Methods for Joint Normalization and Comparison of Hi-C data

The development of chromatin conformation capture technology has opened new avenues of study into the 3D structure and function of the genome. Chromatin structure is known to influence gene regulation, and differences in structure are now emerging as a mechanism of regulation between, e.g., cell differentiation and disease vs. normal states. Hi-C sequencing technology now provides a way to study the 3D interactions of the chromatin over the whole genome. However, like all sequencing technologies, Hi-C suffers from several forms of bias stemming from both the technology and the DNA sequence itself. Several normalization methods have been developed for normalizing individual Hi-C datasets, but little work has been done on developing joint normalization methods for comparing two or more Hi-C datasets. To make full use of Hi-C data, joint normalization and statistical comparison techniques are needed to carry out experiments to identify regions where chromatin structure differs between conditions. We develop methods for the joint normalization and comparison of two Hi-C datasets, which we then extended to more complex experimental designs. Our normalization method is novel in that it makes use of the distance-dependent nature of chromatin interactions. Our modification of the Minus vs. Average (MA) plot to the Minus vs. Distance (MD) plot allows for a nonparametric data-driven normalization technique using loess smoothing. Additionally, we present a simple statistical method using Z-scores for detecting differentially interacting regions between two datasets. Our initial method was published as the Bioconductor R package HiCcompare [http://bioconductor.org/packages/HiCcompare/](http://bioconductor.org/packages/HiCcompare/). We then further extended our normalization and comparison method for use in complex Hi-C experiments with more than two datasets and optional covariates. We extended the normalization method to jointly normalize any number of Hi-C datasets by using a cyclic loess procedure on the MD plot. The cyclic loess normalization technique can remove between dataset biases efficiently and effectively even when several datasets are analyzed at one time. Our comparison method implements a generalized linear model-based approach for comparing complex Hi-C experiments, which may have more than two groups and additional covariates. The extended methods are also available as a Bioconductor R package [http://bioconductor.org/packages/multiHiCcompare/](http://bioconductor.org/packages/multiHiCcompare/). Finally, we demonstrate the use of HiCcompare and multiHiCcompare in several test cases on real data in addition to comparing them to other similar methods (https://doi.org/10.1002/cpbi.76)

Role of the particle's stepping cycle in an asymmetric exclusion process: A model of mRNA translation

Messenger RNA translation is often studied by means of statistical-mechanical models based on the Asymmetric Simple Exclusion Process (ASEP), which considers hopping particles (the ribosomes) on a lattice (the polynucleotide chain). In this work we extend this class of models and consider the two fundamental steps of the ribosome's biochemical cycle following a coarse-grained perspective. In order to achieve a better understanding of the underlying biological processes and compare the theoretical predictions with experimental results, we provide a description lying between the minimal ASEP-like models and the more detailed models, which are analytically hard to treat. We use a mean-field approach to study the dynamics of particles associated with an internal stepping cycle. In this framework it is possible to characterize analytically different phases of the system (high density, low density or maximal current phase). Crucially, we show that the transitions between these different phases occur at different parameter values than the equivalent transitions in a standard ASEP, indicating the importance of including the two fundamental steps of the ribosome's biochemical cycle into the model.Comment: 9 pages, 9 figure

Ribosome recycling induces optimal translation rate at low ribosomal availability

Funding statement The authors thank BBSRC (BB/F00513/X1, BB/I020926/1 and DTG) and SULSA for funding. Acknowledgement The authors thank R. Allen, L. Ciandrini, B. Gorgoni and P. Greulich for very helpful discussions and careful reading of the manuscript.Peer reviewedPublisher PD

