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  • ItemOpen Access
    In vitro detection of in vitro secondary mechanisms of genotoxicity induced by engineered nanomaterials
    (2019-02-13) Evans, Stephen J; Clift, Martin J D; Singh, Neenu; Wills, John W; Hondow, Nicole; Wilkinson, Thomas S; Burgum, Michael J; Brown, Andy P; Jenkins, Gareth J; Doak, Shareen H
    Abstract Background It is well established that toxicological evaluation of engineered nanomaterials (NMs) is vital to ensure the health and safety of those exposed to them. Further, there is a distinct need for the development of advanced physiologically relevant in vitro techniques for NM hazard prediction due to the limited predictive power of current in vitro models and the unsustainability of conducting nano-safety evaluations in vivo. Thus, the purpose of this study was to develop alternative in vitro approaches to assess the potential of NMs to induce genotoxicity by secondary mechanisms. Results This was first undertaken by a conditioned media-based technique, whereby cell culture media was transferred from differentiated THP-1 (dTHP-1) macrophages treated with γ-Fe2O3 or Fe3O4 superparamagnetic iron oxide nanoparticles (SPIONs) to the bronchial cell line 16HBE14o−. Secondly construction and SPION treatment of a co-culture model comprising of 16HBE14o− cells and dTHP-1 macrophages. For both of these approaches no cytotoxicity was detected and chromosomal damage was evaluated by the in vitro micronucleus assay. Genotoxicity assessment was also performed using 16HBE14o− monocultures, which demonstrated only γ-Fe2O3 nanoparticles to be capable of inducing chromosomal damage. In contrast, immune cell conditioned media and dual cell co-culture SPION treatments showed both SPION types to be genotoxic to 16HBE14o− cells due to secondary genotoxicity promoted by SPION-immune cell interaction. Conclusions The findings of the present study demonstrate that the approach of using single in vitro cell test systems precludes the ability to consider secondary genotoxic mechanisms. Consequently, the use of multi-cell type models is preferable as they better mimic the in vivo environment and thus offer the potential to enhance understanding and detection of a wider breadth of potential damage induced by NMs.
  • ItemOpen Access
    Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity
    (2019-02-11) Linker, Stephanie M; Urban, Lara; Clark, Stephen J; Chhatriwala, Mariya; Amatya, Shradha; McCarthy, Davis J; Ebersberger, Ingo; Vallier, Ludovic; Reik, Wolf; Stegle, Oliver; Bonder, Marc J
    Abstract Background Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remains poorly understood. Results We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results show that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on genomic features as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons. These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation. Conclusions Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.
  • ItemOpen Access
    Different analysis methods of Scottish and English child physical activity data explain the majority of the difference between the national prevalence estimates
    (2019-02-11) Williamson, Chloë; Kelly, Paul; Strain, Tessa
    Abstract Background The percentages of children in Scotland and England meeting the aerobic physical activity (PA) recommendation differ greatly according to estimates derived from the respective national health surveys. The Scottish Health Survey (SHeS) usually estimates over 70% meeting the recommendation; Health Survey for England (HSE) estimates are usually below 25%. It is plausible that these differences originate from different analysis methods. The HSE monitors the percentage of children in England that undertake 60 min of moderate-to-vigorous PA on each day of the week (‘Daily Minimum Method’ (DMM)). The SHeS monitors the proportion that undertakes at least seven sessions of moderate-to-vigorous PA, with an average daily duration ≥60 min in Scotland (‘Weekly Average Method’ (WAM)). We aimed to establish how much this difference in analysis methods influences prevalence estimates. Methods PA data from 5 to 15 year olds in the 2015 HSE and SHeS were reanalysed (weighted n = 3840 and 965, respectively). Two comparable pairs of estimates were derived: a DMM and WAM estimate from the HSE not including travel to/from school, and WAM estimates from the HSE and the SHeS including travel to/from school. It is not possible to calculate a DMM estimate from the SHeS due to questionnaire design. Results were presented for the total samples, and by sex and age sub-groups. Results The HSE WAM estimate was 31.7 (95% CI: 30.2–33.3) percentage points higher than the DMM estimate (54.3% (95% CI: 52.6–56.0) and 22.6% (95% CI: 21.2–24.1) respectively). The magnitude of this difference differed by age group but not sex. When comparable WAM estimates were derived from the SHeS and the HSE, the SHeS was 11.8 percentage points higher (73.6% (95% CI: 69.8–77.1) and 61.8% (95% CI: 60.2–63.5) respectively). The magnitude of this difference differed by age group and sex. Conclusions The results indicate that the difference in the analysis method explains the majority (approximately 30 percentage points) of the difference in the child PA prevalence estimates between Scotland and England (leaving approximately 12 percentage points representing true differences or related to questionnaire differences). These results will help national surveillance determine how to increase comparability between the U.K. home nations.
