Search bioRxiv⌕ Search

Biology subjects

Brierley, L.

Publications and source records attributed to Brierley, L..

13 recordsLinked to original sources

Phylogenies as graphs: structured neural networks improve host origin predictions from paramyxovirus sequences

Accurately identifying the host of a virus from its genome sequence is a task with important applications in zoonotic disease surveillance and filling data gaps for metagenomic sampling. Machine learning approaches have seen broad application in making host predictions directly from viral genome sequences. However, most host prediction models do not incorporate information on viral phylogeny, which is strongly correlated with both genome composition and host. We apply a novel graph neural network (GNN) approach which explicitly represents viral phylogeny in model architecture to predict hosts of origin within the paramyxoviruses. We conduct rigorous benchmarking against non-structured neural networks and predictions made using phylogeny alone, showing that GNNs carry distinct advantages over other methods when making predictions where training data is sparse. Validation across different phylogenetic scales shows that simple phylogenetic prediction is effective in many applications and that phylogeny contributes a large proportion of the predictive power of host prediction models, with genome compositional features providing additional power only for specific predictions outside the range of the training data. This novel modelling approach and model validation framework are flexible and can be applied to other viral families.

evolutionary biology↗

Predicting the Risk of Avian Influenza Zoonosis using Viral Genome Sequencing Data

Avian Influenza viruses (AIVs) infect a broad host range despite having a natural reservoir in wild aquatic birds. Whilst most strains stay within their host species, some break the species barrier through genetic adaptations. We are most concerned about zoonotic cases, where a human becomes infected. Despite these events being rare, they are associated with high mortality and introduce the risk of onward human-to-human transmission of AIV. As a novel pathogen within the human population, this could have pandemic potential. Using genetic composition features for 8 AIV proteins drawn from viral sequence data, we employ machine-learning algorithms to classify AIV cases as zoonotic or not. These genetic features encode host 'signatures' which can indicate zoonosis and include frequency measures such as dipeptide composition and amino acid physiochemical properties. We consistently find XGBoost to outperform all other algorithms. We optimise parameters for ten classification models: one for each of the 8 proteins and two combined models. Following this, we show that a multi-model approach gives the best performing prediction for AIV zoonosis. We have identified all 8 proteins as having a role in predicting zoonotic transmission. Of particular importance is the PB2 and HA proteins, with specific amino acid physiochemical properties such as charge, secondary structure and hydrophobicity amongst the most indicative features in our combined models. Our alignment-free computational study can identify AIV cases still within avian hosts which are genetically closest to zoonotic AIV cases, thereby identifying the cases most likely to cross the species barrier. In a resource limited environment, our model could be used to quickly identify high priority cases for further investigation.

genomics↗

An AI for an AI: identifying zoonotic potential of avian influenza viruses via genomic machine learning

Avian influenza remains a serious risk to human health via zoonotic transmission, as well as a feasible pandemic threat. Although limited zoonotic cases have resulted from the current epizootic outbreak, the wide diversity of influenza viruses in avian hosts means the emergence of new strains that could transmit to humans more readily cannot be ruled out. There is therefore a need to anticipate zoonotic potential before spillover occurs. Here, we develop a novel zoonotic prediction model for avian influenza viruses, building upon "host-predictor" machine learning methods that estimate host potential given only a viral genome sequence. We construct a machine learning framework combining individual sub-models of influenza genome segments, each trained on many genomic and proteomic traits (e.g., k-mer composition, codon biases, protein physicochemistry). To prevent over-fitting to heavily sampled lineages and ensure models generalise to phylogenetically distant viruses, we pre-process training data by considering clusters of shared sequence identity. Curated training sets cover [~]4,000 representative, complete genome sequences of avian influenza from 120 subtypes including 9 containing known zoonotic viruses. We combine best-performing models into a single ensemble that can distinguish zoonotic capability of sequences held out from training with strong performance (AUROC = 0.95, F1 score = 0.90), including sequences of rarely-sampled subtypes, e.g., H10N8. Interrogating ensemble model decisions also allows us to identify influential genomic motifs most associated with human infection. These findings suggest specific genomic traits that are key to understanding and monitoring evolution of influenza viruses that circulate within bird populations. Our ensemble model can estimate zoonotic potential for new sequence inputs, offering a means to quickly risk-assess emerging avian influenza strains as soon as a sequence becomes available.

genomics↗

Evaluating the utility of amino acid similarity-aware kmers to represent TCR repertoires for classification

