Publications by authors named "Robert Clarke"

583 Publications

ChIP-GSM: Inferring active transcription factor modules to predict functional regulatory elements.

PLoS Comput Biol 2021 Jul 22;17(7):e1009203. Epub 2021 Jul 22.

Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, Virginia, United States of America.

Transcription factors (TFs) often function as a module including both master factors and mediators binding at cis-regulatory regions to modulate nearby gene transcription. ChIP-seq profiling of multiple TFs makes it feasible to infer functional TF modules. However, when inferring TF modules based on co-localization of ChIP-seq peaks, often many weak binding events are missed, especially for mediators, resulting in incomplete identification of modules. To address this problem, we develop a ChIP-seq data-driven Gibbs Sampler to infer Modules (ChIP-GSM) using a Bayesian framework that integrates ChIP-seq profiles of multiple TFs. ChIP-GSM samples read counts of module TFs iteratively to estimate the binding potential of a module to each region and, across all regions, estimates the module abundance. Using inferred module-region probabilistic bindings as feature units, ChIP-GSM then employs logistic regression to predict active regulatory elements. Validation of ChIP-GSM predicted regulatory regions on multiple independent datasets sharing the same context confirms the advantage of using TF modules for predicting regulatory activity. In a case study of K562 cells, we demonstrate that the ChIP-GSM inferred modules form as groups, activate gene expression at different time points, and mediate diverse functional cellular processes. Hence, ChIP-GSM infers biologically meaningful TF modules and improves the prediction accuracy of regulatory region activities.
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http://dx.doi.org/10.1371/journal.pcbi.1009203DOI Listing
July 2021

A New Natural Defense Against Airborne Pathogens.

QRB Discov 2020 7;1:e5. Epub 2020 Jul 7.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

We propose the nasal administration of calcium-enriched physiological salts as a new hygienic intervention with possible therapeutic application as a response to the rapid and tenacious spread of COVID-19. We test the effectiveness of these salts against viral and bacterial pathogens in animals and humans. We find that aerosol administration of these salts to the airways diminishes the exhalation of the small particles that face masks fail to filter and, in the case of an influenza swine model, completely block airborne transmission of disease. In a study of 10 human volunteers (5 less than 65 years and 5 older than 65 years), we show that delivery of a nasal saline comprising calcium and sodium salts quickly (within 15 min) and durably (up to at least 6 h) diminishes exhaled particles from the human airways. Being predominantly smaller than 1 μm, these particles are below the size effectively filtered by conventional masks. The suppression of exhaled droplets by the nasal delivery of calcium-rich saline with aerosol droplet size of around 10 μm suggests the upper airways as a primary source of bioaerosol generation. The suppression effect is especially pronounced (99%) among those who exhale large numbers of particles. In our study, we found this high-particle exhalation group to correlate with advanced age. We argue for a new hygienic practice of nasal cleansing by a calcium-rich saline aerosol, to complement the washing of hands with ordinary soap, use of a face mask, and social distancing.
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http://dx.doi.org/10.1017/qrd.2020.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453358PMC
July 2020

Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.

EMBO J 2021 Jul 4;40(14):e107182. Epub 2021 Jun 4.

Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, Manchester, UK.

Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine-tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.
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http://dx.doi.org/10.15252/embj.2020107182DOI Listing
July 2021

Inhibition of Antiestrogen-Promoted Pro-Survival Autophagy and Tamoxifen Resistance in Breast Cancer through Vitamin D Receptor.

Nutrients 2021 May 19;13(5). Epub 2021 May 19.

Department of Oncology, Georgetown University, Washington, DC 20057, USA.

We determined how vitamin D receptor (VDR) is linked to disease outcome in estrogen receptor-positive (ER+) breast cancer patients treated with tamoxifen (TAM). Breast cancer patients ( = 581) in four different datasets were divided into those expressing higher (above median) and lower levels of VDR in pretreatment ER+ tumors. Across all datasets, TAM-treated patients with higher pretreatment tumor VDR expression exhibited significantly longer recurrence-free survival. Ingenuity pathway analysis identified autophagy and unfolded protein response (UPR) as top differentially expressed pathways between high and low VDR-expressing ER+ cancers. Activation of VDR with vitamin D (VitD), either calcitriol or its synthetic analog EB1089, sensitized MCF-7-derived, antiestrogen-resistant LCC9 human breast cancer cells to TAM, and attenuated increased UPR and pro-survival autophagy. Silencing of VDR blocked these effects through the IRE1α-JNK pathway. Further, silencing of VDR impaired sensitivity to TAM in antiestrogen-responsive LCC1 cells, and prevented the effects of calcitriol and EB1089 on UPR and autophagy. In a preclinical mouse model, dietary VitD supplementation induced VDR activation and reduced carcinogen-induced ER+ mammary tumor incidence. In addition, IRE1α-JNK signaling was downregulated and survival autophagy was inhibited in mammary tumors of VitD-supplemented mice. Thus, activation of VDR is predictive of reduced risk of breast cancer recurrence in ER+ patients, possibly by inhibiting antiestrogen-promoted pro-survival autophagy.
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http://dx.doi.org/10.3390/nu13051715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159129PMC
May 2021

FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity.

NPJ Breast Cancer 2021 May 28;7(1):65. Epub 2021 May 28.