  • ItemOpen Access
    The development and feasibility of a randomised family-based physical activity promotion intervention: the Families Reporting Every Step to Health (FRESH) study
    (2019-02-09) Guagliano, Justin M; Brown, Helen E; Coombes, Emma; Hughes, Claire; Jones, Andy P; Morton, Katie L; Wilson, Edward C F; van Sluijs, Esther M F
    Abstract Background There is a need for high-quality research aiming to increase physical activity in families. This study assessed the feasibility and acceptability of FRESH (Families Reporting Every Step to Health), a child-led family-based physical activity intervention delivered online. Methods In a two-armed randomised feasibility study, 12 families (with an 8–10-year-old index child) were allocated to a ‘child-only’ (CO) or ‘family’ arm (FAM) of the theory-based FRESH intervention. Both received access to the FRESH website, allowing participants to select step challenges to ‘travel’ to target cities around the world, log their steps, and track their progress as they virtually globetrot. Only index children wore pedometers in CO; in FAM, all family members wore pedometers and worked towards collective goals. All family members were eligible to participate in the evaluation. Mixed-methods process evaluation (questionnaires and family focus groups) at 6-week follow-up consisted of completing questionnaires assessing acceptability of the intervention and accompanying effectiveness evaluation, focussed on physical (e.g. fitness, blood pressure), psychosocial (e.g. social support), and behavioural (e.g. objectively-measured family physical activity) measures. Results All families were retained (32 participants). Parents enjoyed FRESH and all children found it fun. More FAM children wanted to continue with FRESH, found the website easy to use, and enjoyed wearing pedometers. FAM children also found it easier to reach goals. Most CO families would have preferred whole family participation. Compared to CO, FAM exhibited greater website engagement as they travelled to more cities (36 ± 11 vs. 13 ± 8) and failed fewer challenges (1.5 ± 1 vs. 3 ± 1). Focus groups also revealed that most families wanted elements of competition. All children enjoyed being part of the evaluation, and adults disagreed that there were too many intervention measures (overall, 2.4 ± 1.3) or that data collection took too long (overall, 2.2 ± 1.1). Conclusion FRESH was feasible and acceptable to participating families; however, findings favoured the FAM group. Recruitment, intervention fidelity and delivery and some measurement procedures are particular areas that require further attention for optimisation. Testing the preliminary effectiveness of FRESH on family physical activity is a necessary next step. Trial registration This study was registered and given an International Standard Randomised Controlled Trials Number (ISRCTN12789422). Registered 16 March 2016.
  • ItemOpen Access
    Decline in the seroprevalence of syphilis markers among first-time blood donors in Libreville (Gabon) between 2004 and 2016.
    (Springer Science and Business Media LLC, 2019-02-08) Bisseye, Cyrille; Eko Mba, Jean-Marie; Ntsame Ndong, Jophrette Mirelle; Kosiorek, Heidi E; Butterfield, Richard J; Mombo, Landry Erik; M'batchi, Bertrand; Borad, Mitesh J; Nagalo, Bolni Marius; Allain, Jean-Pierre; Bisseye, Cyrille [0000-0002-6888-6317]
    BACKGROUND: Very few studies have been conducted on the seroprevalence of syphilis in Gabon. According to the World Health Organization, the average seroprevalence of syphilis has declined from 5.5 to 1.1% in Central Africa. The aim of this study was to test the hypothesis that syphilis decreased in Gabon between 2004 and 2016 and to identify factors involved in this pattern by testing a large sample of first-time blood donors in the capital Libreville. METHODS: The detection of Treponema pallidum was done using a Rapid Plasma Reagin test (RPR) and confirmed by an ELISA test using the Biorad Syphilis Total Antibody EIA II kit or BioMerieux Trepanostika TP recombinant. Assays were performed by dedicated technicians according to manufacturers' recommendations and following the laboratory standard operating procedures. Test results were manually transferred into the laboratory Excel files and hand-written in the laboratory logbook for syphilis testing. Logistic regression was used to assess the impact of sociodemographic characteristics on syphilis marker seroprevalence in both univariate and multivariable analysis. Odds ratios (OR) and 95% confidence intervals were calculated. RESULTS: The seroprevalence of syphilis markers was 8.4% (95% CI = 7.9-8.9) in 2004 and 2.4% (95% CI = 2.1-2.7) in 2016. The difference was significant [OR = 3.78; 95% CI (3.26-4.38); P < 0.001]. The decrease in syphilis seroprevalence was significant in both women and men and in each age group in univariate analysis. In multivariable analysis, controlling for all sociodemographic factors, the decrease in syphilis seroprevalence from 2004 to 2016 remained significant (OR = 3.29; 95% CI = 2.88-3.88, P < 0.001). The seroprevalence of syphilis decreased significantly in men compared to women and young donors compared to donors aged ≥36 years. CONCLUSIONS: This study shows a significant decline in syphilis seroprevalence in first-time blood donors in Libreville, Gabon. Government actions, including multiple HIV prevention activities, are a likely part of this decline.
