Biobank-scale inference of ancestral recombination graphs enables genealogical analysis of complex traits.

Genome-wide genealogies compactly represent the evolutionary history of a set of genomes and inferring them from genetic data has the potential to facilitate a wide range of analyses. We introduce a method, ARG-Needle, for accurately inferring biobank-scale genealogies from sequencing or genotyping array data, as well as strategies to utilize genealogies to perform association and other complex trait analyses. We use these methods to build genome-wide genealogies using genotyping data for 337,464 UK Biobank individuals and test for association across seven complex traits. Genealogy-based association detects more rare and ultra-rare signals (N = 134, frequency range 0.0007-0.1%) than genotype imputation using ~65,000 sequenced haplotypes (N = 64). In a subset of 138,039 exome sequencing samples, these associations strongly tag (average r = 0.72) underlying sequencing variants enriched (4.8×) for loss-of-function variation. These results demonstrate that inferred genome-wide genealogies may be leveraged in the analysis of complex traits, complementing approaches that require the availability of large, population-specific sequencing panels.

Importance of modelling hERG binding in predicting drug-induced action potential prolongations for drug safety assessment.

Reduction of the rapid delayed rectifier potassium current (I Kr) via drug binding to the human Ether-à-go-go-Related Gene (hERG) channel is a well recognised mechanism that can contribute to an increased risk of Torsades de Pointes. Mathematical models have been created to replicate the effects of channel blockers, such as reducing the ionic conductance of the channel. Here, we study the impact of including state-dependent drug binding in a mathematical model of hERG when translating hERG inhibition to action potential changes. We show that the difference in action potential predictions when modelling drug binding of hERG using a state-dependent model versus a conductance scaling model depends not only on the properties of the drug and whether the experiment achieves steady state, but also on the experimental protocols. Furthermore, through exploring the model parameter space, we demonstrate that the state-dependent model and the conductance scaling model generally predict different action potential prolongations and are not interchangeable, while at high binding and unbinding rates, the conductance scaling model tends to predict shorter action potential prolongations. Finally, we observe that the difference in simulated action potentials between the models is determined by the binding and unbinding rate, rather than the trapping mechanism. This study demonstrates the importance of modelling drug binding and highlights the need for improved understanding of drug trapping which can have implications for the uses in drug safety assessment.

Learning transmission dynamics modelling of COVID-19 using comomodels.

The COVID-19 epidemic continues to rage in many parts of the world. In the UK alone, an array of mathematical models have played a prominent role in guiding policymaking. Whilst considerable pedagogical material exists for understanding the basics of transmission dynamics modelling, there is a substantial gap between the relatively simple models used for exposition of the theory and those used in practice to model the transmission dynamics of COVID-19. Understanding these models requires considerable prerequisite knowledge and presents challenges to those new to the field of epidemiological modelling. In this paper, we introduce an open-source R package, comomodels, which can be used to understand the complexities of modelling the transmission dynamics of COVID-19 through a series of differential equation models. Alongside the base package, we describe a host of learning resources, including detailed tutorials and an interactive web-based interface allowing dynamic investigation of the model properties. We then use comomodels to illustrate three key lessons in the transmission of COVID-19 within R Markdown vignettes.

Unusual Presentation of Pott's puffy tumour in a child: our recent experience and review of the literature.

Pott's puffy tumour (PPT) is a rarely seen, but highly important, complication of frontal sinusitis. Early recognition followed by prompt imaging and treatment of this condition are essential to improve patient outcomes and prevent complications. This case report describes an atypical presentation of radiologically confirmed PPT in a boy who presented with a 2.5-week history of progressive frontal headache and midline frontal swelling. Flexible nasendoscopy revealed no acute findings. Prompt CT imaging confirmed the diagnosis and early surgical intervention via endoscopic approach with aggressive antibiotic therapy led to good recovery. This case highlights the need to remember PPT in assessing any child or adolescent with a new forehead swelling, with or without sinusitis symptoms. If there is strong clinical suspicion, further imaging should not be delayed. Surgical intervention should be performed as early as possible to prevent intracranial complications; antibiotics alone are not sufficient.

