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bioRxiv2017

The Case for Pyriproxyfen as a Potential Cause for Microcephaly; From Biology to Epidemiology

The Zika virus has been the primary suspect in the large increase in incidence of microcephaly in 2015-6 in Brazil. However its role is not confirmed despite individual cases in which viral infections were found in neural tissue. Recently, the disparity between the incidences in different geographic locations has led to questions about the viruss role. Here we consider the alternative possibility that the use of the insecticide pyriproxyfen for control of mosquito populations in Brazilian drinking water is the primary cause. Pyriproxifen is a juvenile hormone analog which has been shown to correspond in mammals to a number of fat soluble regulatory molecules including retinoic acid, a metabolite of vitamin A, with which it has cross-reactivity and whose application during development has been shown to cause microcephaly. Methoprene, another juvenile hormone analog that was approved as an insecticide based upon tests performed in the 1970s, has metabolites that bind to the mammalian retinoid X receptor, and has been shown to cause developmental disorders in mammals. Isotretinoin is another example of a retinoid causing microcephaly in human babies via maternal exposure and activation of the retinoid X receptor in developing fetuses. Moreover, tests of pyriproxyfen by the manufacturer, Sumitomo, widely quoted as giving no evidence for developmental toxicity, actually found some evidence for such an effect, including low brain mass and arhinencephaly--incomplete formation of the anterior cerebral hemispheres--in exposed rat pups. Finally, the pyriproxyfen use in Brazil is unprecedented-- it has never before been applied to a water supply on such a scale. Claims that it is not being used in Recife, the epicenter of microcephaly cases, do not distinguish the metropolitan area of Recife, where it is widely used, and the municipality, and have not been adequately confirmed. Given this combination of information about molecular mechanisms and toxicological evidence, we strongly recommend that the use of pyriproxyfen in Brazil be suspended until the potential causal link to microcephaly is investigated further.

epidemiology↗

bioRxiv2017

Automated collection of pathogen-specific diagnostic data for real-time syndromic epidemiological studies

Health-care and public health professionals rely on accurate, real-time monitoring of infectious diseases for outbreak preparedness and response. Early detection of outbreaks is improved by systems that are pathogen-specific. We describe a system, FilmArray(R) Trend, for rapid disease reporting that is syndrome-based but pathogen-specific. Results from a multiplex molecular diagnostic test are sent directly to a cloud database. www.syndromictrends.com presents these data in near real-time. Trend preserves patient privacy by removing or obfuscating patient identifiers. We summarize the respiratory pathogen results, for 20 organisms from 344,000 patient samples acquired as standard of care testing over the last four years from 20 clinical laboratories in the United States. The majority of pathogens show influenza-like seasonality, rhinovirus has fall and spring peaks and adenovirus and bacterial pathogens show constant detection over the year. Interestingly, the rate of pathogen co-detections, on average 7.7%, matches predictions based on the relative abundance of organisms present.

epidemiology↗

bioRxiv2017

Is the HIV epidemic over? Investigating population dynamics using Bayesian methodology to estimate epidemiological parameters for a system of stochastic differential equations

Current estimates of the HIV epidemic indicate a decrease in the incidence of the disease in the undiagnosed subpopulation over the past 10 years. However, a lack of access to care has not been considered when modeling the population. Populations at high risk for contracting HIV are twice as likely to lack access to reliable medical care. In this paper, we consider three contributors to the HIV population dynamics: susceptible pool exhaustion, lack of access to care, and usage of anti-retroviral therapy (ART) by diagnosed individuals. We consider the change in the proportion of undiagnosed individuals as the parameter in a simple Markov model. We obtain conservative estimates for the proportional change of the infected subpopulations using hierarchical Bayesian statistics. The estimated proportional change is used to derive epidemic parameter estimates for a system of stochastic differential equations (SDEs). Epidemic parameters are modified to capture the dynamics of each of the three contributors, as well as all their possible combinations. Model fit is quantified to determine the best explanation for the observed dynamics in the infected subpopulations.\n\nAuthor summaryUsing a combination of statistics and mathematical modeling, we look at some possible reasons for the reported decrease in the number of undiagnosed people living with HIV. One possibility is that the population of people at significant risk to contract HIV is being depleted (susceptibles). This might happen if significant risk for HIV infection occurs in small percentages of the overall population. Another possibility is that infected individuals lack access to care in some regions due to poverty or other cause. In this case we have to question the accuracy of the estimated size of that population. Finally, most diagnosed individuals report being on medication that reduces their viral load. This greatly reduces their chance to transmit HIV to susceptible individuals. We also combine these possibilities and look at the best explanation for the infected population size.

