Ancestry inference using reference labeled clusters of haplotypes.

BACKGROUND: We present ARCHes, a fast and accurate haplotype-based approach for inferring an individual's ancestry composition. Our approach works by modeling haplotype diversity from a large, admixed cohort of hundreds of thousands, then annotating those models with population information from reference panels of known ancestry. RESULTS: The running time of ARCHes does not depend on the size of a reference panel because training and testing are separate processes, and the inferred population-annotated haplotype models can be written to disk and reused to label large test sets in parallel (in our experiments, it averages less than one minute to assign ancestry from 32 populations using 10 CPU). We test ARCHes on public data from the 1000 Genomes Project and the Human Genome Diversity Project (HGDP) as well as simulated examples of known admixture. CONCLUSIONS: Our results demonstrate that ARCHes outperforms RFMix at correctly assigning both global and local ancestry at finer population scales regardless of the amount of population admixture.

What do we know about managing Dupuytren's disease cost-effectively?

BACKGROUND: Dupuytren's disease (DD) is a common and progressive, fibroproliferative disorder of the palmar and digital fascia of the hand. Various treatments have been recommended for advanced disease or to retard progression of early disease and to prevent deterioration of the finger contracture and quality of life. Recent studies have tried to evaluate the clinical and cost-effectiveness of therapies for DD, but there is currently no systematic assessment and appraisal of the economic evaluations. METHODS: A systematic literature review was conducted, following PRISMA guidelines, to identify studies reporting economic evaluations of interventions for managing DD. Databases searched included the Ovid MEDLINE/Embase (without time restriction), National Health Service (NHS) Economic Evaluation Database (all years) and the National Institute for Health Research (NIHR) Journals Library) Health Technology Assessment (HTA). Cost-effectiveness analyses of treating DD were identified and their quality was assessed using the CHEERS assessment tool for quality of reporting and Phillips checklist for model evaluation. RESULTS: A total of 103 studies were screened, of which 4 met the study inclusion criteria. Two studies were from the US, one from the UK and one from Canada. They all assessed the same interventions for advanced DD, namely collagenase Clostridium histolyticum injection, percutaneous needle fasciotomy and partial fasciectomy. All studies conducting a cost-utility analysis, two implemented a decision analytic model and two a Markov model approach. None of them were based on a single randomised controlled trial, but rather synthesised evidence from various sources. Studies varied in their time horizon, sources of utility estimates and perspective of analysis. The overall quality of study reporting was good based on the CHEERS checklist. The quality of the model reporting in terms of model structure, data synthesis and model consistency varied across the included studies. CONCLUSION: Cost-effectiveness analyses for patients with advanced DD are limited and have applied different approaches with respect to modelling. Future studies should improve the way they are conducted and report their findings according to established guidance for conducting economic modelling of health care technologies. TRIAL REGISTRATION: The protocol was registered ( CRD42016032989 ; date 08/01/2016) with the PROSPERO international prospective register of systematic reviews.

PortEco: a resource for exploring bacterial biology through high-throughput data and analysis tools.

PortEco (http://porteco.org) aims to collect, curate and provide data and analysis tools to support basic biological research in Escherichia coli (and eventually other bacterial systems). PortEco is implemented as a 'virtual' model organism database that provides a single unified interface to the user, while integrating information from a variety of sources. The main focus of PortEco is to enable broad use of the growing number of high-throughput experiments available for E. coli, and to leverage community annotation through the EcoliWiki and GONUTS systems. Currently, PortEco includes curated data from hundreds of genome-wide RNA expression studies, from high-throughput phenotyping of single-gene knockouts under hundreds of annotated conditions, from chromatin immunoprecipitation experiments for tens of different DNA-binding factors and from ribosome profiling experiments that yield insights into protein expression. Conditions have been annotated with a consistent vocabulary, and data have been consistently normalized to enable users to find, compare and interpret relevant experiments. PortEco includes tools for data analysis, including clustering, enrichment analysis and exploration via genome browsers. PortEco search and data analysis tools are extensively linked to the curated gene, metabolic pathway and regulation content at its sister site, EcoCyc.

What are we measuring? A critique of range of motion methods currently in use for Dupuytren's disease and recommendations for practice.