The intra-GCC crises: mapping GCC fragmentation after 2011

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.If shared security perceptions were the foundation of the GCC, 2011 might be analysed as the watershed year in which the GCC begun to fragment from within, as then the divergences between the countries’ security perceptions became markedly exacerbated. It is commonly held that the threat posed to their security by Iranian intent and, at times, actions forced the countries of the GCC to be more aligned. However, the opposite seems to be the case, with both the 2014 and 2017 intraGCC crises being manifestations of conflicting security perceptions formed across the GCC countries in and since 2011. Through an in-depth analysis of the events and of the subsequent reaction of the GCC governments in terms of discourse and foreign policy, we can distinguish between three different categories of conceptualization. While the governments of Saudi Arabia, Bahrain and the UAE perceived domestic protests as an intermestic threat – triggered by the intersection between the international and domestic levels - the leaders of Oman and Kuwait conceptualised their protests as a manageable domestic insecurity, rather than full-fledged externally orchestrated events, arguably because they did not perceive a direct danger to their stability and legitimacy. Finally it can be argued that the government of Qatar did not see any real danger in the protests but instead view them as an opportunity to expand Doha’s regional influence, arguably at Riyadh’s expense. Unpacking what are the fundamental factors shaping such perceptions today would be the key to finding the appropriate framework for analysing GCC security in the futur

Identifying social care research literature: Case studies from guideline development

This is the final version. Available from the publisher via the DOI in this record.Objective – Systematic searching is central to guideline development, yet guidelines in social care present a challenge to systematic searching because they exist within a highly complex policy and service environment. The objective of this study was to highlight challenges and inform practice on identifying social care research literature, drawing on experiences from guideline development in social care. Methods – The researchers reflected on the approaches to searching for research evidence to inform three guidelines. They evaluated the utility of major topic-focused bibliographic database sources through a) determining the yield of citations from the search strategies for two guidelines and b) identifying which databases contain the citations for three guidelines. The researchers also considered the proportion of different study types and their presence in certain databases. Results – There were variations in the ability of the search terms to capture the studies from individual databases, even with low-precision searches. These were mitigated by searching a combination of databases and other resources that were specific to individual topics. A combination of eight databases was important for finding literature for the included topics. Multiple database searching also mitigates the currency of content, topic and study design focus, and consistency of indexing within individual databases. Conclusion – Systematic searching for research evidence in social care requires considerable thought and development so that the search is fit for the particular purpose of supporting guidelines. This study highlights key challenges and reveals trends when utilising some commonly used databases.National Institute for Health and Care Excellence (NICE)National Institute for Health Research (NIHR

Applying machine classifiers to update searches: analysis from two case studies

Manual screening of citation records could be reduced by using machine classifiers to remove records of very low relevance. This seems particularly feasible for update searches, where a machine classifier can be trained from past screening decisions. However, feasibility is unclear for broad topics. To evaluate the performance and implementation of machine classifiers for update searches of public health research. Two case studies. The first study evaluates the impact of using different sets of training data on classifier performance, comparing recall and screening reduction with a manual screening ‘gold standard’. The second study uses screening decisions from a review to train a classifier that is applied to rank the update search results. A stopping threshold was applied in the absence of a gold standard. Time spent screening titles and abstracts of different relevancy-ranked records was measured. Results: Study one: Classifier performance varies according to the training data used; all custom-built classifiers had a recall above 93% at the same threshold, achieving screening reductions between 41% and 74%. Study two: applying a classifier provided a solution for tackling a large volume of search results from the update search, and screening volume was reduced by 61%. A tentative estimate indicates over 25 hours screening time was saved. Custom-built machine classifiers are feasible for reducing screening workload from update searches across a range of public health interventions, with some limitation on recall. Key considerations include selecting a training dataset, agreeing stopping thresholds and processes to ensure smooth workflows

Morphology and structure of the 1999 lava flows at Mount Cameroon Volcano (West Africa) and their bearings on the emplacement dynamics of volume-limited flows