  • ItemOpen Access
    Transcriptome, proteome and draft genome of Euglena gracilis
    (2019-02-07) Ebenezer, ThankGod E; Zoltner, Martin; Burrell, Alana; Nenarokova, Anna; Novák Vanclová, Anna M G; Prasad, Binod; Soukal, Petr; Santana-Molina, Carlos; O’Neill, Ellis; Nankissoor, Nerissa N; Vadakedath, Nithya; Daiker, Viktor; Obado, Samson; Silva-Pereira, Sara; Jackson, Andrew P; Devos, Damien P; Lukeš, Julius; Lebert, Michael; Vaughan, Sue; Hampl, Vladimίr; Carrington, Mark; Ginger, Michael L; Dacks, Joel B; Kelly, Steven; Field, Mark C
    Abstract Background Photosynthetic euglenids are major contributors to fresh water ecosystems. Euglena gracilis in particular has noted metabolic flexibility, reflected by an ability to thrive in a range of harsh environments. E. gracilis has been a popular model organism and of considerable biotechnological interest, but the absence of a gene catalogue has hampered both basic research and translational efforts. Results We report a detailed transcriptome and partial genome for E. gracilis Z1. The nuclear genome is estimated to be around 500 Mb in size, and the transcriptome encodes over 36,000 proteins and the genome possesses less than 1% coding sequence. Annotation of coding sequences indicates a highly sophisticated endomembrane system, RNA processing mechanisms and nuclear genome contributions from several photosynthetic lineages. Multiple gene families, including likely signal transduction components, have been massively expanded. Alterations in protein abundance are controlled post-transcriptionally between light and dark conditions, surprisingly similar to trypanosomatids. Conclusions Our data provide evidence that a range of photosynthetic eukaryotes contributed to the Euglena nuclear genome, evidence in support of the ‘shopping bag’ hypothesis for plastid acquisition. We also suggest that euglenids possess unique regulatory mechanisms for achieving extreme adaptability, through mechanisms of paralog expansion and gene acquisition.
  • ItemOpen Access
    The genome of the soybean cyst nematode (Heterodera glycines) reveals complex patterns of duplications involved in the evolution of parasitism genes
    (2019-02-07) Masonbrink, Rick; Maier, Tom R; Muppirala, Usha; Seetharam, Arun S; Lord, Etienne; Juvale, Parijat S; Schmutz, Jeremy; Johnson, Nathan T; Korkin, Dmitry; Mitchum, Melissa G; Mimee, Benjamin; den Akker, Sebastian E; Hudson, Matthew; Severin, Andrew J; Baum, Thomas J
    Abstract Background Heterodera glycines, commonly referred to as the soybean cyst nematode (SCN), is an obligatory and sedentary plant parasite that causes over a billion-dollar yield loss to soybean production annually. Although there are genetic determinants that render soybean plants resistant to certain nematode genotypes, resistant soybean cultivars are increasingly ineffective because their multi-year usage has selected for virulent H. glycines populations. The parasitic success of H. glycines relies on the comprehensive re-engineering of an infection site into a syncytium, as well as the long-term suppression of host defense to ensure syncytial viability. At the forefront of these complex molecular interactions are effectors, the proteins secreted by H. glycines into host root tissues. The mechanisms of effector acquisition, diversification, and selection need to be understood before effective control strategies can be developed, but the lack of an annotated genome has been a major roadblock. Results Here, we use PacBio long-read technology to assemble a H. glycines genome of 738 contigs into 123 Mb with annotations for 29,769 genes. The genome contains significant numbers of repeats (34%), tandem duplicates (18.7 Mb), and horizontal gene transfer events (151 genes). A large number of putative effectors (431 genes) were identified in the genome, many of which were found in transposons. Conclusions This advance provides a glimpse into the host and parasite interplay by revealing a diversity of mechanisms that give rise to virulence genes in the soybean cyst nematode, including: tandem duplications containing over a fifth of the total gene count, virulence genes hitchhiking in transposons, and 107 horizontal gene transfers not reported in other plant parasitic nematodes thus far. Through extensive characterization of the H. glycines genome, we provide new insights into H. glycines biology and shed light onto the mystery underlying complex host-parasite interactions. This genome sequence is an important prerequisite to enable work towards generating new resistance or control measures against H. glycines.