Simultaneous double laryngeal tumours: a diagnostic and therapeutic challenge.

Leiomyosarcomas are soft tissue tumours that rarely occur in the larynx. This case report describes the presentation and management of a 77-year-old man referred to the otolaryngology clinic with hoarseness who was found to have a large supraglottic leiomyosarcoma after panendoscopy and biopsies. He subsequently underwent laryngectomy for treatment of this tumour but, unexpectedly, the histological analysis of the laryngectomy specimen revealed a second primary tumour in the larynx-a squamous cell carcinoma (SCC). The patient had further treatment with neck radiotherapy. Three years after treatment, there are no signs of recurrence of either tumour. This case report discusses the very few similar cases of leiomyosarcoma coexisting with SCC in the larynx, collating the evidence surrounding the treatment of this rare presentation.

Identity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations.

Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key role in a wide range of analyses. We develop FastSMC, an IBD detection algorithm that combines a fast heuristic search with accurate coalescent-based likelihood calculations. FastSMC enables biobank-scale detection and dating of IBD segments within several thousands of years in the past. We apply FastSMC to 487,409 UK Biobank samples and detect ~214 billion IBD segments transmitted by shared ancestors within the past 1500 years, obtaining a fine-grained picture of genetic relatedness in the UK. Sharing of common ancestors strongly correlates with geographic distance, enabling the use of genomic data to localize a sample's birth coordinates with a median error of 45 km. We seek evidence of recent positive selection by identifying loci with unusually strong shared ancestry and detect 12 genome-wide significant signals. We devise an IBD-based test for association between phenotype and ultra-rare loss-of-function variation, identifying 29 association signals in 7 blood-related traits.

Chaste: Cancer, Heart and Soft Tissue Environment.

Chaste (Cancer, Heart And Soft Tissue Environment) is an open source simulation package for the numerical solution of mathematical models arising in physiology and biology. To date, Chaste development has been driven primarily by applications that include continuum modelling of cardiac electrophysiology ('Cardiac Chaste'), discrete cell-based modelling of soft tissues ('Cell-based Chaste'), and modelling of ventilation in lungs ('Lung Chaste'). Cardiac Chaste addresses the need for a high-performance, generic, and verified simulation framework for cardiac electrophysiology that is freely available to the scientific community. Cardiac chaste provides a software package capable of realistic heart simulations that is efficient, rigorously tested, and runs on HPC platforms. Cell-based Chaste addresses the need for efficient and verified implementations of cell-based modelling frameworks, providing a set of extensible tools for simulating biological tissues. Computational modelling, along with live imaging techniques, plays an important role in understanding the processes of tissue growth and repair. A wide range of cell-based modelling frameworks have been developed that have each been successfully applied in a range of biological applications. Cell-based Chaste includes implementations of the cellular automaton model, the cellular Potts model, cell-centre models with cell representations as overlapping spheres or Voronoi tessellations, and the vertex model. Lung Chaste addresses the need for a novel, generic and efficient lung modelling software package that is both tested and verified. It aims to couple biophysically-detailed models of airway mechanics with organ-scale ventilation models in a package that is freely available to the scientific community. Chaste is designed to be modular and extensible, providing libraries for common scientific computing infrastructure such as linear algebra operations, finite element meshes, and ordinary and partial differential equation solvers. This infrastructure is used by libraries for specific applications, such as continuum mechanics, cardiac models, and cell-based models. The software engineering techniques used to develop Chaste are intended to ensure code quality, re-usability and reliability. Primary applications of the software include cardiac and respiratory physiology, cancer and developmental biology.

Mechanocellular models of epithelial morphogenesis.