Breast Biology Group, Manchester Breast Centre, Oglesby Cancer Research Building, University of Manchester, Manchester, UK.

Cancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.
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http://dx.doi.org/10.1038/s41523-021-00263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163772PMC
May 2021

Gender differences in use of invasive diagnostic and therapeutic procedures for acute ischaemic heart disease in Chinese adults.

Heart 2021 May 27. Epub 2021 May 27.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK

Objective: To investigate gender differences in the use of diagnostic and therapeutic procedures for acute ischaemic heart disease (IHD) in Chinese adults and assess whether socioeconomic or health system factors contribute to such differences.

Methods: In 2004-2008, the China Kadoorie Biobank recruited 512 726 adults from 10 diverse areas in China. Data for 38 928 first hospitalisations with IHD (2911 acute myocardial infarction (AMI), 9817 angina and 26 200 other IHD) were obtained by electronic linkage to health insurance records until 31 December 2016. Multivariate Poisson regression models were used to estimate women-to-men rate ratios (RRs) of having cardiac enzyme tests, coronary angiography and coronary revascularisation.

Results: Among the 38 928 individuals (61% women) with IHD admissions, women were less likely to have AMI (5% vs 12%), but more likely to have angina (26% vs 24%) or other IHD (69% vs 64%). For admissions with AMI, there were no differences in the use of cardiac enzymes between women and men (RR=1.00; 95% CI, 0.97 to 1.03), but women had lower use of coronary angiography (0.80, 0.68 to 0.93) and coronary revascularisation (0.85, 0.74 to 0.99). For angina, the corresponding RRs were: 0.97 (0.94 to 1.00), 0.66 (0.59 to 0.74) and 0.56 (0.47 to 0.67), respectively; while for other IHD, they were 0.97 (0.94 to 1.00), 0.87 (0.76 to 0.99) and 0.61 (0.51 to 0.73), respectively. Adjusting for socioeconomic and health system factors did not significantly alter the women-to-men RRs.

Conclusions: Among Chinese adults hospitalised with acute IHD, women were less likely than men to have coronary angiography and revascularisation, but socioeconomic and health system factors did not contribute to these differences.
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http://dx.doi.org/10.1136/heartjnl-2021-318988DOI Listing
May 2021

Stroke risk prediction using machine learning: a prospective cohort study of 0.5 million Chinese adults.

J Am Med Inform Assoc 2021 May 9. Epub 2021 May 9.

Department of Engineering Science, University of Oxford, Oxford, UK.

Objective: To compare Cox models, machine learning (ML), and ensemble models combining both approaches, for prediction of stroke risk in a prospective study of Chinese adults.

Materials And Methods: We evaluated models for stroke risk at varying intervals of follow-up (<9 years, 0-3 years, 3-6 years, 6-9 years) in 503 842 adults without prior history of stroke recruited from 10 areas in China in 2004-2008. Inputs included sociodemographic factors, diet, medical history, physical activity, and physical measurements. We compared discrimination and calibration of Cox regression, logistic regression, support vector machines, random survival forests, gradient boosted trees (GBT), and multilayer perceptrons, benchmarking performance against the 2017 Framingham Stroke Risk Profile. We then developed an ensemble approach to identify individuals at high risk of stroke (>10% predicted 9-yr stroke risk) by selectively applying either a GBT or Cox model based on individual-level characteristics.

Results: For 9-yr stroke risk prediction, GBT provided the best discrimination (AUROC: 0.833 in men, 0.836 in women) and calibration, with consistent results in each interval of follow-up. The ensemble approach yielded incrementally higher accuracy (men: 76%, women: 80%), specificity (men: 76%, women: 81%), and positive predictive value (men: 26%, women: 24%) compared to any of the single-model approaches.

Discussion And Conclusion: Among several approaches, an ensemble model combining both GBT and Cox models achieved the best performance for identifying individuals at high risk of stroke in a contemporary study of Chinese adults. The results highlight the potential value of expanding the use of ML in clinical practice.
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http://dx.doi.org/10.1093/jamia/ocab068DOI Listing
May 2021

Detection of asymptomatic carotid stenosis in patients with lower-extremity arterial disease: development and external validations of a risk score.

Br J Surg 2021 Apr 19. Epub 2021 Apr 19.

Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Background: Recommendations for screening patients with lower-extremity arterial disease (LEAD) to detect asymptomatic carotid stenosis (ACS) are conflicting. Prediction models might identify patients at high risk of ACS, possibly allowing targeted screening to improve preventive therapy and compliance.

Methods: A systematic search for prediction models for at least 50 per cent ACS in patients with LEAD was conducted. A prediction model in screened patients from the USA with an ankle : brachial pressure index of 0.9 or less was subsequently developed, and assessed for discrimination and calibration. External validation was performed in two independent cohorts, from the UK and the Netherlands.

Results: After screening 4907 studies, no previously published prediction models were found. For development of a new model, data for 112 117 patients were used, of whom 6354 (5.7 per cent) had at least 50 per cent ACS and 2801 (2.5 per cent) had at least 70 per cent ACS. Age, sex, smoking status, history of hypercholesterolaemia, stroke/transient ischaemic attack, coronary heart disease and measured systolic BP were predictors of ACS. The model discrimination had an area under the receiver operating characteristic (AUROC) curve of 0.71 (95 per cent c.i. 0.71 to 0.72) for at least 50 per cent ACS and 0.73 (0.72 to 0.73) for at least 70 per cent ACS. Screening the 20 per cent of patients at greatest risk detected 12.4 per cent with at least 50 per cent ACS (number needed to screen (NNS) 8] and 5.8 per cent with at least 70 per cent ACS (NNS 17). This yielded 44.2 and 46.9 per cent of patients with at least 50 and 70 per cent ACS respectively. External validation showed reliable discrimination and adequate calibration.