BACKGROUND: Range of motion is the most frequently reported measure used in practice to evaluate outcomes. A goniometer is the most reliable tool to assess range of motion yet, the lack of consistency in reporting prevents comparison between studies. The aim of this study is to identify how range of motion is currently assessed and reported in Dupuytren's disease literature. Following analysis recommendations for practice will be made to enable consistency in future studies for comparability. This paper highlights the variation in range of motion reporting in Dupuytren's disease. METHODS: A Participants, Intervention, Comparison, Outcomes and Study design format was used for the search strategy and search terms. Surgery, needle fasciotomy or collagenase injection for primary or recurrent Dupuytren's disease in adults were included if outcomes were monitored using range of motion to record change. A literature search was performed in May 2013 using subject heading and free-text terms to also capture electronic publications ahead of print. In total 638 publications were identified and following screening 90 articles met the inclusion criteria. Data was extracted and entered onto a spreadsheet for analysis. A thematic analysis was carried out to establish any duplication, resulting in the final range of motion measures identified. RESULTS: Range of motion measurement lacked clarity, with goniometry reportedly used in only 43 of the 90 studies, 16 stated the use of a range of motion protocol. A total of 24 different descriptors were identified describing range of motion in the 90 studies. While some studies reported active range of motion, others reported passive or were unclear. Eight of the 24 categories were identified through thematic analysis as possibly describing the same measure, 'lack of joint extension' and accounted for the most frequently used. CONCLUSIONS: Published studies lacked clarity in reporting range of motion, preventing data comparison and meta-analysis. Percentage change lacks context and without access to raw data, does not allow direct comparison of baseline characteristics. A clear description of what is being measured within each study was required. It is recommended that range of motion measuring and reporting for Dupuytren's disease requires consistency to address issues that fall into 3 main categories: Definition of terms, Protocol statement, Outcome reporting.

Systematic review of non-surgical treatments for early dupuytren's disease.

BACKGROUND: Dupuytren's disease is a common fibrotic disorder of the palm characterized by the development of progressive flexion deformities in the digits, leading to significant functional impairment. Surgical excision remains the most common treatment. However, this is only indicated in patients with established contractures rather than those with early disease. Early disease is generally characterized by the presence of palmar nodules with limited or no contracture of the fingers. The ideal treatment would be directed at patients with early progressive disease to prevent future deterioration. Various non-surgical treatment modalities have been described but there is currently no systematic assessment of the role and efficacy of these treatments in patients with early disease. METHODS: Using a PICOS analysis we reviewed publications of studies of patients with early disease who had received physical therapies, pharmacological treatment, or radiotherapy. Following PRISMA guidelines titles and abstract were screened using predefined criteria to identify those reporting outcomes specifically relating to the treatment of early disease. In the absence of a definition of early disease studies were included if early DD was described clinically, with digital contractures not exceeding 30°, Tubiana grades N to 1, and which reported identifiable data. Studies were excluded if data for early DD patients could not be extracted for analysis. RESULTS: In this systematic review, 26 studies were identified and analyzed to evaluate the effect of pharmacological therapy (n = 11), physical therapy (n = 5) and radiotherapy (n = 10) on early Dupuytren's disease. The studies comprised 20 case series, 1 cohort study with the remainder reporting case studies. All publications were graded level of evidence 4 or 5 assessed using the Oxford Centre for Evidence Based Medicine grading. Narrative descriptions of the data are presented. CONCLUSIONS: Physical therapies were the most robustly assessed, using objective measures but the studies were under powered, providing insufficient evidence of efficacy. Intralesional steroid injection and radiotherapy appeared to lead to softening of nodules and to retard disease progression but lacked rigorous evaluation and studies were poorly designed. There is an urgent need for adequately powered double blinded randomized trials for this common disorder which affects 4 % of the population. TRIAL REGISTRATION: The protocol was registered ( CRD42015008986 16 November 2015) with the PROSPERO international prospective register of systematic reviews.

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: a systematic review and recommendations for future practice.

BACKGROUND: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. METHODS: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren's disease where outcomes had been monitored using functional measures. RESULTS: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. CONCLUSIONS: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren's disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren's disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes.

Microarray databases: standards and ontologies.

A single microarray can provide information on the expression of tens of thousands of genes. The amount of information generated by a microarray-based experiment is sufficiently large that no single study can be expected to mine each nugget of scientific information. As a consequence, the scale and complexity of microarray experiments require that computer software programs do much of the data processing, storage, visualization, analysis and transfer. The adoption of common standards and ontologies for the management and sharing of microarray data is essential and will provide immediate benefit to the research community.

Critical care drowning admissions in Southwest England 2009-2020, a retrospective study.

