An incrementally updatable and scalable system for large-scale sequence search using the Bentley-Saxe transformation.

MOTIVATION: In the past few years, researchers have proposed numerous indexing schemes for searching large datasets of raw sequencing experiments. Most of these proposed indexes are approximate (i.e. with one-sided errors) in order to save space. Recently, researchers have published exact indexes-Mantis, VariMerge and Bifrost-that can serve as colored de Bruijn graph representations in addition to serving as k-mer indexes. This new type of index is promising because it has the potential to support more complex analyses than simple searches. However, in order to be useful as indexes for large and growing repositories of raw sequencing data, they must scale to thousands of experiments and support efficient insertion of new data. RESULTS: In this paper, we show how to build a scalable and updatable exact raw sequence-search index. Specifically, we extend Mantis using the Bentley-Saxe transformation to support efficient updates, called Dynamic Mantis. We demonstrate Dynamic Mantis's scalability by constructing an index of ≈40K samples from SRA by adding samples one at a time to an initial index of 10K samples. Compared to VariMerge and Bifrost, Dynamic Mantis is more efficient in terms of index-construction time and memory, query time and memory and index size. In our benchmarks, VariMerge and Bifrost scaled to only 5K and 80 samples, respectively, while Dynamic Mantis scaled to more than 39K samples. Queries were over 24× faster in Mantis than in Bifrost (VariMerge does not immediately support general search queries we require). Dynamic Mantis indexes were about 2.5× smaller than Bifrost's indexes and about half as big as VariMerge's indexes. AVAILABILITY AND IMPLEMENTATION: Dynamic Mantis implementation is available at https://github.com/splatlab/mantis/tree/mergeMSTs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

How does mode of travel affect risks posed to other road users? An analysis of English road fatality data, incorporating gender and road type.

BACKGROUND: Most analysis of road injuries examines the risk experienced by people using different modes of transport, for instance, pedestrian fatalities per-head or per-km. A small but growing field analyses the impact that the use of different transport modes has on other road users, for instance, injuries to others per-km driven. METHODS: This paper moves the analysis of risk posed to others forward by comparing six different vehicular modes, separating road types (major vs minor roads in urban vs rural settings). The comparison of risk posed by men and women for all these modes is also novel. RESULTS: Per-vehicle kilometre, buses and lorries pose much the highest risk to others, while cycles pose the lowest. Motorcycles pose a substantially higher per-km risk to others than cars. The fatality risk posed by cars or vans to ORUs per km is higher in rural areas. Risk posed is generally higher on major roads, although not in the case of lorries, suggesting a link to higher speeds. Men pose higher per-km risk to others than women for all modes except buses, as well as being over-represented among users of the most dangerous vehicles. CONCLUSIONS: Future research should examine more settings, adjust for spatial and temporal confounders, or examine how infrastructure or route characteristics affect risk posed to others. Although for most victims the other vehicle involved is a car, results suggest policy-makers should also seek to reduce disproportionate risks posed by the more dangerous vehicles, for instance, by discouraging motorcycling. Finally, given higher risk posed to others by men across five of six modes analysed, policy-makers should consider how to reduce persistent large gender imbalances in jobs involving driving.

Partially Fluorinated Copolymers as Oxygen Sensitive 19 F MRI Agents.

Effective diagnosis of disease and its progression can be aided by 19 F magnetic resonance imaging (MRI) techniques. Specifically, the inherent sensitivity of the spin-lattice relaxation time (T1 ) of 19 F nuclei to oxygen partial pressure makes 19 F MRI an attractive non-invasive approach to quantify tissue oxygenation in a spatiotemporal manner. However, there are only few materials with the adequate sensitivity to be used as oxygen-sensitive 19 F MRI agents at clinically relevant field strengths. Motivated by the limitations in current technologies, we report highly fluorinated monomers that provide a platform approach to realize water-soluble, partially fluorinated copolymers as 19 F MRI agents with the required sensitivity to quantify solution oxygenation at clinically relevant magnetic field strengths. The synthesis of a systematic library of partially fluorinated copolymers enabled a comprehensive evaluation of copolymer structure-property relationships relevant to 19 F MRI. The highest-performing material composition demonstrated a signal-to-noise ratio that corresponded to an apparent 19 F density of 220 mm, which surpasses the threshold of 126 mm 19 F required for visualization on a three Tesla clinical MRI. Furthermore, the T1 of these high performing materials demonstrated a linear relationship with solution oxygenation, with oxygen sensitivity reaching 240×10-5  mmHg-1 s-1 . The relationships between material composition and 19 F MRI performance identified herein suggest general structure-property criteria for the further improvement of modular, water-soluble 19 F MRI agents for quantifying oxygenation in environments relevant to medical imaging.

