CCRaVAT and QuTie - enabling analysis of rare variants in large-scale case control and quantitative trait association studies

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies have been successful in finding common variants influencing common traits. However, these associations only account for a fraction of trait heritability. There has been a shift in the field towards studying low frequency and rare variants, which are now widely recognised as putative complex trait determinants. Despite this increasing focus on examining the role of low frequency and rare variants in complex disease susceptibility, there is a lack of user-friendly analytical packages implementing powerful association tests for the analysis of rare variants.</p> <p>Results</p> <p>We have developed two software tools, CCRaVAT (Case-Control Rare Variant Analysis Tool) and QuTie (Quantitative Trait), which enable efficient large-scale analysis of low frequency and rare variants. Both programs implement a collapsing method examining the accumulation of low frequency and rare variants across a locus of interest that has more power than single variant analysis. CCRaVAT carries out case-control analyses whereas QuTie has been developed for continuous trait analysis.</p> <p>Conclusions</p> <p>CCRaVAT and QuTie are easy to use software tools that allow users to perform genome-wide association analysis on low frequency and rare variants for both binary and quantitative traits. The software is freely available and provides the genetics community with a resource to perform association analysis on rarer genetic variants.</p

Understanding symptoms in RYR1-Related Myopathies: A mixed-methods analysis based on participants' experience

Background: In rare diseases such as ryanodine receptor 1-related myopathies (RYR1-RM), health-related quality of life (HRQoL) measures are critically important so clinicians and researchers can better understand what symptoms are most important to participants, with the ultimate goal of finding tangible solutions for them. Objectives: The main objective of this study was to characterize symptoms in individuals with RYR1-RM to inform future research. A secondary objective of this study was to analyze positive and negative sentiments regarding symptoms and treatment effects post N-acetylcysteine (NAC) administration in individuals with RYR1-RM. Methods: The study used a mixed-methods design applying methodological triangulation. Qualitative data were collected via semi-structured interviews at three visits to characterize symptoms in individuals with RYR1-RM and to analyze treatment effects. Qualitative data were then transformed into quantitative results to measure the frequency with which each symptom was mentioned by participants. Results: A total of 12 symptoms were identified as areas of interest to participants with RYR1-RM, highlighting fatigue and weakness as key symptoms. Data transformation categorized more than 1000 citations, reporting a greater number of positive comments for post-intervention interviews than for baseline and pre-intervention visits and that NAC group participants stated more positive comments regarding treatment effect than did the placebo group. Conclusions: We present a comprehensive characterization of symptoms in RYR1-RM and how those symptoms influence HRQoL. Furthermore, the introduction of mixed methods may be a valuable way to better understand patient-centered data in rare diseases to support affected individuals in coping with their symptoms

Quantifying the Relationship between Capability and Health in Older People: Can't Map, Won't Map

BACKGROUND: Intuitively, health and capability are distinct but linked concepts. This study aimed to quantify the link between a measure of health status (EQ-5D-3L) and capability (ICECAP-O) using regression-based methods. METHODS: EQ-5D-3L and ICECAP-O data were collected from a sample of older people ( n = 584), aged over 65 years, requiring a hospital visit and/or care home resident, and recruited to one of 3 studies forming the Medical Crisis in Older People (MCOP) program in England. The link of EQ-5D-3L with 1) ICECAP-O tariff scores were estimated using ordinary least squares (OLS) or censored least absolute deviation (CLAD) regression models; and 2) ICECAP-O domain scores was estimated using multinomial logistic (MNL) regression. Mean absolute error (MAE), root mean squared error (RMSE), absolute difference (AD) between mean observed and estimated values, and the R(2) statistic were used to judge model performance. RESULTS: In this sample of older people ( n = 584), higher scores on the EQ-5D-3L were shown to be linked with higher ICECAP-O scores when using linear regression. An OLS-regression model was identified to be the best performing model with the lowest error statistics (AD = 0.0000; MAE = 0.1208; MSE = 0.1626) and highest goodness of fit ( R(2) = 0.3532); model performance was poor when predicting the lower ICECAP-O tariff scores. The three domains of the EQ-5D-3L showing a statistically significant quantifiable link with the ICECAP-O tariff score were self-care, usual activities, and anxiety/depression. CONCLUSION: A quantifiable, but weak, link between health (EQ-5D-3L) and capability (ICECAP-O) was identified. The findings from this study add further support that the ICECAP-O is providing complimentary information to the EQ-5D-3L. Mapping between the 2 measures is not advisable and the measures should not be used as direct substitutes to capture the impact of interventions in economic evaluations

Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy

Purpose: To characterize Health-Related Quality of Life (HRQoL) in ambulant individuals with RYR1-RM and to determine if a qualitative PRO tool (subjective self-assessment) complements PROMIS and Neuro-QoL scales to detect changes in HRQoL in ambulant individuals with RYR1-RM post N-acetylcysteine (NAC) treatment. Methods: The study used a mixed methods research (MMR) design applying methodological triangulation. Qualitative data were collected via semi-structured interviews using open-ended questions. Quantitative data were gathered through PROMIS and Neuro-QoL instruments. Additionally, qualitative data were transformed into quantitative data for subjective self-assessment and frequency analyses. Results: Qualitative results identified five domains and 33 subdomains as areas of interest. The most valuable were the importance of social impacts, the development of several coping strategies, both physical and psychological, and the identification of fatigue and weakness as key symptoms. Data transformation then categorized more than 3100 citations on frequency analyses, globally and by domain, visit, and participant. Regarding quantitative results, there was no clear evidence that any of the three PRO tools captured positive changes as a result of NAC treatment. Conclusion: Qualitative results showed a comprehensive characterization of HRQoL in this population based on a symptom/patient-centered approach. These findings will inform future studies. Furthermore, given the similar findings across our multiple methods and endpoints, the introduction of MMR may be a valuable, complementary approach to clinical trials. MMR may be especially useful to incorporate in order to address and follow the FDA's guidance and prioritization on the inclusion of affected individuals' perspectives in clinical trials

Time lags: insights from the U.S. Long Term Ecological Research Network

Ecosystems across the United States are changing in complex ways that are difficult to predict. Coordinated long-term research and analysis are required to assess how these changes will affect a diverse array of ecosystem services. This paper is part of a series that is a product of a synthesis effort of the U.S. National Science Foundation’s Long Term Ecological Research (LTER) network. This effort revealed that each LTER site had at least one compelling scientific case study about “what their site would look like” in 50 or 100 yr. As the site results were prepared, themes emerged, and the case studies were grouped into separate papers along five themes: state change, connectivity, resilience, time lags, and cascading effects and compiled into this special issue. This paper addresses the time lags theme with five examples from diverse biomes including tundra (Arctic), coastal upwelling (California Current Ecosystem), montane forests (Coweeta), and Everglades freshwater and coastal wetlands (Florida Coastal Everglades) LTER sites. Its objective is to demonstrate the importance of different types of time lags, in different kinds of ecosystems, as drivers of ecosystem structure and function and how these can effectively be addressed with long-term studies. The concept that slow, interactive, compounded changes can have dramatic effects on ecosystem structure, function, services, and future scenarios is apparent in many systems, but they are difficult to quantify and predict. The case studies presented here illustrate the expanding scope of thinking about time lags within the LTER network and beyond. Specifically, they examine what variables are best indicators of lagged changes in arctic tundra, how progressive ocean warming can have profound effects on zooplankton and phytoplankton in waters off the California coast, how a series of species changes over many decades can affect Eastern deciduous forests, and how infrequent, extreme cold spells and storms can have enduring effects on fish populations and wetland vegetation along the Southeast coast and the Gulf of Mexico. The case studies highlight the need for a diverse set of LTER (and other research networks) sites to sort out the multiple components of time lag effects in ecosystems

Early childhood epilepsies:epidemiology, classification, aetiology, and socio-economic determinants

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

EON-ROSE and the Canadian Cordillera Array – Building Bridges to Span Earth System Science in Canada

EON-ROSE (Earth-System Observing Network - Réseau d’Observation du Système terrestrE) is a new initiative for a pan-Canadian research collaboration to holistically examine Earth systems from the ionosphere into the core. The Canadian Cordillera Array (CC Array) is the pilot phase, and will extend across the Cordillera from the Beaufort Sea to the U.S. border. The vision for EON-ROSE is to install a network of telemetered observatories to monitor solid Earth, environmental and atmospheric processes. EON-ROSE is an inclusive, combined effort of Canadian universities, federal, provincial and territorial government agencies, industry, and international collaborators. Brainstorming sessions and several workshops have been held since May 2016. The first station will be installed at Kluane Lake Research Station in southwestern Yukon during the summer of 2018. The purpose of this report is to provide a framework for continued discussion and development.RÉSUMÉEON-ROSE (Earth-System Observing Network - Réseau d’Observation du Système terrestrE) est une nouvelle initiative de collaboration de recherche pancanadienne visant à étudier de manière holistique les systèmes terrestres, depuis l’ionosphère jusqu’au noyau. Le Réseau canadien de la cordillère (CC Array) en est la phase pilote, laquelle couvrira toute la Cordillère, de la mer de Beaufort jusqu’à la frontière étasunienne. L’objectif d’EON-ROSE est d’installer un réseau d’observatoires télémétriques pour suivre en continu les processusterrestres, environnementaux et atmosphériques. EON-ROSE est un effort combiné et inclusif des universités canadiennes, des organismes gouvernementaux fédéraux, provinciaux et territoriaux, de l’industrie et de collaborateurs internationaux. Des séances de remue-méninges et plusieurs ateliers ont été tenus depuis mai 2016. La première station sera installée à la station de recherche du lac Kluane, dans le sud-ouest du Yukon, au cours de l’été 2018. Le but du présent rapport est de fournir un cadre de discussion et de développement continu