Conclusion: The present risk score can predict significant ACS in patients with LEAD. This approach may inform targeted screening of high-risk individuals to enhance the detection of ACS.
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http://dx.doi.org/10.1093/bjs/znab040DOI Listing
April 2021

ChIP-BIT2: a software tool to detect weak binding events using a Bayesian integration approach.

BMC Bioinformatics 2021 Apr 15;22(1):193. Epub 2021 Apr 15.

Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA, 22203, USA.

Background: ChIP-seq combines chromatin immunoprecipitation assays with sequencing and identifies genome-wide binding sites for DNA binding proteins. While many binding sites have strong ChIP-seq 'peak' observations and are well captured, there are still regions bound by proteins weakly, with a relatively low ChIP-seq signal enrichment. These weak binding sites, especially those at promoters and enhancers, are functionally important because they also regulate nearby gene expression. Yet, it remains a challenge to accurately identify weak binding sites in ChIP-seq data due to the ambiguity in differentiating these weak binding sites from the amplified background DNAs.

Results: ChIP-BIT2 ( http://sourceforge.net/projects/chipbitc/ ) is a software package for ChIP-seq peak detection. ChIP-BIT2 employs a mixture model integrating protein and control ChIP-seq data and predicts strong or weak protein binding sites at promoters, enhancers, or other genomic locations. For binding sites at gene promoters, ChIP-BIT2 simultaneously predicts their target genes. ChIP-BIT2 has been validated on benchmark regions and tested using large-scale ENCODE ChIP-seq data, demonstrating its high accuracy and wide applicability.

Conclusion: ChIP-BIT2 is an efficient ChIP-seq peak caller. It provides a better lens to examine weak binding sites and can refine or extend the existing binding site collection, providing additional regulatory regions for decoding the mechanism of gene expression regulation.
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http://dx.doi.org/10.1186/s12859-021-04108-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051094PMC
April 2021

Liver-specific T regulatory type-1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP.

Cell Rep 2021 Mar;34(13):108919

Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada; Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain. Electronic address:

Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (B) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.
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http://dx.doi.org/10.1016/j.celrep.2021.108919DOI Listing
March 2021

Abdominal and gluteo-femoral markers of adiposity and risk of vascular-metabolic mortality in a prospective study of 150 000 Mexican adults.

Eur J Prev Cardiol 2021 Mar 9. Epub 2021 Mar 9.

School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Aims: Results of previous studies of abdominal adiposity and risk of vascular-metabolic mortality in Hispanic populations have been conflicting. We report results from a large prospective study of Mexican adults with high levels of abdominal adiposity.

Methods And Results: A total of 159 755 adults aged ≥35 years from Mexico City were enrolled in a prospective study and followed for 16 years. Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) associated with three markers of abdominal adiposity (waist circumference, waist-hip ratio, and waist-height ratio) and one marker of gluteo-femoral adiposity (hip circumference) for cause-specific mortality before age 75 years. To reduce reverse causality, deaths in the first 5 years of follow-up and participants with diabetes or other prior chronic disease were excluded. Among 113 163 participants without prior disease and aged 35-74 years at recruitment, all adiposity markers were positively associated with vascular-metabolic mortality. Comparing the top versus bottom tenth of the sex-specific distributions, the vascular-metabolic mortality RRs at ages 40-74 years were 2.32 [95% confidence interval (CI) 1.84-2.94] for waist circumference, 2.22 (1.71-2.88) for the waist-hip ratio, 2.63 (2.06-3.36) for the waist-height ratio, and 1.58 (1.29-1.93) for hip circumference. The RRs corresponding to each standard deviation (SD) higher usual levels of these adiposity markers were 1.34 (95% CI 1.27-1.41), 1.31 (1.23-1.39), 1.38 (1.31-1.45), and 1.18 (1.13-1.24), respectively. For the markers of abdominal adiposity, the RRs did not change much after further adjustment for other adiposity markers, but for hip circumference the association was reversed; given body mass index and waist circumference, the RR for vascular-metabolic mortality for each one SD higher usual hip circumference was 0.80 (0.75-0.86).

Conclusions: In this study of Mexican adults, abdominal adiposity (and in particular the waist-height ratio) was strongly and positively associated with vascular-metabolic mortality. For a given amount of general and abdominal adiposity, however, higher hip circumference was associated with lower vascular-metabolic mortality.
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http://dx.doi.org/10.1093/eurjpc/zwab038DOI Listing
March 2021

Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.

Nat Commun 2021 03 9;12(1):1502. Epub 2021 Mar 9.

University of Cambridge, Department of Pharmacology, Cambridge, UK.

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.
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http://dx.doi.org/10.1038/s41467-021-21783-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940427PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Utility of risk prediction models to detect atrial fibrillation in screened participants.

Eur J Prev Cardiol 2021 May;28(6):586-595

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford OX3 7LF, UK.