The morphology and structure of the 1999 lava flows at Mount Cameroon volcano are documented and discussed in relation to local and source dynamics. Structures are analysed qualitatively and more detailed arguments are developed on the processes of levee formation and systematic links between flow dynamics and levee-channel interface geometry. The flows have clear channels bordered by four main types of levees: initial, accretionary, rubble and overflow levees. Thermally immature pahoehoe lava units with overflow drapes define the proximal zone, whereas rubble and accretionary levees are common in the distal region bordering thermally mature aa clinker or blocky aa flow channels. Pressure ridges, squeeze-ups and pahoehoe ropes are the prevalent compressive structures. Standlines displayed on clinkery breccias are interpreted to represent levee-channel interactions in response to changing flow levels. These data complement previous knowledge on lava flow morphology, thus far dominated by Etnean and Hawaiian examples

Social Values Related to the Development of Health and Care Guidance: Literature review for NICE by its Research Support Unit. Report of the Research Support Unit for the National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence develops guidance for the allocation of resources for services in clinical and public health and social care. It has a policy of social values underpinning this work that was last updated in 2008. This report is of a review of the literature on social values to help inform the further updating of this policy. The review involved a semi iterative search for literature that was then screened for ideas relevant to health and care guidance. These ideas and the main issues they raise are reported under eight major social value categories. Twenty one themes arising from the review are also provided. The literature raises many issues about the nature of social values that can be applied to guidance development. It needs to be emphasized that not all of these issues should necessarily be applied to guidance development. They are simply issues that have been raised in the literature and this review provides an opportunity for them to be considered. Many of the ideas that have been proposed are in tension with each other and could not all be achieved. It should also be emphasized that many of the issues raise considerable practical challenges in terms of methods, data and financial and timeliness. The review does not assume that any of these issues or ideas could or should necessarily be part of NICE’s policy on social values in guidance production. The review simply provides a list of ideas, issues and themes from the literature for consideration

Prevalence of mental health disorders in adult minority ethnic populations in England: A systematic review

The aim of this project, commissioned by the Department of Health in England, was to undertake a systematic review of the survey literature that has estimated the prevalence of mental health disorders among adults from minority ethnic groups in England. Findings about the estimated prevalence of different mental health disorders, and about the extent and nature of the available survey evidence, are to be used to inform the design of a sampling strategy aimed at boosting the sample of people from minority ethnic groups in the Adult Psychiatric Morbidity Survey (APMS) due in 2021

Piloting and producing a map of Millennium Cohort Study Data usage: Where are data underutilised and where is granularity lost?

The UK Millennium Cohort Study (MCS) is a longitudinal interdisciplinary study following the lives of 19,000 children born in the UK in 2000/1. Information has been collected at 9 months, 3, 5, 7 and 11 years, with the next sweep of data collection underway among study members who are aged 14 years. A wide range of data have been collected from children, parents and guardians, the partners of parents/guardians, older siblings and teachers, as well as sub-studies that collected data from health visitors; these include self-reported and objectively measured/verified data. This study sets out to examine how MCS data are utilised. To fit within the remit of the study, we hone in on ten priority question areas (Strengths and Difficulties Questionnaire, Child Social Behaviour Questionnaire, Diet, BMI, Immunisations, School Dis/like, Self-reported Friendships, Self-reported feelings, Screen Time, Hobbies). In total we found 481 unique studies that were using MCS data and undertaking primary analysis up to July 2015. Data that are collected through a recognised scale with defined thresholds or cut-off points for identifying constructs of interest and/or data that can provide a unique insight into a policy-relevant issue, are those most widely used in the MCS data. Measures that have been collected across sweeps – diet, BMI, SDQ and screen time - are all comparatively well used. Those measures that have started to be collected at age 7 (and first made available in 2010) have had lower usage. Data that were collected from the child’s own reports (e.g. friendships and feelings) have seldom been utilised in comparison to data collected through parental reports (e.g. SDQ). Collection of data from multiple informants did not always correlate with higher levels of usage. Imposing thresholds on data was found to be problematic in some cases, for example for BMI, where a number of different thresholds for overweight and obesity were in use. The use of different thresholds can lead to substantial differences in the results obtained. This is the first review using systematic methods that has explored MCS data use. We set out a number of ideas for good practice around the use of and reporting of MCS data