epidemiology↗

bioRxiv2018

Epidemiological Study of Autism Subgroups Using Autism Treatment Evaluation Checklist (ATEC) Score

Here we report the results of the subgroup analyses of an observational cohort of children whose parents completed the Autism Treatment Evaluation Checklist (ATEC) over the period of several years. A linear mixed effects model was used to evaluate longitudinal changes in ATEC scores within different patient subgroups. All groups decreased their mean ATEC score over time indicating improvement of symptoms, however there were significant differences between the groups. Younger children improved more than the older children. Children with milder ASD improved more than children with more severe ASD in the Communication subscale. There was no difference in improvement between females vs. males. One surprising finding was that children from developed English-speaking countries improved less than children from non-English-speaking countries.

epidemiology↗

bioRxiv2018

The relationship between transmission time and clustering methods in Mycobacterium tuberculosis epidemiology

BackgroundTracking recent transmission is a vital part of controlling widespread pathogens such as Mycobacterium tuberculosis. Multiple methods with specific performance characteristics exist for detecting recent transmission chains, usually by clustering strains based on genotype similarities. With such a large variety of methods available, informed selection of an appropriate approach for determining transmissions within a given setting/time period is difficult.\n\nMethodsThis study combines whole genome sequence (WGS) data derived from 324 isolates collected 2005-2010 in Kinshasa, Democratic Republic of Congo (DRC), a high endemic setting, with phylodynamics to unveil the timing of transmission events posited by a variety of standard genotyping methods. Clustering data based on Spoligotyping, 24-loci MIRU-VNTR typing, WGS based SNP (Single Nucleotide Polymorphism) and core genome multi locus sequence typing (cgMLST) typing were evaluated.\n\nFindingsOur results suggest that clusters based on Spoligotyping could encompass transmission events that occurred over 70 years prior to sampling while 24-loci-MIRU-VNTR often represented two or more decades of transmission. Instead, WGS based genotyping applying low SNP or cgMLST allele thresholds allows for determination of recent transmission events in timespans of up to 10 years e.g. for a 5 SNP/allele cut-off.\n\nInterpretationWith the rapid uptake of WGS methods in surveillance and outbreak tracking, the findings obtained in this study can guide the selection of appropriate clustering methods for uncovering relevant transmission chains within a given time-period. For high resolution cluster analyses, WGS-SNP and cgMLST based analyses have similar clustering/timing characteristics even for data obtained from a high incidence setting.

epidemiology↗

bioRxiv2018

Molecular epidemiology and drug resistance patterns of Mycobacterium tuberculosis complex isolates from university students and the local community in Eastern Ethiopia