Aims: Atrial fibrillation (AF) is associated with higher risk of stroke. While the prevalence of AF is low in the general population, risk prediction models might identify individuals for selective screening of AF. We aimed to systematically identify and compare the utility of established models to predict prevalent AF.

Methods And Results: Systematic search of PubMed and EMBASE for risk prediction models for AF. We adapted established risk prediction models and assessed their predictive performance using data from 2.5M individuals who attended vascular screening clinics in the USA and the UK and in the subset of 1.2M individuals with CHA2DS2-VASc ≥2. We assessed discrimination using area under the receiver operating characteristic (AUROC) curves and agreement between observed and predicted cases using calibration plots. After screening 6959 studies, 14 risk prediction models were identified. In our cohort, 10 464 (0.41%) participants had AF. For discrimination, six prediction model had AUROC curves of 0.70 or above in all individuals and those with CHA2DS2-VASc ≥2. In these models, calibration plots showed very good concordance between predicted and observed risks of AF. The two models with the highest observed prevalence in the highest decile of predicted risk, CHARGE-AF and MHS, showed an observed prevalence of AF of 1.6% with a number needed to screen of 63. Selective screening of the 10% highest risk identified 39% of cases with AF.

Conclusion: Prediction models can reliably identify individuals at high risk of AF. The best performing models showed an almost fourfold higher prevalence of AF by selective screening of individuals in the highest decile of risk compared with systematic screening of all cases.

Registration: This systematic review was registered (PROSPERO CRD42019123847).
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http://dx.doi.org/10.1093/eurjpc/zwaa082DOI Listing
May 2021

Improved prediction of fracture risk leveraging a genome-wide polygenic risk score.

Genome Med 2021 Feb 3;13(1):16. Epub 2021 Feb 3.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Room H-413, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada.

Background: Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction.

Methods: We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors.

Results: A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072.

Conclusions: We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
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http://dx.doi.org/10.1186/s13073-021-00838-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860212PMC
February 2021

BVLOS UAS Operations in Highly-Turbulent Volcanic Plumes.

Front Robot AI 2020 27;7:549716. Epub 2020 Oct 27.

Rabaul Volcanological Observatory, Rabaul, Papua New Guinea.

Long-range, high-altitude Unoccupied Aerial System (UAS) operations now enable measurements of volcanic gas chemistry at globally-significant active volcanoes. However, the extreme environments encountered within volcanic plumes present significant challenges for both air frame development and in-flight control. As part of a multi-disciplinary field deployment in May 2019, we flew fixed wing UAS Beyond Visual Line of Sight (BVLOS) over Manam volcano, Papua New Guinea, to measure real-time gas concentrations within the volcanic plume. By integrating aerial gas measurements with ground- and satellite-based sensors, our aim was to collect data that would constrain the emission rate of environmentally-important volcanic gases, such as carbon dioxide, whilst providing critical insight into the state of the subsurface volcanic system. Here, we present a detailed analysis of three BVLOS flights into the plume of Manam volcano and discuss the challenges involved in operating in highly turbulent volcanic plumes. Specifically, we report a detailed description of the system, including ground and air components, and flight plans. We present logged flight data for two successful flights to evaluate the aircraft performance under the atmospheric conditions experienced during plume traverses. Further, by reconstructing the sequence of events that led to the failure of the third flight, we identify a number of lessons learned and propose appropriate recommendations to reduce risk in future flight operations.
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http://dx.doi.org/10.3389/frobt.2020.549716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805736PMC
October 2020

Visual Odometry Using Pixel Processor Arrays for Unmanned Aerial Systems in GPS Denied Environments.

Front Robot AI 2020 29;7:126. Epub 2020 Sep 29.

Flight Lab, Department of Aerospace Engineering, University of Bristol, Bristol, United Kingdom.

Environments in which Global Positioning Systems (GPS), or more generally Global Navigation Satellite System (GNSS), signals are denied or degraded pose problems for the guidance, navigation, and control of autonomous systems. This can make operating in hostile GNSS-Impaired environments, such as indoors, or in urban and natural canyons, impossible or extremely difficult. Pixel Processor Array (PPA) cameras-in conjunction with other on-board sensors-can be used to address this problem, aiding in tracking, localization, and control. In this paper we demonstrate the use of a PPA device-the SCAMP vision chip-combining perception and compute capabilities on the same device for aiding in real-time navigation and control of aerial robots. A PPA consists of an array of Processing Elements (PEs), each of which features light capture, processing, and storage capabilities. This allows various image processing tasks to be efficiently performed directly on the sensor itself. Within this paper we demonstrate visual odometry and target identification running concurrently on-board a single PPA vision chip at a combined frequency in the region of 400 Hz. Results from outdoor multirotor test flights are given along with comparisons against baseline GPS results. The SCAMP PPA's High Dynamic Range (HDR) and ability to run multiple algorithms at adaptive rates makes the sensor well suited for addressing outdoor flight of small UAS in GNSS challenging or denied environments. HDR allows operation to continue during the transition from indoor to outdoor environments, and in other situations where there are significant variations in light levels. Additionally, the PPA only needs to output specific information such as the optic flow and target position, rather than having to output entire images. This significantly reduces the bandwidth required for communication between the sensor and on-board flight computer, enabling high frame rate, low power operation.
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http://dx.doi.org/10.3389/frobt.2020.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805748PMC
September 2020

Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence.