Insights gained through interpretation of models trained on the T-cell receptor (TCR) repertoire contribute to advances in understanding of immune-mediated disease. This has the potential to improve diagnostic tests and treatments, particularly for autoimmune diseases. However, TCR repertoire datasets with samples from donors of known autoimmune disease status generally include orders of magnitude fewer samples than TCR sequences. Promising TCR repertoire classification approaches consider relationships between non-identical TCR sequences. In particular, kmer methods demonstrate strong and stable performance for small datasets. We propose a TCR repertoire representation that considers the relationships between amino acids within kmers flexibly and efficiently, which makes exploration of a wide range of TCR sequence features feasible. XGBoost models are trained and tested on kmer representations of TCR repertoire datasets including samples from patients with coeliac disease as well as donors with previous cytomegalovirus infection. We show that kmers that use small representative alphabets of amino acids are capable of training models that perform similarly or better than kmers based on all 20 amino acids. We find that, for cytomegalovirus infection status classification, defining amino acid relationships using BLOSUM62 can lead to a model with stronger performance as compared to an Atchley factor definition. Finally, we detail kmers or motifs which are important in each classification model and highlight the challenge of training truly interpretable TCR repertoire classification models which, if overcome, could lead to biomarker discovery for autoimmune diseases. Author summaryTCR repertoire classification models can provide valuable understanding of autoimmune diseases if they can accurately infer autoimmune disease status and are biologically interpretable. Based on a kmer representation of the TCR repertoire, which has been shown to be most appropriate to train classification models on smaller datasets, we develop a computationally efficient method of grouping amino acid sequences to add knowledge to immune status classification model inputs, and consider its effect on interpretability. We find that most of the 4mer-based feature types we tested perform well in combination with an XGBoost model, where some benefit may be gained by applying a greatly-reduced alphabet of amino acids based on BLOSUM62 for cytomegalovirus serostatus classification. Our proposed reduced alphabet methodology is an alternative to kmer clustering which allows more efficient exploration of amino acid relationships and results in a more interpretable feature space.

immunology↗

Ecology and environment predict spatially stratified risk of highly pathogenic avian influenza in wild birds across Europe

Highly pathogenic avian influenza (HPAI) represents a threat to animal and human health, with the ongoing H5N1 outbreak within the H5 2.3.4.4b clade being the largest on record. However, it remains unclear what factors have contributed to its intercontinental spread. We use Bayesian additive regression trees, a machine learning method designed for probabilistic modelling of complex nonlinear phenomena, to construct species distribution models (SDMs) for HPAI clade 2.3.4.4b presence. We identify factors driving geospatial patterns of infection and project risk distributions across Europe. Our models are time-stratified to capture both seasonal changes in risk and shifts in epidemiology associated with the succession of H5N6/H5N8 by H5N1 within the clade. While previous studies aimed to model HPAI presence from physical geography, we explicitly consider wild bird ecology by including estimates of bird species richness, abundance of specific taxa, and "abundance indices" describing total abundance of birds with high-risk behavioural traits. Our projections of HPAI clade 2.3.4.4b indicate a shift in persistent, year-round risk towards cold, low-lying regions of northwest Europe associated with H5N1. Methodologically, we demonstrate that while most variation in risk can be explained by climate and physical geography, adding host ecology is a valuable refinement to SDMs of HPAI.

ecology↗

Mammal virus diversity estimates are unstable due to accelerating discovery effort

Host-virus association data form the backbone of research into eco-evolutionary drivers of viral diversity and host-level zoonotic risk. However, knowledge of the wildlife virome is inherently constrained by historical discovery effort, and there are concerns that the reliability of ecological inference from host-virus data may be undermined by taxonomic and geographical sampling biases. Here, we evaluate whether current estimates of host-level viral diversity in wild mammals are stable enough to be considered biologically meaningful, by analysing a comprehensive dataset of discovery dates of 6,571 unique mammal host-virus associations between 1930 and 2018. We show that virus discovery rates in mammal hosts are still either constant or accelerating, with little evidence of declines towards viral richness asymptotes in even highly-sampled hosts. Consequently, inference of relative viral richness across host species has been unstable over time, particularly in bats, where intensified surveillance since the early 2000s caused a rapid rearrangement of species ranked viral richness. Our results show that comparative inference of host-level virus diversity across mammals is highly sensitive to even short-term changes in sampling effort. We advise caution to avoid overinterpreting patterns in current data, since our findings suggest that an analysis conducted today could feasibly draw quite different conclusions than one conducted only a decade ago.

ecology↗

The Global Virome in One Network (VIRION): an atlas of vertebrate-virus associations