  • ItemOpen Access
    Perspectives on male partner notification and treatment for syphilis among antenatal women and their partners in Kampala and Wakiso districts, Uganda
    (2019-02-06) Nakku-Joloba, Edith; Kiguli, Juliet; Kayemba, Christine N; Twimukye, Adeline; Mbazira, Joshua K; Parkes-Ratanshi, Rosalind; Birungi, Monica; Kyenkya, Joshua; Byamugisha, Josaphat; Gaydos, Charlotte; Manabe, Yukari C
    Abstract Background Syphilis screening can be successfully integrated into antenatal clinics, and potentially avert significant morbidity and mortality to unborn infants. A minority of male partners report for testing and treatment, increasing the likelihood of reinfection. We conducted a qualitative study to understand factors influencing male partners to seek treatment after syphilis notification by their pregnant partners. Methods A purposeful sample of 54 adults who participated in the STOP (Syphilis Treatment of Partners) study was stratified by gender (24 women, 30 male partners) and enrolled for in-depth interviews which were audio recorded, transcribed, and analyzed using the thematic approach. Results The participants’ median age (IQR) was 32 years (25–44), 87% were married, and 57.4% (31/74) had attained secondary education. Fourteen of 22 (63%) female participants reported that they sometimes experienced domestic violence. Male participant’s knowledge of syphilis and their perception of their valued role as responsible fathers of an unborn baby facilitated return. Female’s fear of partner‘s violence and poor communication between partners, were barriers against delivery of the notification forms to partners and subsequent treatment of partners. For men, fear of injection pain, perceptions of syphilis as a genetic disease and as a woman’s problem, busy work schedules, poor access to good STD services, shared facilities with women in clinics, as well as HIV-related stigma were important barrier factors. Conclusions The return to the clinic for treatment of male partners after partner notification by infected pregnant women, was low due to limited knowledge about syphilis, fear of painful injection, fears of domestic violence, lack of communication skills (individual characteristics) and syphilis disease characteristics such as signs and symptoms. This, combined with health services characteristics such as structural barriers that hinder male partner treatment, low access, low capacity, work/time challenges, inadequate laboratory services and low clinic personnel capacity; threatens efforts to eliminate mother-to-child infection of syphilis. Improved public messaging about syphilis, better services, legal and policy frameworks supporting STD notification and treatment in resource-constrained settings are needed for effective STD control. Trial registration NCT02262390 ., Date Registered October 8 2014.
  • ItemOpen Access
    DeepPVP: phenotype-based prioritization of causative variants using deep learning
    (2019-02-06) Boudellioua, Imane; Kulmanov, Maxat; Schofield, Paul N.; Gkoutos, Georgios V.; Hoehndorf, Robert
    Abstract Background Prioritization of variants in personal genomic data is a major challenge. Recently, computational methods that rely on comparing phenotype similarity have shown to be useful to identify causative variants. In these methods, pathogenicity prediction is combined with a semantic similarity measure to prioritize not only variants that are likely to be dysfunctional but those that are likely involved in the pathogenesis of a patient’s phenotype. Results We have developed DeepPVP, a variant prioritization method that combined automated inference with deep neural networks to identify the likely causative variants in whole exome or whole genome sequence data. We demonstrate that DeepPVP performs significantly better than existing methods, including phenotype-based methods that use similar features. DeepPVP is freely available at . Conclusions DeepPVP further improves on existing variant prioritization methods both in terms of speed as well as accuracy.