Embryonic epithelia achieve complex morphogenetic movements, including in-plane reshaping, bending and folding, through the coordinated action and rearrangement of individual cells. Technical advances in molecular and live-imaging studies of epithelial dynamics provide a very real opportunity to understand how cell-level processes facilitate these large-scale tissue rearrangements. However, the large datasets that we are now able to generate require careful interpretation. In combination with experimental approaches, computational modelling allows us to challenge and refine our current understanding of epithelial morphogenesis and to explore experimentally intractable questions. To this end, a variety of cell-based modelling approaches have been developed to describe cell-cell mechanical interactions, ranging from vertex and 'finite-element' models that approximate each cell geometrically by a polygon representing the cell's membrane, to immersed boundary and subcellular element models that allow for more arbitrary cell shapes. Here, we review how these models have been used to provide insights into epithelial morphogenesis and describe how such models could help future efforts to decipher the forces and mechanical and biochemical feedbacks that guide cell and tissue-level behaviour. In addition, we discuss current challenges associated with using computational models of morphogenetic processes in a quantitative and predictive way.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.

Policies for replacing long-term indwelling urinary catheters in adults.

BACKGROUND: Long-term indwelling catheters are used commonly in people with lower urinary tract problems in home, hospital and specialised health-care settings. There are many potential complications and adverse effects associated with long-term catheter use. The effect of health-care policies related to the replacement of long-term urinary catheters on patient outcomes is unclear. OBJECTIVES: To determine the effectiveness of different policies for replacing long-term indwelling urinary catheters in adults. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 19 May 2016), and the reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials investigating policies for replacing long-term indwelling urinary catheters in adults were included. DATA COLLECTION AND ANALYSIS: At least two review authors independently performed data extraction and assessed risk of bias of all the included trials. Quality of evidence was assessed by adopting the GRADE approach. Any discrepancies were resolved by discussion between the review authors or an independent arbitrator. We contacted the authors of included trials to seek clarification where required. MAIN RESULTS: Three trials met the inclusion criteria, with a total of 107 participants in three different health-care settings: A USA veterans administration nursing home; a geriatric centre in Israel; and a community nursing service in Hong Kong. Data were available for three of the pre-stated comparisons. Priefer and colleagues evaluated different time intervals between catheter replacement (n = 17); Firestein and colleagues evaluated the use of antibiotic prophylaxis at the time of replacement (n = 70); and Cheung and colleagues compared two different types of cleaning solutions (n = 20).All the included trials were small and under-powered. The reporting of the trials was inadequate and as a result, risk of bias assessment was judged to be unclear for the majority of the domains in two out of the three trials. There was insufficient evidence to indicate that (i) there was a lower incidence of symptomatic UTI in people whose catheter was changed both monthly and when clinically indicated (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.13 to 0.95; very low quality evidence) compared to only when clinically indicated, (ii) there was not enough evidence to assess the effect of antibiotic prophylaxis on reducing: positive urine cultures at 7 days (RR 0.91, 95% CI 0.79 to 1.04); infection (RR 1.41, 95% CI 0.55 to 3.65); or death (RR 2.12, 95% CI 0.20 to 22.30; very low quality evidence), (iii) there was no statistically significant difference in the incidence of asymptomatic bacteruria at 7 days (RR 0.80, 95% CI 0.42 to 1.52) between people receiving water or chlorhexidine solution for periurethral cleansing at the time of catheter replacement. However, none of the 16 participants developed a symptomatic catheter-associated urinary tract infection (CAUTI) at day 14.The following outcomes were considered critical for decision-making and were also selected for the 'Summary of findings' table: (i) participant satisfaction, (ii) condition-specific quality of life, (iii) urinary tract trauma, and (iv) formal economic analysis. However, none of the trials reported these outcomes.None of the trials compared the following comparisons: (i) replacing catheter versus other policy e.g. washouts, (ii) replacing in the home environment versus clinical environment, (iii) clean versus aseptic technique for replacing catheter, (iv) lubricant A versus lubricant B or no lubricant, and (v) catheter user versus carer versus health professional performing the catheter replacement procedure. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to assess the value of different policies for replacing long-term urinary catheters on patient outcomes. In particular, there are a number of policies for which there are currently no trial data; and a number of important outcomes which have not been assessed, including patient satisfaction, quality of life, urinary tract trauma, and economic outcomes. There is an immediate need for rigorous, adequately powered randomised controlled trials which assess important clinical outcomes and abide by the principles and recommendations of the CONSORT statement.