Data cataloguing viral diversity on Earth have been fragmented across sources, disciplines, formats, and various degrees of open collation, posing challenges for research on macroecology, evolution, and public health. Here, we solve this problem by establishing a dynamically-maintained database of vertebrate-virus associations, called The Global Virome in One Network (VIRION). The VIRION database has been assembled through both reconciliation of static datasets and integration of dynamically-updated databases. These data sources are all harmonized against one taxonomic backbone, including metadata on host and virus taxonomic validity and higher classification; additional metadata on sampling methodology and evidence strength are also available in a harmonized format. In total, the VIRION database is the largest open-source, open-access database of its kind, with roughly half a million unique records that include 9,521 resolved virus "species" (of which 1,661 are ICTV ratified), 3,692 resolved vertebrate host species, and 23,147 unique interactions between taxonomically-valid organisms. Together, these data cover roughly a quarter of mammal diversity, a tenth of bird diversity, and ~6% of the estimated total diversity of vertebrates, and a much larger proportion of their virome than any previous database. We show how these data can be used to test hypotheses about microbiology, ecology, and evolution, and make suggestions for best practices that address the unique mix of evidence that coexists in these data.

microbiology↗

Preprints in motion: tracking changes between posting and journal publication

Amidst the COVID-19 pandemic, preprints in the biomedical sciences are being posted and accessed at unprecedented rates, drawing widespread attention from the general public, press and policymakers for the first time. This phenomenon has sharpened longstanding questions about the reliability of information shared prior to journal peer review. Does the information shared in preprints typically withstand the scrutiny of peer review, or are conclusions likely to change in the version of record? We assessed preprints from bioRxiv and medRxiv that had been posted and subsequently published in a journal through 30th April 2020, representing the initial phase of the pandemic response. We utilised a combination of automatic and manual annotations to quantify how an article changed between the preprinted and published version. We found that the total number of figure panels and tables changed little between preprint and published articles. Moreover, the conclusions of 7.2% of non-COVID-19-related and 17.2% of COVID-19-related abstracts undergo a discrete change by the time of publication, but the majority of these changes do not qualitatively change the conclusions of the paper.

scientific communication and education↗

Data proliferation, reconciliation, and synthesis in viral ecology

The fields of viral ecology and evolution have rapidly expanded in the last two decades, driven by technological improvements, and motivated by efforts to discover potentially zoonotic wildlife viruses under the rubric of pandemic prevention. One consequence has been a massive proliferation of host-virus association data, which comprise the backbone of research in viral macroecology and zoonotic risk prediction. These data remain fragmented across numerous data portals and projects, each with their own scope, structure, and reporting standards. Here, we propose that synthesis of host-virus association data is a central challenge to improve our understanding of the global virome and develop foundational theory in viral ecology. To illustrate this, we build an open reconciled mammal-virus database from four key published datasets, applying a standardized taxonomy and metadata. We show that reconciling these datasets provides a substantially richer view of the mammal virome than that offered by any one individual database. We argue for a shift in best practice towards the incremental development and use of synthetic datasets in viral ecology research, both to improve comparability and replicability across studies, and to facilitate future efforts to use machine learning to predict the structure and dynamics of the global virome.

ecology↗

Predicting the animal hosts of coronaviruses from compositional biases of spike protein and whole genome sequences through machine learning

The COVID-19 pandemic has demonstrated the serious potential for novel zoonotic coronaviruses to emerge and cause major outbreaks. The immediate animal origin of the causative virus, SARS-CoV-2, remains unknown, a notoriously challenging task for emerging disease investigations. Coevolution with hosts leads to specific evolutionary signatures within viral genomes that can inform likely animal origins. We obtained a set of 650 spike protein and 511 whole genome nucleotide sequences from 225 and 187 viruses belonging to the family Coronaviridae, respectively. We then trained random forest models independently on genome composition biases of spike protein and whole genome sequences, including dinucleotide and codon usage biases in order to predict animal host (of nine possible categories, including human). In hold-one-out cross-validation, predictive accuracy on unseen coronaviruses consistently reached [~]73%, indicating evolutionary signal in spike proteins to be just as informative as whole genome sequences. However, different composition biases were informative in each case. Applying optimised random forest models to classify human sequences of MERS-CoV and SARS-CoV revealed evolutionary signatures consistent with their recognised intermediate hosts (camelids, carnivores), while human sequences of SARS-CoV-2 were predicted as having bat hosts (suborder Yinpterochiroptera), supporting bats as the suspected origins of the current pandemic. In addition to phylogeny, variation in genome composition can act as an informative approach to predict emerging virus traits as soon as sequences are available. More widely, this work demonstrates the potential in combining genetic resources with machine learning algorithms to address long-standing challenges in emerging infectious diseases.