  • ItemOpen Access
    A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts
    (2019-01-31) Guyatt, Anna L; Brennan, Rebecca R; Burrows, Kimberley; Guthrie, Philip A I; Ascione, Raimondo; Ring, Susan M; Gaunt, Tom R; Pyle, Angela; Cordell, Heather J; Lawlor, Debbie A; Chinnery, Patrick F; Hudson, Gavin; Rodriguez, Santiago
    Abstract Background Mitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist. We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16–43 years at mtDNA CN assay) and 1338 UKBS females (17–69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children and UKBS males. Results A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], β (change in SD units of mtDNA CN per allele) [SE] − 0.084 [0.016], p = 1.54e−07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, β [SE] 0.262 [0.034], p = 1.40e−14), but not other study groups. In a meta-analysis of unrelated individuals (N = 11,253), we replicated a published association in TFAM (β [SE] 0.046 [0.017], p = 0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS. Conclusions In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.
  • ItemOpen Access
    Assessing the impact of the Barbados sugar-sweetened beverage tax on beverage sales: an observational study
    (2019-01-30) Alvarado, Miriam; Unwin, Nigel; Sharp, Stephen J; Hambleton, Ian; Murphy, Madhuvanti M; Samuels, T. A; Suhrcke, Marc; Adams, Jean
    Abstract Background The World Health Organization has advocated for sugar-sweetened beverage (SSB) taxes as part of a broader non-communicable disease prevention strategy, and these taxes have been recently introduced in a wide range of settings. However, much is still unknown about how SSB taxes operate in various contexts and as a result of different tax designs. In 2015, the Government of Barbados implemented a 10% ad valorem (value-based) tax on SSBs. It has been hypothesized that this tax structure may inadvertently encourage consumers to switch to cheaper sugary drinks. We aimed to assess whether and to what extent there has been a change in sales of SSBs following implementation of the SSB tax. Methods We used electronic point of sale data from a major grocery store chain and applied an interrupted time series (ITS) design to assess grocery store SSB and non-SSB sales from January 2013 to October 2016. We controlled for the underlying time trend, seasonality, inflation, tourism and holidays. We conducted sensitivity analyses using a cross-country control (Trinidad and Tobago) and a within-country control (vinegar). We included a post-hoc stratification by price tertile to assess the extent to which consumers may switch to cheaper sugary drinks. Results We found that average weekly sales of SSBs decreased by 4.3% (95%CI 3.6 to 4.9%) compared to expected sales without a tax, primarily driven by a decrease in carbonated SSBs sales of 3.6% (95%CI 2.9 to 4.4%). Sales of non-SSBs increased by 5.2% (95%CI 4.5 to 5.9%), with bottled water sales increasing by an average of 7.5% (95%CI 6.5 to 8.3%). The sensitivity analyses were consistent with the uncontrolled results. After stratifying by price, we found evidence of substitution to cheaper SSBs. Conclusions This study suggests that the Barbados SSB tax was associated with decreased sales of SSBs in a major grocery store chain after controlling for underlying trends. This finding was robust to sensitivity analyses. We found evidence to suggest that consumers may have changed their behaviour in response to the tax by purchasing cheaper sugary drinks, in addition to substituting to untaxed products. This has important implications for the design of future SSB taxes.
  • ItemOpen Access
    Correction to: Concordance analysis of microarray studies identifies representative gene expression changes in Parkinson's disease: a comparison of 33 human and animal studies.
    (Springer Science and Business Media LLC, 2019-01-30) Oerton, Erin; Bender, Andreas; Bender, Andreas [0000-0002-6683-7546]
    Following publication of the original article [1], the authors reported the following errors on their article.
  • ItemOpen Access
    From genome integrity to cancer
    (BioMed Central, 2019-01-29) Nik-Zainal, Serena
  • ItemOpen Access
    Re-formulating Gehan’s design as a flexible two-stage single-arm trial
    (2019-01-28) Grayling, Michael J; Mander, Adrian P
    Abstract Background Gehan’s two-stage design was historically the design of choice for phase II oncology trials. One of the reasons it is less frequently used today is that it does not allow for a formal test of treatment efficacy, and therefore does not control conventional type-I and type-II error-rates. Methods We describe how recently developed methodology for flexible two-stage single-arm trials can be used to incorporate the hypothesis test commonly associated with phase II trials in to Gehan’s design. We additionally detail how this hypothesis test can be optimised in order to maximise its power, and describe how the second stage sample sizes can be chosen to more readily provide the operating characteristics that were originally envisioned by Gehan. Finally, we contrast our modified Gehan designs to Simon’s designs, based on two examples motivated by real clinical trials. Results Gehan’s original designs are often greatly under- or over-powered when compared to type-II error-rates typically used in phase II. However, we demonstrate that the control parameters of his design can be chosen to resolve this problem. With this, though, the modified Gehan designs have operating characteristics similar to the more familiar Simon designs. Conclusions The trial design settings in which Gehan’s design will be preferable over Simon’s designs are likely limited. Provided the second stage sample sizes are chosen carefully, however, one scenario of potential utility is when the trial’s primary goal is to ascertain the treatment response rate to a certain precision.