Squeakr: an exact and approximate k-mer counting system.

Motivation: k-mer-based algorithms have become increasingly popular in the processing of high-throughput sequencing data. These algorithms span the gamut of the analysis pipeline from k-mer counting (e.g. for estimating assembly parameters), to error correction, genome and transcriptome assembly, and even transcript quantification. Yet, these tasks often use very different k-mer representations and data structures. In this article, we show how to build a k-mer-counting and multiset-representation system using the counting quotient filter, a feature-rich approximate membership query data structure. We introduce the k-mer-counting/querying system Squeakr (Simple Quotient filter-based Exact and Approximate Kmer Representation), which is based on the counting quotient filter. This off-the-shelf data structure turns out to be an efficient (approximate or exact) representation for sets or multisets of k-mers. Results: Squeakr takes 2×-4.3× less time than the state-of-the-art to count and perform a random-point-query workload. Squeakr is memory-efficient, consuming 1.5×-4.3× less memory than the state-of-the-art. It offers competitive counting performance. In fact, it is faster for larger k-mers, and answers point queries (i.e. queries for the abundance of a particular k-mer) over an order-of-magnitude faster than other systems. The Squeakr representation of the k-mer multiset turns out to be immediately useful for downstream processing (e.g. de Bruijn graph traversal) because it supports fast queries and dynamic k-mer insertion, deletion, and modification. Availability and implementation: https://github.com/splatlab/squeakr available under BSD 3-Clause License. Contact: ppandey@cs.stonybrook.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

deBGR: an efficient and near-exact representation of the weighted de Bruijn graph.

MOTIVATION: Almost all de novo short-read genome and transcriptome assemblers start by building a representation of the de Bruijn Graph of the reads they are given as input. Even when other approaches are used for subsequent assembly (e.g. when one is using 'long read' technologies like those offered by PacBio or Oxford Nanopore), efficient k -mer processing is still crucial for accurate assembly, and state-of-the-art long-read error-correction methods use de Bruijn Graphs. Because of the centrality of de Bruijn Graphs, researchers have proposed numerous methods for representing de Bruijn Graphs compactly. Some of these proposals sacrifice accuracy to save space. Further, none of these methods store abundance information, i.e. the number of times that each k -mer occurs, which is key in transcriptome assemblers. RESULTS: We present a method for compactly representing the weighted de Bruijn Graph (i.e. with abundance information) with essentially no errors. Our representation yields zero errors while increasing the space requirements by less than 18-28% compared to the approximate de Bruijn graph representation in Squeakr. Our technique is based on a simple invariant that all weighted de Bruijn Graphs must satisfy, and hence is likely to be of general interest and applicable in most weighted de Bruijn Graph-based systems. AVAILABILITY AND IMPLEMENTATION: https://github.com/splatlab/debgr . CONTACT: rob.patro@cs.stonybrook.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The finite state projection approach to analyze dynamics of heterogeneous populations.

Population modeling aims to capture and predict the dynamics of cell populations in constant or fluctuating environments. At the elementary level, population growth proceeds through sequential divisions of individual cells. Due to stochastic effects, populations of cells are inherently heterogeneous in phenotype, and some phenotypic variables have an effect on division or survival rates, as can be seen in partial drug resistance. Therefore, when modeling population dynamics where the control of growth and division is phenotype dependent, the corresponding model must take account of the underlying cellular heterogeneity. The finite state projection (FSP) approach has often been used to analyze the statistics of independent cells. Here, we extend the FSP analysis to explore the coupling of cell dynamics and biomolecule dynamics within a population. This extension allows a general framework with which to model the state occupations of a heterogeneous, isogenic population of dividing and expiring cells. The method is demonstrated with a simple model of cell-cycle progression, which we use to explore possible dynamics of drug resistance phenotypes in dividing cells. We use this method to show how stochastic single-cell behaviors affect population level efficacy of drug treatments, and we illustrate how slight modifications to treatment regimens may have dramatic effects on drug efficacy.