Aim: In the United Kingdom (UK), 600 deaths per annum are attributable to drowning. Despite this there is scarce critical care data on drowning patients globally. We describe drowning cases admitted to critical care units with a focus on functional outcomes. Materials and Methods: Medical records for critical care admissions following a drowning event were retrospectively reviewed across six hospitals in Southwest England for cases presenting in the period between 2009 and 2020. Data was collected according to the Utstein international consensus guidelines on drowning. Results: Forty-nine patients were included, 36 males and 13 females, including seven children. Median submersion duration was 2.5 min 20 cases were in cardiac arrest when rescued. At discharge 22 patients had preserved functional status, 10 patients had a reduced functional status. 17 patients died in hospital. Conclusion: Admission to critical care following drowning is uncommon and associated with high rates of mortality and poor functional outcomes. We find that 31% of those who survived a drowning event subsequently required an increased level of assistance with their activities of daily living.

Cost-effectiveness of adalimumab for early-stage Dupuytren's disease : an economic evaluation based on a randomized controlled trial and individual-patient simulation model.

AIMS: To estimate the potential cost-effectiveness of adalimumab compared with standard care alone for the treatment of early-stage Dupuytren's disease (DD) and the value of further research from an NHS perspective. METHODS: We used data from the Repurposing anti-TNF for Dupuytren's disease (RIDD) randomized controlled trial of intranodular adalimumab injections in patients with early-stage progressive DD. RIDD found that intranodular adalimumab injections reduced nodule hardness and size in patients with early-stage DD, indicating the potential to control disease progression. A within-trial cost-utility analysis compared four adalimumab injections with no further treatment against standard care alone, taking a 12-month time horizon and using prospective data on EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and resource use from the RIDD trial. We also developed a patient-level simulation model similar to a Markov model to extrapolate trial outcomes over a lifetime using data from the RIDD trial and a literature review. This also evaluated repeated courses of adalimumab each time the nodule reactivated (every three years) in patients who initially responded. RESULTS: The within-trial economic evaluation found that adalimumab plus standard care cost £503,410 per quality-adjusted life year (QALY) gained versus standard care alone over a 12-month time horizon. The model-based extrapolation suggested that, over a lifetime, repeated courses of adalimumab could cost £14,593 (95% confidence interval £7,534 to £42,698) per QALY gained versus standard care alone. If the NHS was willing to pay £20,000/QALY gained, there is a 77% probability that adalimumab with retreatment is the best value for money. CONCLUSION: Repeated courses of adalimumab are likely to be a cost-effective treatment for progressive early-stage DD. The value of perfect parameter information that would eliminate all uncertainty around the parameters estimated in RIDD and the duration of quiescence was estimated to be £105 per patient or £272 million for all 2,584,411 prevalent cases in the UK. Cite this article: Bone Jt Open 2022;3(11):898-906.

Scaling the Virtual Fitness Buddy Ecosystem as a School-Based Physical Activity Intervention for Children.

Childhood obesity is a growing concern as it can lead to lifelong health problems that carry over into adulthood. A substantial contributing factor to obesity is the physical activity (PA) habits that are formed in early childhood, as these habits tend to sustain throughout adulthood. To aid children in forming healthy PA habits, we designed a mixed reality system called the Virtual Fitness Buddy ecosystem, in which children can interact with a virtual pet agent. As a child exercises, their pet becomes slimmer, faster, and able to play more games with them. Our initial deployment of this project showed promise but was only designed for a short-term intervention lasting three days. More recently, we have scaled it from a pilot grade study to a 9-month intervention comprised of 422 children. Ultimately, our goal is to scale this project to be a nationwide primary prevention program to encourage moderate to vigorous PA in children. This article explores the challenges and lessons learned during the design and deployment of this system at scale in the field.

Anti-tumour necrosis factor therapy for early-stage Dupuytren's disease (RIDD): a phase 2b, randomised, double-blind, placebo-controlled trial.