BackgroundPrevious studies suggest the burden of pulmonary tuberculosis (PTB) in Ethiopia may be greater in university students relative to the overall population. However, little is known about the transmission dynamics of PTB among students and members of the communities surrounding university campuses in Eastern Ethiopia.\n\nMethodsA cross sectional study was conducted in Eastern Ethiopia among culture-confirmed PTB cases from university students (n=36) and community members diagnosed at one of four hospitals (n=152) serving the surrounding area. Drug susceptibility testing (DST) was performed on Mycobacterium Tuberculosis Complex (MTBC) isolates using BD Bactec MGIT 960 and molecular genotyping was performed using spoligotyping and 24-loci MIRU-VNTR. MTBC strains with Identical genotyping patterns were assigned to molecular clusters as surrogate marker for recent transmission and further contact tracing was initiated among clustered patients.\n\nResultsAmong all study participants, four MTBC lineages and 11 sub-lineages were identified, with Ethiopia_3 being most common sub-lineage (29.4%) and associated with strain clustering (P= 0.016). We identified 13 (8.1%) strains phylogenetically related to the known Ethiopian sub-lineages with a distinct Spoligotyping patterns and designated as Ethiopia_4. The clustering rate of MTB strains was 52.9% for university students and 66.7% for community members with a Recent Transmission Index (RTI) of 17.6% and 48.4%, respectively. Female gender, urban residence, and new TB cases were significantly associated with strain clustering (p<0.05). Forty-eight (30%) of the study participants were resistant to one or more first line anti TB drugs, three patients were classified as multidrug resistant (MDR), defined by isoniazid and rifampicin resistance.\n\nConclusionWe found evidence of significant PTB cases clustering and recent transmission among Ethiopian university students and the local community in eastern Ethiopia; with Ethiopia_3 being the predominant circulating sub-lineage. A country wide comprehensive molecular surveillance and drug resistance profiling of MTBC strains and Implementation of TB control programs within universities and the surrounding community should be considered to decrease TB transmission.

epidemiology↗

bioRxiv2018

Variations in neonatal age segments mortality in Kenyas malaria epidemiological zones by community uptake of iron-supplements and anti-malaria drugs during pregnancy: Analysis based on 2014 Kenya demographic and health survey

IntroductionAlthough past studies have established that iron-supplements and anti-malaria drugs taken by mothers during pregnancy reduce the risk of neonatal deaths in high prone malaria areas, little is known about their impact on mortality risks in neonatal age segments in Kenya. The study objective was to analyse variations in neonatal age segments mortality rates by uptake of these two antenatal care services and determine their effects on the age segments mortality in Kenyas malaria zones.\n\nData and methodsThis study used data from the 2014 Kenya Demographic and Health Survey (KDHS). Survival status information for 20,794 children born less than 60 months prior to interview date and reported mothers uptake of iron-supplements and anti-malaria drugs during last pregnancy was analysed. Life table method was used to estimate mortality rates and Poisson multivariate regression models were fitted to determine relative risks of death for the study variables.\n\nResultsThe results show that variations in neonatal age segments mortality in Kenyas malaria zones are statistically insignificant. The contributions of early neonatal (0 to 7 days) to neonatal mortality rate are 80% and 100% in low and high malaria zones, respectively. Combined high community uptake of iron-supplements and anti-malaria drugs during pregnancy reduce significantly mortality risk in late neonatal (8 days to less than one month) in all malaria zones when effects of other risk factors are controlled for.\n\nConclusionsThe findings suggest that future decline in neonatal mortality in all Kenyas malaria zones depend mainly on reduction of early neonatal mortality. High community uptake of iron-supplements and anti-malaria drugs during pregnancy has significant reduction effect on late neonatal mortality in all malaria zones. This study recommends improvement of future KDHS data quality, especially on care for small and sick neonates.

epidemiology↗

bioRxiv2018

Applying optimal control theory to complex epidemiological models to inform real-world disease management

Mathematical models provide a rational basis to inform how, where and when to control disease. Assuming an accurate spatially-explicit simulation model can be fitted to spread data, it is straightforward to use it to test the performance of a range of management strategies. However, the typical complexity of simulation models and the vast set of possible controls mean that only a small subset of all possible strategies can ever be tested. An alternative approach - optimal control theory - allows the very best control to be identified unambiguously. However, the complexity of the underpinning mathematics means that disease models used to identify this optimum must be very simple. We highlight two frameworks for bridging the gap between detailed epidemic simulations and optimal control theory: open-loop and model predictive control. Both these frameworks approximate a simulation model with a simpler model more amenable to mathematical analysis. Using an illustrative example model we show the benefits of using feedback control, in which the approximation and control are updated as the epidemic progresses. Our work illustrates a new methodology to allow the insights of optimal control theory to inform practical disease management strategies, with the potential for application to diseases of plants, animals and humans.

epidemiology↗

bioRxiv2016

Declaring a tuberculosis outbreak over with genomic epidemiology

We report an updated method for inferring the time at which an infectious disease was transmitted between persons from a time-labelled pathogen genome phylogeny. We applied the method to 48 Mycobacterium tuberculosis genomes as part of a real-time public health outbreak investigation, demonstrating that although active tuberculosis (TB) cases were diagnosed through 2013, no transmission events took place beyond mid-2012. Subsequent cases were the result of progression from latent TB infection to active disease and not recent transmission. This evolutionary genomic approach was used to declare the outbreak over in January 2015.

