wellbeing and clinical disease measures over time captured by multivariate trajectories of disease activity in individuals with juvenile idiopathic arthritis in the UK: a multicentre prospective longitudinal study

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course. METHODS: In this multicentre prospective longitudinal study, we included children and young people recruited before Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in active joint count, physician's global assessment, and patient or parental global evaluation, we used latent profile analysis at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following 3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony. FINDING: Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS, 239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions of children and young people had high patient or parent global scores despite low or improving joint counts and physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitis-related JIA and lower socioeconomic status, compared with those in other groups. INTERPRETATION: Almost one in four children and young people with JIA in our study reported persistent, high patient or parent global scores despite having low or improving active joint counts and physician's global scores. Distinct patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise health-care services and treatment plans for individuals with JIA. FUNDING: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and National Institute for Health Research