SYSBIONS: nested sampling for systems biology.

MOTIVATION: Model selection is a fundamental part of the scientific process in systems biology. Given a set of competing hypotheses, we routinely wish to choose the one that best explains the observed data. In the Bayesian framework, models are compared via Bayes factors (the ratio of evidences), where a model's evidence is the support given to the model by the data. A parallel interest is inferring the distribution of the parameters that define a model. Nested sampling is a method for the computation of a model's evidence and the generation of samples from the posterior parameter distribution. RESULTS: We present a C-based, GPU-accelerated implementation of nested sampling that is designed for biological applications. The algorithm follows a standard routine with optional extensions and additional features. We provide a number of methods for sampling from the prior subject to a likelihood constraint. AVAILABILITY AND IMPLEMENTATION: The software SYSBIONS is available from http://www.theosysbio.bio.ic.ac.uk/resources/sysbions/ CONTACT: m.stumpf@imperial.ac.uk, robert.johnson11@imperial.ac.uk.

Promoting healthy populations as a pandemic preparedness strategy: a simulation study from Mexico.

Background: The underlying health status of populations was a major determinant of the impact of the COVID-19 pandemic, particularly obesity prevalence. Mexico was one of the most severely affected countries during the COVID-19 pandemic and its obesity prevalence is among the highest in the world. It is unknown by how much the COVID-19 burden could have been reduced if systemic actions had been implemented to reduce excess weight in Mexico before the onset of the pandemic. Methods: Using a dynamic epidemic model based on nationwide data, we compare actual deaths with those under hypothetical scenarios assuming a lower body mass index in the Mexican population, as observed historically. We also model the number of deaths that would have been averted due to earlier implementation of front-of-pack warning labels or due to increases in taxes on sugar-sweetened beverages and non-essential high-energy foods in Mexico. Findings: We estimate that 52.5% (95% prediction interval (PI) 43.2, 61.6%) of COVID-19 deaths were attributable to obesity for adults aged 20-64 and 23.8% (95% PI 18.7, 29.1%) for those aged 65 and over. Had the population BMI distribution remained as it was in 2000, 2006, or 2012, COVID-19 deaths would have been reduced by an expected 20.6% (95% PI 16.9, 24.6%), 9.9% (95% PI 7.3, 12.9%), or 6.9% (95% PI 4.5, 9.5%), respectively. If the food-labelling intervention introduced in 2020 had been introduced in 2018, an expected 6.2% (95% PI 5.2, 7.3%) of COVID-19 deaths would have been averted. If taxes on sugar-sweetened beverages and high-energy foods had been doubled, trebled, or quadrupled in 2018, COVID-19 deaths would have been reduced by an expected 4.1% (95% PI 2.5, 5.7%), 7.9% (95% PI 4.9, 11.0%), or 11.6% (95% PI 7.3, 15.8%), respectively. Interpretation: Public health interventions targeting underlying population health, including non-communicable chronic diseases, is a promising line of action for pandemic preparedness that should be included in all pandemic plans. Funding: This study received funding from Bloomberg Philanthropies, awarded to Juan A. Rivera from the National Institute of Public Health; Community Jameel, the UK Medical Research Council (MRC), Kenneth C Griffin, and the World Health Organization.

Bayesian profile regression for clustering analysis involving a longitudinal response and explanatory variables.

The identification of sets of co-regulated genes that share a common function is a key question of modern genomics. Bayesian profile regression is a semi-supervised mixture modelling approach that makes use of a response to guide inference toward relevant clusterings. Previous applications of profile regression have considered univariate continuous, categorical, and count outcomes. In this work, we extend Bayesian profile regression to cases where the outcome is longitudinal (or multivariate continuous) and provide PReMiuMlongi, an updated version of PReMiuM, the R package for profile regression. We consider multivariate normal and Gaussian process regression response models and provide proof of principle applications to four simulation studies. The model is applied on budding yeast data to identify groups of genes co-regulated during the Saccharomyces cerevisiae cell cycle. We identify 4 distinct groups of genes associated with specific patterns of gene expression trajectories, along with the bound transcriptional factors, likely involved in their co-regulation process.