Genomics↗

bioRxiv2016

Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim. We estimate that 30% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 7.6-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 151 AJ enriched protein-altering alleles that overlap with \"pathogenic\" ClinVar alleles, including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohns disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically evaluate whether strong acting rare alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohns disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are strongly enriched in AJ, including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10-16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC to pinpoint genetic variation that contributes to variable disease predisposition across populations.

Genetics↗

bioRxiv2016

Genetic,transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimers disease.

Multiple pathogens have been detected in Alzheimers disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans, C.Neoformans, Bornavirus, B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, C.Pneumoniae, P.Gingivalis, H.Pylori, T.Gondii, T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2 and presenilin variants. 30/78 AD genes are expressed in the blood brain barrier (BBB), which is disrupted by AD risk factors (ageing, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolaemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption and smoking). The BBB and AD benefit from statins, NSAIDs, oestrogen, melatonin and the Mediterranean diet. Polymicrobial involvement is supported by the upregulation of pathogen sensors/defenders (bacterial, fungal, viral) in the AD brain, blood or CSF. Cerebral pathogen invasion permitted by BBB inadequacy, activating a hyper-efficient immune/inflammatory system, betaamyloid and other antimicrobial defence may be responsible for AD which may respond to antibiotic, antifungal or antiviral therapy.

Neuroscience↗

bioRxiv2016

SNVPhyl: A Single Nucleotide Variant Phylogenomics pipeline for microbial genomic epidemiology

MotivationThe recent widespread application of whole-genome sequencing (WGS) for microbial disease investigations has spurred the development of new bioinformatics tools, including a notable proliferation of phylogenomics pipelines designed for infectious disease surveillance and outbreak investigation. Transitioning the use of WGS data out of the research lab and into the front lines of surveillance and outbreak response requires user-friendly, reproducible, and scalable pipelines that have been well validated.\n\nResultsSNVPhyl (Single Nucleotide Variant Phylogenomics) is a bioinformatics pipeline for identifying high-quality SNVs and constructing a whole genome phylogeny from a collection of WGS reads and a reference genome. Individual pipeline components are integrated into the Galaxy bioinformatics framework, enabling data analysis in a user-friendly, reproducible, and scalable environment. We show that SNVPhyl can detect SNVs with high sensitivity and specificity and identify and remove regions of high SNV density (indicative of recombination). SNVPhyl is able to correctly distinguish outbreak from non-outbreak isolates across a range of variant-calling settings, sequencing-coverage thresholds, or in the presence of contamination.\n\nAvailabilitySNVPhyl is available as a Galaxy workflow, Docker and virtual machine images, and a Unix-based command-line application. SNVPhyl is released under the Apache 2.0 license and available at http://snvphyl.readthedocs.io/ or at https://github.com/phac-nml/snvphyl-galaxy.

bioinformatics↗

bioRxiv2016

Creating a National Vector Surveillance System: Integrated mosquito trap data and digital epidemiology