Background: Dupuytren's disease is a common fibrotic condition that causes the fingers to flex irreversibly into the palm. Treatments for late-stage disease all have limitations, and there is no approved treatment for early-stage disease. We identified tumour necrosis factor as a therapeutic target in Dupuytren's disease, and in a dose ranging trial found 40 mg adalimumab in 0·4 mL to be most efficacious. Here we aimed to assess the effects of intranodular injection of adalimumab in early-stage disease. Methods: In this phase 2b, randomised, double-blind, placebo-controlled trial adults with early-stage Dupuytren's disease and an established clinically distinct nodule with a clear history of progression in the preceding 6 months were recruited from two clinical centres in the UK and were randomly assigned 1:1 to receive four injections of adalimumab or saline every 3 months. Participants and assessors were masked. The primary outcome was nodule hardness measured with a durometer at 12 months. Data were analysed by linear mixed effects regression models in the intention-to-treat population with multiple imputation for missing primary outcome data. The trial is registered at the ISRCTN registry, ISRCTN 27786905 and is complete. Findings: Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were enrolled. 47 (34%) participants were female and 93 (66%) were male. Mean age of participants was 59·7 years (SD 10·0). Primary outcome data were available from 113 participants. Nodule hardness was lower (-4·6 AU [95% CI -7·1 to -2·2], p=0·0002) in the adalimumab compared with the saline group at 12 months. There were no related serious adverse events; the most common adverse events were minor injection site reactions. Interpretation: Intranodular injections of adalimumab in participants with early-stage Dupuytren's disease resulted in softening and reduction in size of the nodules. Longer follow-up would be required to assess the effect of tumour necrosis factor inhibition on disease progression, extension deficit and hand function.

COVID-19 susceptibility and severity risks in a cross-sectional survey of over 500 000 US adults.

OBJECTIVES: The enormous toll of the COVID-19 pandemic has heightened the urgency of collecting and analysing population-scale datasets in real time to monitor and better understand the evolving pandemic. The objectives of this study were to examine the relationship of risk factors to COVID-19 susceptibility and severity and to develop risk models to accurately predict COVID-19 outcomes using rapidly obtained self-reported data. DESIGN: A cross-sectional study. SETTING: AncestryDNA customers in the USA who consented to research. PARTICIPANTS: The AncestryDNA COVID-19 Study collected self-reported survey data on symptoms, outcomes, risk factors and exposures for over 563 000 adult individuals in the USA in just under 4 months, including over 4700 COVID-19 cases as measured by a self-reported positive test. RESULTS: We replicated previously reported associations between several risk factors and COVID-19 susceptibility and severity outcomes, and additionally found that differences in known exposures accounted for many of the susceptibility associations. A notable exception was elevated susceptibility for men even after adjusting for known exposures and age (adjusted OR=1.36, 95% CI=1.19 to 1.55). We also demonstrated that self-reported data can be used to build accurate risk models to predict individualised COVID-19 susceptibility (area under the curve (AUC)=0.84) and severity outcomes including hospitalisation and critical illness (AUC=0.87 and 0.90, respectively). The risk models achieved robust discriminative performance across different age, sex and genetic ancestry groups within the study. CONCLUSIONS: The results highlight the value of self-reported epidemiological data to rapidly provide public health insights into the evolving COVID-19 pandemic.

Expanded COVID-19 phenotype definitions reveal distinct patterns of genetic association and protective effects.

Multiple COVID-19 genome-wide association studies (GWASs) have identified reproducible genetic associations indicating that there is a genetic component to susceptibility and severity risk. To complement these studies, we collected deep coronavirus disease 2019 (COVID-19) phenotype data from a survey of 736,723 AncestryDNA research participants. With these data, we defined eight phenotypes related to COVID-19 outcomes: four phenotypes that align with previously studied COVID-19 definitions and four 'expanded' phenotypes that focus on susceptibility given exposure, mild clinical manifestations and an aggregate score of symptom severity. We performed a replication analysis of 12 previously reported COVID-19 genetic associations with all eight phenotypes in a trans-ancestry meta-analysis of AncestryDNA research participants. In this analysis, we show distinct patterns of association at the 12 loci with the eight outcomes that we assessed. We also performed a genome-wide discovery analysis of all eight phenotypes, which did not yield new genome-wide significant loci but did suggest that three of the four 'expanded' COVID-19 phenotypes have enhanced power to capture protective genetic associations relative to the previously studied phenotypes. Thus, we conclude that continued large-scale ascertainment of deep COVID-19 phenotype data would likely represent a boon for COVID-19 therapeutic target identification.

Annotare--a tool for annotating high-throughput biomedical investigations and resulting data.

UNLABELLED: Computational methods in molecular biology will increasingly depend on standards-based annotations that describe biological experiments in an unambiguous manner. Annotare is a software tool that enables biologists to easily annotate their high-throughput experiments, biomaterials and data in a standards-compliant way that facilitates meaningful search and analysis. AVAILABILITY AND IMPLEMENTATION: Annotare is available from http://code.google.com/p/annotare/ under the terms of the open-source MIT License (http://www.opensource.org/licenses/mit-license.php). It has been tested on both Mac and Windows.