Sci Rep 2021 01 11;11(1):385. Epub 2021 Jan 11.

Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA, 22203, USA.

Exploring complex modularization of intracellular signal transduction pathways is critical to understanding aberrant cellular responses during disease development and drug treatment. IMPALA (Inferred Modularization of PAthway LAndscapes) integrates information from high throughput gene expression experiments and genome-scale knowledge databases to identify aberrant pathway modules, thereby providing a powerful sampling strategy to reconstruct and explore pathway landscapes. Here IMPALA identifies pathway modules associated with breast cancer recurrence and Tamoxifen resistance. Focusing on estrogen-receptor (ER) signaling, IMPALA identifies alternative pathways from gene expression data of Tamoxifen treated ER positive breast cancer patient samples. These pathways were often interconnected through cytoplasmic genes such as IRS1/2, JAK1, YWHAZ, CSNK2A1, MAPK1 and HSP90AA1 and significantly enriched with ErbB, MAPK, and JAK-STAT signaling components. Characterization of the pathway landscape revealed key modules associated with ER signaling and with cell cycle and apoptosis signaling. We validated IMPALA-identified pathway modules using data from four different breast cancer cell lines including sensitive and resistant models to Tamoxifen. Results showed that a majority of genes in cell cycle/apoptosis modules that were up-regulated in breast cancer patients with short survivals (< 5 years) were also over-expressed in drug resistant cell lines, whereas the transcription factors JUN, FOS, and STAT3 were down-regulated in both patient and drug resistant cell lines. Hence, IMPALA identified pathways were associated with Tamoxifen resistance and an increased risk of breast cancer recurrence. The IMPALA package is available at https://dlrl.ece.vt.edu/software/ .
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http://dx.doi.org/10.1038/s41598-020-79603-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801429PMC
January 2021

Data-driven detection of subtype-specific differentially expressed genes.

Sci Rep 2021 01 11;11(1):332. Epub 2021 Jan 11.

Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA, 22203, USA.

Among multiple subtypes of tissue or cell, subtype-specific differentially-expressed genes (SDEGs) are defined as being most-upregulated in only one subtype but not in any other. Detecting SDEGs plays a critical role in the molecular characterization and deconvolution of multicellular complex tissues. Classic differential analysis assumes a null hypothesis whose test statistic is not subtype-specific, thus can produce a high false positive rate and/or lower detection power. Here we first introduce a One-Versus-Everyone Fold Change (OVE-FC) test for detecting SDEGs. We then propose a scaled test statistic (OVE-sFC) for assessing the statistical significance of SDEGs that applies a mixture null distribution model and a tailored permutation test. The OVE-FC/sFC test was validated on both type 1 error rate and detection power using extensive simulation data sets generated from real gene expression profiles of purified subtype samples. The OVE-FC/sFC test was then applied to two benchmark gene expression data sets of purified subtype samples and detected many known or previously unknown SDEGs. Subsequent supervised deconvolution results on synthesized bulk expression data, obtained using the SDEGs detected from the independent purified expression data by the OVE-FC/sFC test, showed superior performance in deconvolution accuracy when compared with popular peer methods.
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http://dx.doi.org/10.1038/s41598-020-79704-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801594PMC
January 2021

Development and Internal Validation of a Risk Score to Detect Asymptomatic Carotid Stenosis.

Eur J Vasc Endovasc Surg 2021 03 7;61(3):365-373. Epub 2021 Jan 7.

Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Objective: Asymptomatic carotid stenosis (ACS) is associated with an increased risk of ischaemic stroke and myocardial infarction. Risk scores have been developed to detect individuals at high risk of ACS, thereby enabling targeted screening, but previous external validation showed scope for refinement of prediction by adding additional predictors. The aim of this study was to develop a novel risk score in a large contemporary screened population.

Methods: A prediction model was developed for moderate (≥50%) and severe (≥70%) ACS using data from 596 469 individuals who attended screening clinics. Variables that predicted the presence of ≥50% and ≥70% ACS independently were determined using multivariable logistic regression. Internal validation was performed using bootstrapping techniques. Discrimination was assessed using area under the receiver operating characteristic curves (AUROCs) and agreement between predicted and observed cases using calibration plots.

Results: Predictors of ≥50% and ≥70% ACS were age, sex, current smoking, diabetes mellitus, prior stroke/transient ischaemic attack, coronary artery disease, peripheral arterial disease, blood pressure, and blood lipids. Models discriminated between participants with and without ACS reliably, with an AUROC of 0.78 (95% confidence interval [CI] 0.77-0.78) for ≥ 50% ACS and 0.82 (95% CI 0.81-0.82) for ≥ 70% ACS. The number needed to screen in the highest decile of predicted risk to detect one case with ≥50% ACS was 13 and that of ≥70% ACS was 58. Targeted screening of the highest decile identified 41% of cases with ≥50% ACS and 51% with ≥70% ACS.

Conclusion: The novel risk model predicted the prevalence of ACS reliably and performed better than previous models. Targeted screening among the highest decile of predicted risk identified around 40% of all cases with ≥50% ACS. Initiation or intensification of cardiovascular risk management in detected cases might help to reduce both carotid related ischaemic strokes and myocardial infarctions.
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http://dx.doi.org/10.1016/j.ejvs.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994015PMC
March 2021

Lp(a) (Lipoprotein[a]), an Exemplar for Precision Medicine: Insights From UK Biobank.