According to the World Health Organization, every year more than a billion people are infected with vector-borne diseases worldwide. There are no vaccines for most vector-borne diseases. Vector control, therefore, is often the only way to prevent outbreaks. Despite the major impact of vectors on human health, knowledge gaps exist regarding their natural population dynamics. Even the most basic information--such as spatiotemporal abundance-- is not available. Mosquitoes transmit malaria and the viruses causing Yellow Fever, West Nile, Dengue, Chikungunya, and Zika in the Americas. The Americas have a long history of mosquito control efforts, including the unsustained but successful Aedes aegypti eradication initiative. In the US, municipalities have independently created agencies for mosquito control and monitoring. We propose that the ensemble of US mosquito control agencies can, and should, be used to develop a national--and potentially international--system for Cross-Scale Vector Monitoring and Control (CSVMaC), in which local level monitoring and control efforts are cross-linked by unified real-time data streaming to build the data capital needed to gain a mechanistic understanding of vector population dynamics. Vectors, and the pathogens they transmit, know no jurisdictions. The vision of CSVMaC is, therefore, to provide data for (i) the general study of mosquito ecology and (ii) to inform vector control during epidemics/outbreaks that impact multiple jurisdictions (i.e., counties, states, etc.). We reveal >1000 mosquito control agencies in the US with enormous troves of data that are hidden among many data silos. For CSVMaC, we propose the creation of a nationally-coordinated open-access database to collate mosquito data. The database would provide scientific and public health communities with highly resolved spatiotemporal data on arboviral disease vectors, empowering new interventions and insights while leveraging pre-existing human efforts, operational infrastructure, and investments already funded by taxpayers.

ecology↗

bioRxiv2017

Genomic epidemiology of global Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli

The dissemination of carbapenem resistance in Escherichia coli has major implications for the management of common human infections. blaKPC, encoding a transmissible carbapenemase (KPC), has historically largely been associated with Klebsiella pneumoniae, a predominant plasmid (pKpQIL), and a specific transposable element (Tn4401, ~10kb). Here we characterize the genetic features of the emergence of blaKPC in global E. coli, 2008-2013, using both long-and short-read whole genome sequencing.\n\nAmongst 43/45 successfully sequenced blaKPC-E. coli strains, we identified high strain (n=21 sequence types, 18% of annotated genes in the core genome); plasmid ([≥]9 replicon types); and blaKPC-associated, mobile genetic element (MGE) diversity (50% not within complete Tn4401 elements). We also found evidence of interspecies, regional and international plasmid spread. In several cases blaKPC was found on high copy number, small Col-like plasmids, previously associated with horizontal transmission of resistance genes in the absence of antimicrobial selection pressures.\n\nE. coli is a common human pathogen, but also a commensal in a multiple environmental and animal reservoirs, and easily transmissible. The association of blaKPC with a range of MGEs previously linked to the successful spread of widely endemic resistance mechanisms (e.g. blaTEM, blaCTX-M) suggests that it is likely to become similarly prevalent.

microbiology↗

bioRxiv2017

Genetic Epidemiology And Mendelian Randomization For Informing Disease Therapeutics: Conceptual And Methodological Challenges

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets (1-4), but this has yet to be realised at a level reflecting expectation. One reason for this, we suggest, is that GWAS to date have generally not focused on phenotypes that directly relate to the progression of disease, and thus speak to disease treatment.

genetics↗

bioRxiv2017

The Genetic Epidemiology of Developmental Dysplasia of the Hip: A Genome-Wide Association Study Harnessing National Clinical Audit Data