Implementation of GenePattern within the Stanford Microarray Database.

Hundreds of researchers across the world use the Stanford Microarray Database (SMD; http://smd.stanford.edu/) to store, annotate, view, analyze and share microarray data. In addition to providing registered users at Stanford access to their own data, SMD also provides access to public data, and tools with which to analyze those data, to any public user anywhere in the world. Previously, the addition of new microarray data analysis tools to SMD has been limited by available engineering resources, and in addition, the existing suite of tools did not provide a simple way to design, execute and share analysis pipelines, or to document such pipelines for the purposes of publication. To address this, we have incorporated the GenePattern software package directly into SMD, providing access to many new analysis tools, as well as a plug-in architecture that allows users to directly integrate and share additional tools through SMD. In this article, we describe our implementation of the GenePattern microarray analysis software package into the SMD code base. This extension is available with the SMD source code that is fully and freely available to others under an Open Source license, enabling other groups to create a local installation of SMD with an enriched data analysis capability.

TB database: an integrated platform for tuberculosis research.

The effective control of tuberculosis (TB) has been thwarted by the need for prolonged, complex and potentially toxic drug regimens, by reliance on an inefficient vaccine and by the absence of biomarkers of clinical status. The promise of the genomics era for TB control is substantial, but has been hindered by the lack of a central repository that collects and integrates genomic and experimental data about this organism in a way that can be readily accessed and analyzed. The Tuberculosis Database (TBDB) is an integrated database providing access to TB genomic data and resources, relevant to the discovery and development of TB drugs, vaccines and biomarkers. The current release of TBDB houses genome sequence data and annotations for 28 different Mycobacterium tuberculosis strains and related bacteria. TBDB stores pre- and post-publication gene-expression data from M. tuberculosis and its close relatives. TBDB currently hosts data for nearly 1500 public tuberculosis microarrays and 260 arrays for Streptomyces. In addition, TBDB provides access to a suite of comparative genomics and microarray analysis software. By bringing together M. tuberculosis genome annotation and gene-expression data with a suite of analysis tools, TBDB (http://www.tbdb.org/) provides a unique discovery platform for TB research.

The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele.

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.

The identification of novel orally active mGluR5 antagonist GSK2210875.

The identification of novel orally active mGluR5 antagonist GSK2210875 is described.

The Functional Genomics Experiment model (FuGE): an extensible framework for standards in functional genomics.

The Functional Genomics Experiment data model (FuGE) has been developed to facilitate convergence of data standards for high-throughput, comprehensive analyses in biology. FuGE models the components of an experimental activity that are common across different technologies, including protocols, samples and data. FuGE provides a foundation for describing entire laboratory workflows and for the development of new data formats. The Microarray Gene Expression Data society and the Proteomics Standards Initiative have committed to using FuGE as the basis for defining their respective standards, and other standards groups, including the Metabolomics Standards Initiative, are evaluating FuGE in their development efforts. Adoption of FuGE by multiple standards bodies will enable uniform reporting of common parts of functional genomics workflows, simplify data-integration efforts and ease the burden on researchers seeking to fulfill multiple minimum reporting requirements. Such advances are important for transparent data management and mining in functional genomics and systems biology.

The Stanford Tissue Microarray Database.

The Stanford Tissue Microarray Database (TMAD; http://tma.stanford.edu) is a public resource for disseminating annotated tissue images and associated expression data. Stanford University pathologists, researchers and their collaborators worldwide use TMAD for designing, viewing, scoring and analyzing their tissue microarrays. The use of tissue microarrays allows hundreds of human tissue cores to be simultaneously probed by antibodies to detect protein abundance (Immunohistochemistry; IHC), or by labeled nucleic acids (in situ hybridization; ISH) to detect transcript abundance. TMAD archives multi-wavelength fluorescence and bright-field images of tissue microarrays for scoring and analysis. As of July 2007, TMAD contained 205 161 images archiving 349 distinct probes on 1488 tissue microarray slides. Of these, 31 306 images for 68 probes on 125 slides have been released to the public. To date, 12 publications have been based on these raw public data. TMAD incorporates the NCI Thesaurus ontology for searching tissues in the cancer domain. Image processing researchers can extract images and scores for training and testing classification algorithms. The production server uses the Apache HTTP Server, Oracle Database and Perl application code. Source code is available to interested researchers under a no-cost license.