Arterioscler Thromb Vasc Biol 2021 01 23;41(1):475-477. Epub 2020 Dec 23.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine (H.W.), University of Oxford, United Kingdom.

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http://dx.doi.org/10.1161/ATVBAHA.120.315549DOI Listing
January 2021

Preparation of a User-Defined Peptide Gel for Controlled 3D Culture Models of Cancer and Disease.

J Vis Exp 2020 12 3(166). Epub 2020 Dec 3.

Division of Cancer & Stem Cells, School of Medicine, Nottingham Biodiscovery Institute, University of Nottingham;

There is a growing awareness that cells grown in 3D better model in vivo behavior than those grown in 2D. In this protocol, we describe a simple and tunable 3D hydrogel, suitable for culturing cells and tissue in a setting that matches their native environment. This is particularly important for researchers investigating the initiation, growth, and treatment of cancer where the interaction between cells and their local extracellular matrix is a fundamental part of the model. Moving to 3D culture can be challenging and is often associated with a lack of reproducibility due to high batch-to-batch variation in animal-derived 3D culture matrices. Similarly, handling issues can limit the usefulness of synthetic hydrogels. In response to this need, we have optimized a simple self-assembling peptide gel, to enable the culture of relevant cell line models of cancer and disease, as well as patient-derived tissue/cells. The gel itself is free from matrix components, apart from those added during encapsulation or deposited into the gel by the encapsulated cells. The mechanical properties of the hydrogels can also be altered independent of matrix addition. It, therefore, acts as a 'blank slate' allowing researchers to build a 3D culture environment that reflects the target tissue of interest and to dissect the influences of mechanical forces and/or biochemical control of cell behavior independently.
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http://dx.doi.org/10.3791/61710DOI Listing
December 2020

Frailty index and all-cause and cause-specific mortality in Chinese adults: a prospective cohort study.

Lancet Public Health 2020 12;5(12):e650-e660

Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.

Background: The fraily index is a useful proxy measure of accelerated biological ageing and in estimating all-cause and cause-specific mortality in older individuals in European and US populations. However, the predictive value of the frailty index in other populations outside of Europe and the USA and in adults younger than 50 years is unknown. We aimed to examine the association between the frailty index and mortality in a population of Chinese adults.

Methods: In this prospective cohort study, we used data from the China Kadoorie Biobank. We included adults aged 30-79 years from ten areas (five urban areas and five rural areas) of China who had no missing values for the items that made up the frailty index. We did not exclude participants on the basis of baseline morbidity status. We calculated the follow-up person-years from the baseline date to either the date of death, loss to follow-up, or Dec 31, 2017, whichever came first, through linkage with the registries of China's Disease Surveillance Points system and local residential records. Active follow-up visits to local communities were done annually for participants who were not linked to any established registries. Causes of death from official death certificates were supplemented, if necessary, by reviewing medical records or doing standard verbal autopsy procedures. The frailty index was calculated using 28 baseline variables, all of which were health status deficits measured by use of questionnaires and physical examination. We defined three categories of frailty status: robust (frailty index ≤0·10), prefrail (frailty index >0·10 to <0·25), and frail (frailty index ≥0·25). The primary outcomes were all-cause mortality and cause-specific mortality in Chinese adults aged 30-79 years. We used a Cox proportional hazards model to estimate the associations between the frailty index and all-cause and cause-specific mortality, adjusting for chronological age, education, and lifestyle factors.

Findings: 512 723 participants, recruited between June 25, 2004, and July 15, 2008, were followed up for a median of 10·8 years (IQR 10·2-13·1; total follow-up 5 551 974 person-years). 291 954 (56·9%) people were categorised as robust, 205 075 (40·0%) people were categorised as prefrail, and 15 694 (3·1%) people were categorised as frail. Women aged between 45 years and 79 years had a higher mean frailty index and a higher prevalence of frailty than did men. During follow-up, 49 371 deaths were recorded. After adjustment for established and potential risk factors for death, each 0·1 increment in the frailty index was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1·68, 95% CI 1·66-1·71). Such associations were stronger among younger adults than among older adults (p<0·0001), with HRs per 0·1 increment of the frailty index of 1·95 (95% CI 1·87-2·03) for those younger than 50 years, 1·80 (1·76-1·83) for those aged 50-64 years, and 1·56 (1·53-1·59) for those 65 years and older. After adjustments, there was no difference between the sexes in the association between the frailty index and all-cause mortality (p=0·75). For each 0·1 increment of the frailty index, the corresponding HRs for risk of death were 1·89 (95% CI 1·83-1·94) from ischaemic heart disease, 1·84 (1·79-1·89) from cerebrovascular disease, 1·19 (1·16-1·22) from cancer, 2·54 (2·45-2·63) from respiratory disease, 1·78 (1·59-2·00) from infection, and 1·78 (1·73-1·83) from all other causes.

Interpretation: The frailty index is associated with all-cause and cause-specific mortality independent of chronological age in younger and older Chinese adults. The identification of younger adults with accelerated ageing by use of surrogate measures could be useful for the prevention of premature death and the extension of healthy active life expectancy.