  • ItemOpen Access
    Research approvals iceberg: how a ‘low-key’ study in England needed 89 professionals to approve it and how we can do better
    (2019-01-25) Petrova, Mila; Barclay, Stephen
    Abstract Background The red tape and delays around research ethics and governance approvals frequently frustrate researchers yet, as the lesser of two evils, are largely accepted as unavoidable. Here we quantify aspects of the research ethics and governance approvals for one interview- and questionnaire-based study conducted in England which used the National Health Service (NHS) procedures and the electronic Integrated Research Application System (IRAS). We demonstrate the enormous impact of existing approvals processes on costs of studies, including opportunity costs to focus on the substantive research, and suggest directions for radical system change. Main text We have recorded 491 exchanges with 89 individuals involved in research ethics and governance approvals, generating 193 pages of email text excluding attachments. These are conservative estimates (e.g. only records of the research associate were used). The exchanges were conducted outside IRAS, expected to be the platform where all necessary documents are provided and questions addressed. Importantly, the figures exclude the actual work of preparing the ethics documentation (such as the ethics application, information sheets and consent forms). We propose six areas of work to enable system change: 1. Support the development of a broad range of customised research ethics and governance templates to complement generic, typically clinical trials orientated, ones; 2. Develop more sophisticated and flexible frameworks for study classification; 3. Link with associated processes for assessment, feedback, monitoring and reporting, such as ones involving funders and patient and public involvement groups; 4. Invest in a new generation IT infrastructure; 5. Enhance system capacity through increasing online reviewer participation and training; and 6. Encourage researchers to quantify the approvals processes for their studies. Conclusion Ethics and governance approvals are burdensome for historical reasons and not because of the nature of the task. There are many opportunities to improve their efficiency and analytic depth in an age of innovation, increased connectivity and distributed working. If we continue to work under current systems, we are perpetuating, paradoxically, an unethical system of research approvals by virtue of its wastefulness and impoverished ethical debate.
  • ItemOpen Access
    The association between adherence to the Mediterranean diet and hepatic steatosis: cross-sectional analysis of two independent studies, the UK Fenland Study and the Swiss CoLaus Study
    (2019-01-24) Khalatbari-Soltani, Saman; Imamura, Fumiaki; Brage, Soren; De Lucia Rolfe, Emanuella; Griffin, Simon J; Wareham, Nicholas J; Marques-Vidal, Pedro; Forouhi, Nita G
    Abstract Background and aims The risk of hepatic steatosis may be reduced through changes to dietary intakes, but evidence is sparse, especially for dietary patterns including the Mediterranean diet. We investigated the association between adherence to the Mediterranean diet and prevalence of hepatic steatosis. Methods Cross-sectional analysis of data from two population-based adult cohorts: the Fenland Study (England, n = 9645, 2005–2015) and CoLaus Study (Switzerland, n = 3957, 2009–2013). Habitual diet was assessed using cohort-specific food frequency questionnaires. Mediterranean diet scores (MDSs) were calculated in three ways based on adherence to the Mediterranean dietary pyramid, dietary cut-points derived from a published review, and cohort-specific tertiles of dietary consumption. Hepatic steatosis was assessed by abdominal ultrasound and fatty liver index (FLI) in Fenland and by FLI and non-alcoholic fatty liver disease (NAFLD) score in CoLaus. FLI includes body mass index (BMI), waist circumference, gamma-glutamyl transferase, and triglyceride; NAFLD includes diabetes, fasting insulin level, fasting aspartate-aminotransferase (AST), and AST/alanine transaminase ratio. Associations were assessed using Poisson regression. Results In Fenland, the prevalence of hepatic steatosis was 23.9% and 27.1% based on ultrasound and FLI, respectively, and in CoLaus, 25.3% and 25.7% based on FLI and NAFLD score, respectively. In Fenland, higher adherence to pyramid-based MDS was associated with lower prevalence of hepatic steatosis assessed by ultrasound (prevalence ratio (95% confidence interval), 0.86 (0.81, 0.90) per one standard deviation of MDS). This association was attenuated [0.95 (0.90, 1.00)] after adjustment for body mass index (BMI). Associations of similar magnitude were found for hepatic steatosis assessed by FLI in Fenland [0.82 (0.78, 0.86)] and in CoLaus [0.85 (0.80, 0.91)], and these were also attenuated after adjustment for BMI. Findings were similar when the other two MDS definitions were used. Conclusions Greater adherence to the Mediterranean diet was associated with lower prevalence of hepatic steatosis, largely explained by adiposity. These findings suggest that an intervention promoting a Mediterranean diet may reduce the risk of hepatic steatosis.