The societal value of SARS-CoV-2 booster vaccination in Indonesia.

OBJECTIVES: To estimate the expected socio-economic value of booster vaccination in terms of averted deaths and averted closures of businesses and schools using simulation modelling. METHODS: The value of booster vaccination in Indonesia is estimated by comparing simulated societal costs under a twelve-month, 187-million-dose Moderna booster vaccination campaign to costs without boosters. The costs of an epidemic and its mitigation consist of lost lives, economic closures and lost education; cost-minimising non-pharmaceutical mitigation is chosen for each scenario. RESULTS: The cost-minimising non-pharmaceutical mitigation depends on the availability of vaccines: the differences between the two scenarios are 14 to 19 million years of in-person education and $153 to $204 billion in economic activity. The value of the booster campaign ranges from $2,500 ($1,400-$4,100) to $2,800 ($1,700-$4,600) per dose in the first year, depending on life-year valuations. CONCLUSIONS: The societal benefits of booster vaccination are substantial. Much of the value of vaccination resides in the reduced need for costly non-pharmaceutical mitigation. We propose cost minimisation as a tool for policy decision-making and valuation of vaccination, taking into account all socio-economic costs, and not averted deaths alone.

Industrial production of microbial protein products.

Microbial proteins provide a sustainable and nutritious alternative to traditional animal and plant-based proteins. Various strains have been demonstrated to generate biomass from a wide variety of substrates, from organic waste (e.g. banana peel) to gases (e.g. methane). Industrial production of microbial protein has proven difficult from both design (e.g. production rate) and regulatory (e.g. allergenicity of product) perspectives for both feed and food-grade products. Through use of low-cost microfluidics devices, early bioprocess design can be intensified, achieving high strain screening throughput with low titres. Integration of industrial waste streams (e.g. flue-gases, lignocellulosic residues) can reduce cost and carbon footprint of feedstock, while bespoke reactor design (e.g. Quorn's airlift U-loop fermenter) can remediate issues of low mass-transfer and product quality.

Quantifying Efficiency Gains of Innovative Designs of Two-Arm Vaccine Trials for COVID-19 Using an Epidemic Simulation Model.

Clinical trials of a vaccine during an epidemic face particular challenges, such as the pressure to identify an effective vaccine quickly to control the epidemic, and the effect that time-space-varying infection incidence has on the power of a trial. We illustrate how the operating characteristics of different trial design elements maybe evaluated using a network epidemic and trial simulation model, based on COVID-19 and individually randomized two-arm trials with a binary outcome. We show that "ring" recruitment strategies, prioritizing participants at an imminent risk of infection, can result in substantial improvement in terms of power in the model we present. In addition, we introduce a novel method to make more efficient use of the data from the earliest cases of infection observed in the trial, whose infection may have been too early to be vaccine-preventable. Finally, we compare several methods of response-adaptive randomization (RAR), discussing their advantages and disadvantages in the context of our model and identifying particular adaptation strategies that preserve power and estimation properties, while slightly reducing the number of infections, given an effective vaccine.

Data needs for integrated economic-epidemiological models of pandemic mitigation policies.

The COVID-19 pandemic and the mitigation policies implemented in response to it have resulted in economic losses worldwide. Attempts to understand the relationship between economics and epidemiology has led to a new generation of integrated mathematical models. The data needs for these models transcend those of the individual fields, especially where human interaction patterns are closely linked with economic activity. In this article, we reflect upon modelling efforts to date, discussing the data needs that they have identified, both for understanding the consequences of the pandemic and policy responses to it through analysis of historic data and for the further development of this new and exciting interdisciplinary field.

Early intervention for at risk children: 3-year follow-up.

Childhood behavioral and emotional symptoms are linked with distress and dysfunction that may persist into adulthood. Effective and practical early prevention could make a significant contribution to the well-being of individuals and the functioning of communities. School-based targeted interventions are relatively easy and inexpensive to deliver and have been shown to reduce symptoms in the short term. The current study evaluates the 2- and 3-year outcome of targeted school-based drama group therapy (DGT) as compared to teaching maths and English. It shows a rapid decline in teacher-observed behavioral symptoms following DGT. By a year post intervention, symptom rates following both interventions converged and remained low throughout follow-up. Drama group therapy is rapidly effective in reducing symptoms. However, the findings also suggest that despite differing content, school-based small-group interventions are likely to share some effective components.