Funding: The National Natural Science Foundation of China, the National Key R&D Program of China, the Chinese Ministry of Science and Technology, the Kadoorie Charitable Foundation, and the Wellcome Trust.
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http://dx.doi.org/10.1016/S2468-2667(20)30113-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708389PMC
December 2020

Associations of Adiposity, Circulating Protein Biomarkers, and Risk of Major Vascular Diseases.

JAMA Cardiol 2021 Mar;6(3):276-286

Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom.

Importance: Obesity is associated with a higher risk of cardiovascular disease (CVD), but little is known about the role that circulating protein biomarkers play in this association.

Objective: To examine the observational and genetic associations of adiposity with circulating protein biomarkers and the observational associations of proteins with incident CVD.

Design, Setting, And Participants: This subcohort study included 628 participants from the prospective China Kadoorie Biobank who did not have a history of cancer at baseline. The Olink platform measured 92 protein markers in baseline plasma samples. Data were collected from June 2004 to January 2016 and analyzed from January 2019 to June 2020.

Exposures: Measured body mass index (BMI) obtained during the baseline survey and genetically instrumented BMI derived using 571 externally weighted single-nucleotide variants.

Main Outcomes And Measures: Cross-sectional associations of adiposity with biomarkers were examined using linear regression. Associations of biomarkers with CVD risk were assessed using Cox regression among those without prior cancer or CVD at baseline. Mendelian randomization was conducted to derive genetically estimated associations of BMI with biomarkers.

Findings: In observational analyses of 628 individuals (mean [SD] age, 52.2 [10.5] years; 385 women [61.3%]), BMI (mean [SD], 23.9 [3.6]) was positively associated with 27 proteins (per 1-SD higher BMI; eg, interleukin-6: 0.21 [95% CI, 0.12-0.29] SD; interleukin-18: 0.13 [95% CI, 0.05-0.21] SD; monocyte chemoattractant protein-1: 0.12 [95% CI, 0.04-0.20] SD; hepatocyte growth factor: 0.31 [95% CI, 0.24-0.39] SD), and inversely with 3 proteins (Fas ligand: -0.11 [95% CI, -0.19 to -0.03] SD; TNF-related weak inducer of apoptosis, -0.14 [95% CI, -0.23 to -0.06] SD; and carbonic anhydrase 9: (-0.14 [95% CI, -0.22 to -0.05] SD), with similar associations identified for other adiposity traits (eg, waist circumference [r = 0.96]). In mendelian randomization, the associations of genetically elevated BMI with specific proteins were directionally consistent with the observational associations. In meta-analyses of genetically elevated BMI with 8 proteins, combining present estimates with previous studies, the most robust associations were shown for interleukin-6 (per 1-SD higher BMI; 0.21 [95% CI, 0.13-0.29] SD), interleukin-18 (0.16 [95% CI, 0.06-0.26] SD), monocyte chemoattractant protein-1 (0.21 [95% CI, 0.11-0.30] SD), monocyte chemotactic protein-3 (0.12 [95% CI, 0.03-0.21] SD), TNF-related apoptosis-inducing ligand (0.23 [95% CI, 0.13-0.32] SD), and hepatocyte growth factor (0.14 [95% CI, 0.06-0.22] SD). Of the 30 BMI-associated biomarkers, 10 (including interleukin-6, interleukin-18, and hepatocyte growth factor) were nominally associated with incident CVD.

Conclusions And Relevance: Mendelian randomization shows adiposity to be associated with a range of protein biomarkers, with some biomarkers also showing association with CVD risk. Future studies are warranted to validate these findings and assess whether proteins may be mediators between adiposity and CVD.
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http://dx.doi.org/10.1001/jamacardio.2020.6041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711564PMC
March 2021

Author Correction: BICORN: An R package for integrative inference of de novo cis-regulatory modules.

Sci Rep 2020 Oct 7;10(1):16962. Epub 2020 Oct 7.

Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA, 22203, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-74149-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542141PMC
October 2020

IntAPT: integrated assembly of phenotype-specific transcripts from multiple RNA-seq profiles.

Bioinformatics 2021 05;37(5):650-658

Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 22203, USA.

Motivation: High-throughput RNA sequencing has revolutionized the scope and depth of transcriptome analysis. Accurate reconstruction of a phenotype-specific transcriptome is challenging due to the noise and variability of RNA-seq data. This requires computational identification of transcripts from multiple samples of the same phenotype, given the underlying consensus transcript structure.

Results: We present a Bayesian method, integrated assembly of phenotype-specific transcripts (IntAPT), that identifies phenotype-specific isoforms from multiple RNA-seq profiles. IntAPT features a novel two-layer Bayesian model to capture the presence of isoforms at the group layer and to quantify the abundance of isoforms at the sample layer. A spike-and-slab prior is used to model the isoform expression and to enforce the sparsity of expressed isoforms. Dependencies between the existence of isoforms and their expression are modeled explicitly to facilitate parameter estimation. Model parameters are estimated iteratively using Gibbs sampling to infer the joint posterior distribution, from which the presence and abundance of isoforms can reliably be determined. Studies using both simulations and real datasets show that IntAPT consistently outperforms existing methods for the IntAPT. Experimental results demonstrate that, despite sequencing errors, IntAPT exhibits a robust performance among multiple samples, resulting in notably improved identification of expressed isoforms of low abundance.