  • ItemOpen Access
    Fine mapping chromatin contacts in capture Hi-C data
    (2019-01-23) Eijsbouts, Christiaan Q; Burren, Oliver S; Newcombe, Paul J; Wallace, Chris
    Abstract Background Hi-C and capture Hi-C (CHi-C) are used to map physical contacts between chromatin regions in cell nuclei using high-throughput sequencing. Analysis typically proceeds considering the evidence for contacts between each possible pair of fragments independent from other pairs. This can produce long runs of fragments which appear to all make contact with the same baited fragment of interest. Results We hypothesised that these long runs could result from a smaller subset of direct contacts and propose a new method, based on a Bayesian sparse variable selection approach, which attempts to fine map these direct contacts. Our model is conceptually novel, exploiting the spatial pattern of counts in CHi-C data. Although we use only the CHi-C count data in fitting the model, we show that the fragments prioritised display biological properties that would be expected of true contacts: for bait fragments corresponding to gene promoters, we identify contact fragments with active chromatin and contacts that correspond to edges found in previously defined enhancer-target networks; conversely, for intergenic bait fragments, we identify contact fragments corresponding to promoters for genes expressed in that cell type. We show that long runs of apparently co-contacting fragments can typically be explained using a subset of direct contacts consisting of <10% of the number in the full run, suggesting that greater resolution can be extracted from existing datasets. Conclusions Our results appear largely complementary to those from a per-fragment analytical approach, suggesting that they provide an additional level of interpretation that may be used to increase resolution for mapping direct contacts in CHi-C experiments.
  • ItemOpen Access
    Sociodemographic patterns of health insurance coverage in Namibia
    (2019-01-22) Allcock, Sophie H; Young, Elizabeth H; Sandhu, Manjinder S
    Abstract Introduction Health insurance has been found to increase healthcare utilisation and reduce catastrophic health expenditures in a number of countries; however, coverage is often unequally distributed among populations. The sociodemographic patterns of health insurance in Namibia are not fully understood. We aimed to assess the prevalence of health insurance, the relation between health insurance and health service utilisation and to explore the sociodemographic factors associated with health insurance in Namibia. Such findings may help to inform health policy to improve financial access to healthcare in the country. Methods Using data on 14,443 individuals, aged 15 to 64 years, from the 2013 Namibia Demographic and Health Survey, the association between health insurance and health service utilisation was investigated using multivariable mixed effects Poisson regression analyses, adjusted for sociodemographic covariates and regional, enumeration area and household clustering. Multivariable mixed effects Poisson regression analyses were also conducted to explore the association between key sociodemographic factors and health insurance, adjusted for covariates and clustering. Effect modification by sex, education level and wealth quintile was also explored. Results Just 17.5% of this population were insured (men: 20.2%; women: 16.2%). In fully-adjusted analyses, education was significantly positively associated with health insurance, independent of other sociodemographic factors (higher education RR: 3.98; 95% CI: 3.11–5.10; p < 0.001). Female sex (RR: 0.83; 95% CI: 0.74–0.94; p = 0.003) and wealth (highest wealth quintile RR: 13.47; 95% CI: 9.06–20.04; p < 0.001) were also independently associated with insurance. There was a complex interaction between sex, education and wealth in the context of health insurance. With increasing education level, women were more likely to be insured (p for interaction < 0.001), and education had a greater impact on the likelihood of health insurance in lower wealth quintiles. Conclusions In this population, health insurance was associated with health service utilisation but insurance coverage was low, and was independently associated with sex, education and wealth. Education may play a key role in health insurance coverage, especially for women and the less wealthy. These findings may help to inform the targeting of strategies to improve financial protection from healthcare-associated costs in Namibia.