Health impacts of changes in travel patterns in Greater Accra Metropolitan Area, Ghana.

BACKGROUND: Health impact assessments of alternative travel patterns are urgently needed to inform transport and urban planning in African cities, but none exists so far. OBJECTIVE: To quantify the health impacts of changes in travel patterns in the Greater Accra Metropolitan Area, Ghana. METHODS: We estimated changes to population exposures to physical activity, air pollution, and road traffic fatality risk and consequent health burden (deaths and years of life lost prematurely - YLL) in response to changes in transportation patterns. Five scenarios were defined in collaboration with international and local partners and stakeholders to reflect potential local policy actions. RESULTS: Swapping bus and walking trips for car trips can lead to more than 400 extra deaths and 20,500 YLL per year than travel patterns observed in 2009. If part of the rise in motorisation is from motorcycles, we estimated an additional nearly 370 deaths and over 18,500 YLL per year. Mitigating the rise in motorisation by swapping long trips by car or taxi to bus trips is the most beneficial for health, averting more than 600 premature deaths and over 31,500 YLL per year. Without significant improvements in road safety, reduction of short motorised trips in favour of cycling and walking had no significant net health benefits as non-communicable diseases deaths and YLL benefits were offset by increases in road traffic deaths. In all scenarios, road traffic fatalities were the largest contributor to changes in deaths and YLL. CONCLUSIONS: Rising motorisation, particularly from motorcycles, can cause significant increase in health burden in the Greater Accra Metropolitan Area. Mitigating rising motorisation by improving public transport would benefit population health. Tackling road injury risk to ensure safe walking and cycling is a top priority. In the short term, this will save lives from injury. Longer term it will help halt the likely fall in physical activity.

An Efficient, Scalable, and Exact Representation of High-Dimensional Color Information Enabled Using de Bruijn Graph Search.

The colored de Bruijn graph (cdbg) and its variants have become an important combinatorial structure used in numerous areas in genomics, such as population-level variation detection in metagenomic samples, large-scale sequence search, and cdbg-based reference sequence indices. As samples or genomes are added to the cdbg, the color information comes to dominate the space required to represent this data structure. In this article, we show how to represent the color information efficiently by adopting a hierarchical encoding that exploits correlations among color classes-patterns of color occurrence-present in the de Bruijn graph (dbg). A major challenge in deriving an efficient encoding of the color information that takes advantage of such correlations is determining which color classes are close to each other in the high-dimensional space of possible color patterns. We demonstrate that the dbg itself can be used as an efficient mechanism to search for approximate nearest neighbors in this space. While our approach reduces the encoding size of the color information even for relatively small cdbgs (hundreds of experiments), the gains are particularly consequential as the number of potential colors (i.e., samples or references) grows into thousands. We apply this encoding in the context of two different applications; the implicit cdbg used for a large-scale sequence search index, Mantis, as well as the encoding of color information used in population-level variation detection by tools such as Vari and Rainbowfish. Our results show significant improvements in the overall size and scalability of representation of the color information. In our experiment on 10,000 samples, we achieved >11 × better compression compared to Ramen, Ramen, Rao (RRR).

Preprints and Scholarly Communication: Adoption, Practices, Drivers and Barriers.

Background: Since 2013, there has been a dramatic increase in the number of preprint servers available online. To date, little is known about the position of researchers, funders, research performing organisations and other stakeholders with respect to this fast-paced landscape. In this article, we explore the benefits and challenges of preprint posting, along with issues such as infrastructure and financial sustainability. We also discuss the definition of a 'preprint' in different communities, and the impact this has on further uptake. Methods: This study is based on 38 detailed semi-structured interviews of key stakeholders based on a purposive heterogeneous sampling approach. Interviews were undertaken between October 2018 and January 2019. These were recorded, transcribed and subjected to thematic analysis to identify trends. Interview questions were designed based on Innovation Diffusion Theory, which is also used to interpret the results of this study. Results: Our study is the first using empirical data to understand the new wave of preprint servers and found that early and fast dissemination is the most appealing feature of the practice. The main concerns are related to the lack of quality assurance and the 'Ingelfinger rule'. We identified trust as an essential enabler of preprint posting and stress the enabling role of Twitter in showcasing preprints and enabling comments on these. Conclusions: The preprints landscape is evolving fast and disciplinary communities are at different stages in the innovation diffusion process. The landscape is characterised by significant experimentation, which leads to the conclusion that a one-size-fits-all approach to preprints is not feasible. Cooperation and active engagement between the stakeholders involved will play an important role in the future. In our paper, we share questions for the further development of the preprints landscape, with the most important being whether preprint posting will develop as a publisher- or researcher-centric practice.