Availability And Implementation: The IntAPT package is available at http://github.com/henryxushi/IntAPT.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097681PMC
May 2021

Observational and Genetic Associations of Body Mass Index and Hepatobiliary Diseases in a Relatively Lean Chinese Population.

JAMA Netw Open 2020 10 1;3(10):e2018721. Epub 2020 Oct 1.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute University of Oxford, Oxford, United Kingdom.

Importance: There is some support for the existence of genetic associations between adiposity and certain hepatobiliary diseases in Western populations. However, there is little evidence of such genetic associations in China, where the causes of these diseases may differ from those in Western populations and the mean body mass index (BMI) is much lower.

Objectives: To compare the observational associations of BMI with hepatobiliary diseases and liver biomarkers with the genetic associations between BMI and these factors and to assess whether the genetic associations of BMI with liver diseases differed by hepatitis B virus infection status.

Design, Setting, And Participants: This cohort study used data from the prospective China Kadoorie Biobank, including 473 938 adults aged 30 to 79 years without hepatobiliary diseases at baseline from 10 diverse areas in China from June 25, 2004, to July 15, 2008. A random sample of 75 736 participants with genotyping data was included in the Mendelian randomization analysis. Follow-up was completed January 1, 2017 (median [interquartile range] length of follow-up, 10.2 [9.2-11.1] years). Data were analyzed from January to October 2019.

Exposures: Measured BMI obtained during the baseline survey and genetically instrumented BMI derived using 92 single-nucleotide variations.

Main Outcomes And Measures: Incident cases of hepatobiliary diseases, liver enzymes, fatty liver index, and fibrosis score.

Results: Among 473 938 individuals (276 041 [58.2%] women), the mean (SD) age was 52 (10.9) years and mean (SD) BMI was 23.8 (3.4). Baseline BMI was associated with higher risks of chronic liver disease (adjusted risk ratio per 1-SD increase, 1.14; 95% CI, 1.11 to 1.17) and gallbladder disease (adjusted risk ratio per 1-SD increase, 1.29; 95% CI, 1.27 to 1.31), with heterogeneity by disease subtype (P < .001). Genetically instrumented BMI was associated with higher risks of chronic liver disease (risk ratio per 1-SD increase, 1.55; 95% CI, 1.08 to 2.24) and gallbladder disease (risk ratio per 1-SD increase, 1.40; 95% CI, 1.11 to 1.76), with no heterogeneity between subtypes. A meta-analysis of the genetic associations in China Kadoorie Biobank and those calculated in UK Biobank gave a risk ratio of 1.55 (95% CI, 1.30 to 1.84) for chronic liver disease and 1.42 (95% CI, 1.22 to 1.64) for gallbladder disease. In the China Kadoorie Biobank study, there were positive genetic associations of BMI with liver enzymes, steatosis, and fibrosis scores, consistent with observational associations. The genetic associations of BMI with liver diseases and biomarkers did not differ by hepatitis B virus infection status.

Conclusions And Relevance: In this cohort study of a relatively lean Chinese population, there were positive genetic associations of BMI with hepatobiliary diseases. These results suggest that maintaining a healthy weight through diet and physical activity may help prevent hepatobiliary diseases.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.18721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532388PMC
October 2020

Achieving Country-Wide Scale for Helping Babies Breathe and Helping Babies Survive.

Pediatrics 2020 10;146(Suppl 2):S194-S207

Critical Care and Anaesthesiology Research Group, Stavanger University Hospital, Stavanger, Norway.

Helping Babies Breathe (HBB) was piloted in 2009 as a program targeted to reduce neonatal mortality (NM). The program has morphed into a suite of programs termed Helping Babies Survive that includes Essential Care for Every Baby. Since 2010, the HBB and Helping Babies Survive training programs have been taught to >850 000 providers in 80 countries. Initial HBB training is associated with a significant improvement in knowledge and skills. However, at refresher training, there is a knowledge-skill gap evident, with a falloff in skills. Accumulating evidence supports the role for frequent refresher resuscitation training in facilitating skills retention. Beyond skill acquisition, HBB has been associated with a significant reduction in early NM (<24 hours) and fresh stillbirth rates. To evaluate the large-scale impact of the growth of skilled birth attendants, we analyzed NM rates in sub-Saharan Africa ( = 11) and Nepal (as areas of growing HBB implementation). All have revealed a consistent reduction in NM at 28 days between 2009 and 2018; a mean reduction of 5.34%. The number of skilled birth attendants, an indirect measure of HBB sustained rollout, reveals significant correlation with NM, fresh stillbirth, and perinatal mortality rates, highlighting HBB's success and the need for continued efforts to train frontline providers. A novel live newborn resuscitation trainer as well as a novel app (HBB Prompt) have been developed, increasing knowledge and skills while providing simulation-based repeated practice. Ongoing challenges in sustaining resources (financial and other) for newborn programming emphasize the need for innovative implementation strategies and training tools.
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http://dx.doi.org/10.1542/peds.2020-016915KDOI Listing
October 2020

Finding meaning in the consultation: introducing the hermeneutic window.

Br J Gen Pract 2020 10 1;70(699):502-503. Epub 2020 Oct 1.

Health Education England, London.

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http://dx.doi.org/10.3399/bjgp20X712865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518895PMC
October 2020