  • ItemOpen Access
    Differences in objectively measured physical activity and sedentary behaviour between white Europeans and south Asians recruited from primary care: cross-sectional analysis of the PROPELS trial
    (2019-01-21) Biddle, Gregory J H; Edwardson, Charlotte L; Rowlands, Alex V; Davies, Melanie J; Bodicoat, Danielle H; Hardeman, Wendy; Eborall, Helen; Sutton, Stephen; Griffin, Simon; Khunti, Kamlesh; Yates, Thomas
    Abstract Background Self-reported data have consistently shown South Asians (SAs) to be less physically active than White Europeans (WEs) in developed countries, however objective data is lacking. Differences in sedentary time have not been elucidated in this population. This study aimed to quantify differences in objectively measured physical activity and sedentary behaviour between WEs and SAs recruited from primary care and to investigate differences in demographic and lifestyle correlates of these behaviours. Methodology Baseline data were utilised from a randomised control trial recruiting individuals identified at high risk of type 2 diabetes from primary care. Light intensity physical activity, moderate-to-vigorous intensity physical activity (MVPA) and steps were measured using the Actigraph GT3X+, while sitting, standing and stepping time were measured using the activPAL3™. Devices were worn concurrently for seven days. Demographic (employment, sex, age, education, postcode) and behavioural (fruit and vegetable consumption, alcohol consumption, smoking status) characteristics were measured via self and interview administered questionnaires. Results A total of 963 WE (age = 62 ± 8, female 51%) and 289 SA (age = 55 ± 11, female 43%) were included. Compared to WEs, SAs did less MVPA (24 vs 33 min/day, p = 0.001) and fewer steps (6404 vs 7405 per day, p ≤ 0.001), but sat less (516 vs 552 min/day, p ≤ 0.001) and stood more (328 vs 283 min/day, p ≤ 0.001). Ethnicity also modified the extent to which demographic and behavioural factors act as correlates of physical activity and sedentary behaviour. Differences between sex in levels of MVPA and sitting time were greater in SAs compared to WEs, with SA women undertaking the least amount of MVPA (19 min/day), the least sitting time (475 min/day) and most standing time (377 min/day) than any other group. Smoking and alcohol status also acted as stronger correlates of sitting time in SAs compared to WEs. In contrast, education level acted as a stronger correlate of physical activity in WEs compared to SAs. Conclusion SAs were less active yet less sedentary than WEs, which demonstrates the need to tailor the behavioural targets of interventions in multi-ethnic communities. Common correlates of physical activity and sedentary behaviour also differed between ethnicities. Trial registration ISRCTN83465245 Trial registration date: 14/06/2012.
  • ItemOpen Access
    A neural classification method for supporting the creation of BioVerbNet
    (BioMed Central, 2019-01-18) Chiu, Billy; Majewska, Olga; Pyysalo, Sampo; Wey, Laura; Stenius, Ulla; Korhonen, Anna; Palmer, Martha
    Abstract Background VerbNet, an extensive computational verb lexicon for English, has proved useful for supporting a wide range of Natural Language Processing tasks requiring information about the behaviour and meaning of verbs. Biomedical text processing and mining could benefit from a similar resource. We take the first step towards the development of BioVerbNet: A VerbNet specifically aimed at describing verbs in the area of biomedicine. Because VerbNet-style classification is extremely time consuming, we start from a small manual classification of biomedical verbs and apply a state-of-the-art neural representation model, specifically developed for class-based optimization, to expand the classification with new verbs, using all the PubMed abstracts and the full articles in the PubMed Central Open Access subset as data. Results Direct evaluation of the resulting classification against BioSimVerb (verb similarity judgement data in biomedicine) shows promising results when representation learning is performed using verb class-based contexts. Human validation by linguists and biologists reveals that the automatically expanded classification is highly accurate. Including novel, valid member verbs and classes, our method can be used to facilitate cost-effective development of BioVerbNet. Conclusion This work constitutes the first effort on applying a state-of-the-art architecture for neural representation learning to biomedical verb classification. While we discuss future optimization of the method, our promising results suggest that the automatic classification released with this article can be used to readily support application tasks in biomedicine.