genomics↗

Preprinting a pandemic: the role of preprints in the COVID-19 pandemic

The world continues to face a life-threatening viral pandemic. The virus underlying the COVID-19 disease, SARS-CoV-2, has caused over 98 million confirmed cases and 2.2 million deaths since January 2020. Although the most recent respiratory viral pandemic swept the globe only a decade ago, the way science operates and responds to current events has experienced a paradigm shift in the interim. The scientific community has responded rapidly to the COVID-19 pandemic, releasing over 125,000 COVID-19 related scientific articles within 10 months of the first confirmed case, of which more than 30,000 were hosted by preprint servers. We focused our analysis on bioRxiv and medRxiv, two growing preprint servers for biomedical research, investigating the attributes of COVID-19 preprints, their access and usage rates, as well as characteristics of their propagation on online platforms. Our data provides evidence for increased scientific and public engagement with preprints related to COVID-19 (COVID-19 preprints are accessed more, cited more, and shared more on various online platforms than non-COVID-19 preprints), as well as changes in the use of preprints by journalists and policymakers. We also find evidence for changes in preprinting and publishing behaviour: COVID-19 preprints are shorter and reviewed faster. Our results highlight the unprecedented role of preprints and preprint servers in the dissemination of COVID-19 science, and the impact of the pandemic on the scientific communication landscape.

scientific communication and education↗

Evolutionary origins of epidemic potential among human RNA viruses

To have epidemic potential, a pathogen must be able to spread in human populations, but of human-infective RNA viruses only a minority can do so. We investigated the evolution of human transmissibility through parallel analyses of 1755 virus genome sequences from 39 RNA virus genera. We identified 57 lineages containing human-transmissible species and estimated that at least 74% of these lineages have evolved directly from non-human viruses in other mammals or birds, a public health threat recently designated \"Disease X\". Human-transmissible viruses rarely evolve from virus lineages that can infect but not transmit between humans. This result cautions against focussing surveillance and mitigation efforts narrowly on currently known human-infective virus lineages and supports calls for a better understanding of RNA virus diversity in non-human hosts.

evolutionary biology↗

Tissue Tropism and Transmission Ecology Predict Virulence of Human RNA Viruses

Novel infectious diseases continue to emerge within human populations. Predictive studies have begun to identify pathogen traits associated with emergence. However, emerging pathogens vary widely in virulence, a key determinant of their ultimate risk to public health. Here, we use structured literature searches to review the virulence of each of the 214 known human-infective RNA virus species. We then use a machine learning framework to determine whether viral virulence can be predicted by ecological traits including human-to-human transmissibility, transmission routes, tissue tropisms and host range. Using severity of clinical disease as a measurement of virulence, we identified potential risk factors using predictive classification tree and random forest ensemble models. The random forest model predicted literature-assigned disease severity of test data with 90.3% accuracy, compared to a null accuracy of 74.2%. In addition to viral taxonomy, the ability to cause systemic infection, having renal and/or neural tropism, direct contact or respiratory transmission, and limited (0 < R0 [&le;] 1) human-to-human transmissibility were the strongest predictors of severe disease. We present a novel, comparative perspective on the virulence of all currently known human RNA virus species. The risk factors identified may provide novel perspectives in understanding the evolution of virulence and elucidating molecular virulence mechanisms. These risk factors could also improve planning and preparedness in public health strategies as part of a predictive framework for novel human infections.\n\nAuthor SummaryNewly emerging infectious diseases present potentially serious threats to global health. Although studies have begun to identify pathogen traits associated with the emergence of new human diseases, these do not address why emerging infections vary in the severity of disease they cause, often termed virulence. We test whether ecological traits of human viruses can act as predictors of virulence, as suggested by theoretical studies. We conduct the first systematic review of virulence across all currently known human RNA virus species. We adopt a machine learning approach by constructing a random forest, a model that aims to optimally predict an outcome using a specific structure of predictors. Predictions matched literature-assigned ratings for 28 of 31 test set viruses. Our predictive model suggests that higher virulence is associated with infection of multiple organ systems, nervous systems or the renal systems. Higher virulence was also associated with contact-based or airborne transmission, and limited capability to transmit between humans. These risk factors may provide novel starting points for questioning why virulence should evolve and identifying causative mechanisms of virulence. In addition, our work could suggest priority targets for infectious disease surveillance and future public health risk strategies.\n\nBlurbComparative analysis using machine learning shows specificity of tissue tropism and transmission biology can act as predictive risk factors for virulence of human RNA viruses.

epidemiology↗