Isolated cutaneous anaplastic large cell lymphoma progressing to severe systemic disease with myocardial involvement and central nervous system infiltration.

Anaplastic large cell lymphoma (ALCL) is a rare tumor comprising around 10-15% of childhood lymphomas. We describe the case of a female who initially presented with localized skin disease associated with an insect bite. However, she subsequently relapsed with widespread systemic ALK-positive ALCL that included lymphoma deposits in the myocardium, a very rare manifestation. Her disease responded well to chemotherapy but she later developed a fatal relapse in the CNS. We also present data on an immune response to ALK, demonstrating a fluctuation in the levels of circulating antibodies to ALK corresponding to the different phases of her illness.

Mantis: A Fast, Small, and Exact Large-Scale Sequence-Search Index.

Sequence-level searches on large collections of RNA sequencing experiments, such as the NCBI Sequence Read Archive (SRA), would enable one to ask many questions about the expression or variation of a given transcript in a population. Existing approaches, such as the sequence Bloom tree, suffer from fundamental limitations of the Bloom filter, resulting in slow build and query times, less-than-optimal space usage, and potentially large numbers of false-positives. This paper introduces Mantis, a space-efficient system that uses new data structures to index thousands of raw-read experiments and facilitates large-scale sequence searches. In our evaluation, index construction with Mantis is 6× faster and yields a 20% smaller index than the state-of-the-art split sequence Bloom tree (SSBT). For queries, Mantis is 6-108× faster than SSBT and has no false-positives or -negatives. For example, Mantis was able to search for all 200,400 known human transcripts in an index of 2,652 RNA sequencing experiments in 82 min; SSBT took close to 4 days.

Estimating city-level travel patterns using street imagery: A case study of using Google Street View in Britain.

BACKGROUND: Street imagery is a promising and growing big data source providing current and historical images in more than 100 countries. Studies have reported using this data to audit road infrastructure and other built environment features. Here we explore a novel application, using Google Street View (GSV) to predict travel patterns at the city level. METHODS: We sampled 34 cities in Great Britain. In each city, we accessed 2000 GSV images from 1000 random locations. We selected archived images from time periods overlapping with the 2011 Census and the 2011-2013 Active People Survey (APS). We manually annotated the images into seven categories of road users. We developed regression models with the counts of images of road users as predictors. The outcomes included Census-reported commute shares of four modes (combined walking plus public transport, cycling, motorcycle, and car), as well as APS-reported past-month participation in walking and cycling. RESULTS: We found high correlations between GSV counts of cyclists ('GSV-cyclists') and cycle commute mode share (r = 0.92)/past-month cycling (r = 0.90). Likewise, GSV-pedestrians was moderately correlated with past-month walking for transport (r = 0.46), GSV-motorcycles was moderately correlated with commute share of motorcycles (r = 0.44), and GSV-buses was highly correlated with commute share of walking plus public transport (r = 0.81). GSV-car was not correlated with car commute mode share (r = -0.12). However, in multivariable regression models, all outcomes were predicted well, except past-month walking. The prediction performance was measured using cross-validation analyses. GSV-buses and GSV-cyclists are the strongest predictors for most outcomes. CONCLUSIONS: GSV images are a promising new big data source to predict urban mobility patterns. Predictive power was the greatest for those modes that varied the most (cycle and bus). With its ability to identify mode of travel and capture street activity often excluded in routinely carried out surveys, GSV has the potential to be complementary to new and traditional data. With half the world's population covered by street imagery, and with up to 10 years historical data available in GSV, further testing across multiple settings is warranted both for cross-sectional and longitudinal assessments.