BackgroundDevelopmental dysplasia of the hip (DDH) is a common, heritable condition characterised by abnormal formation of the hip joint, but has a poorly understood genetic architecture due to small sample sizes. We apply a novel case-ascertainment approach using national clinical audit (NCA) data to conduct the largest DDH genome-wide association study (GWAS) to date, and replicate our findings in independent cohorts.\n\nMethodsWe used the English National Joint Registry (NJR) dataset to collect DNA and conducted a GWAS in 770 DDH cases and 3364 controls. We tested the variant most strongly associated with DDH in independent replication cohorts comprising 1129 patients and 4652 controls.\n\nResultsThe heritable component of DDH attributable to common variants was 55% and distributed similarly across autosomal and the X-chromosomes. Variation within the GDF5 gene promoter was strongly and reproducibly associated with DDH (rs143384, OR 1.44 [95% CI 1.34-1.56], p=3.55x10-22). Two further replicating loci showed suggestive association with DDH near NFIB (rs4740554, OR 1.30 [95% CI 1.16-1.45], p=4.44x10-6) and LOXL4 (rs4919218, 1.19 [1.10-1.28] p=4.38x10-6). Through gene-based enrichment we identify GDF5, UQCC1, MMP24, RETSAT and PDRG1 association with DDH (p<1.2x10-7). Using the UK Biobank and arcOGEN cohorts to generate polygenic risk scores we find that risk alleles for hip osteoarthritis explain <0.5% of the variance in DDH susceptibility.\n\nConclusionUsing the NJR as a proof-of-principle, we describe the genetic architecture of DDH and identify several candidate intervention loci and demonstrate a scalable recruitment strategy for genetic studies that is transferrable to other complex diseases.\n\nKey MessagesO_LIWe report the first genome-wide scan for DDH in a European population, and the first to use national clinical audit data for case-ascertainment in complex disease.\nC_LIO_LIThe heritable component of DDH attributable to common variants is 55% and is distributed similarly across autosomal and the X-chromosomes.\nC_LIO_LIVariation within the GDF5 gene promoter is strongly and reproducibly associated with DDH, with fine-mapping indicating rs143384 as the likely casual variant.\nC_LIO_LIEnrichment analyses implicate GDF5, UQCC1, MMP24, RETSAT and PDRG1 as candidate targets for intervention in DDH.\nC_LIO_LIDDH shares little common genetic aetiology with idiopathic osteoarthritis of the hip, despite sharing variation within the GDF5 promoter as a common risk factor.\nC_LI

genetics↗

bioRxiv2017

Epidemiology of paediatric gastrointestinal colonisation by extended spectrum cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates in north-west Cambodia

Extended-spectrum cephalosporin resistance (ESC-R) in Escherichia coli and Klebsiella pneumoniae is a healthcare threat; high gastrointestinal carriage rates are reported from South-east Asia. Colonisation prevalence data in Cambodia are lacking. We determined gastrointestinal colonisation prevalence of ESC-resistant E. coli (ESC-R-EC) and K. pneumoniae (ESC-R-KP) in Cambodian children/adolescents and associated risk factors; characterised relevant resistance genes, their genetic contexts, and the genetic relatedness of ESC-R strains using whole genome sequencing (WGS). Faeces and questionnaire data were obtained from individuals <16 years in northwestern Cambodia, 2012. WGS of cultured ESC-R-EC/KP was performed (Illumina). Maximum likelihood phylogenies were used to characterise relatedness of isolates; ESC-R-associated resistance genes and their genetic contexts were identified from de novo assemblies using BLASTn and automated/manual annotation. 82/148 (55%) of children/adolescents were ESC-R-EC/KP colonised; 12/148 (8%) were co-colonised with both species. Independent risk factors for colonisation were hospitalisation (OR: 3.12, 95%, CI [1.52-6.38]) and intestinal parasites (OR: 3.11 [1.29-7.51]); school attendance conferred decreased risk (OR: 0.44 [0.21-0.92]. ESC-R strains were diverse; the commonest ESC-R mechanisms were blaCTX-M 1 and 9 sub-family variants. Structures flanking these genes were highly variable, and for blaCTX-M-15, -55 and -27, frequently involved IS26. Chromosomal blaCTX-M integration was common in E. coli. Gastrointestinal ESC-R-EC/KP colonisation is widespread in Cambodian children/adolescents; hospital admission and intestinal parasites are independent risk factors. The genetic contexts of blaCTX-M are highly mosaic, consistent with rapid horizontal exchange. Chromosomal integration of blaCTX-M may result in stable propagation in these community-associated pathogens.

microbiology↗

bioRxiv2018

epiTAD: a web application for visualizing high throughput chromosome conformation capture data in the context of genetic epidemiology

The increasing availability of public data resources coupled with advancements in genomic technology has created greater opportunities for researchers to examine the genome on a large and complex scale. To meet the need for integrative genome wide exploration, we present epiTAD. This web-based tool enables researchers to compare genomic structures and annotations across multiple databases and platforms in an interactive manner in order to facilitate in silico discovery. epiTAD can be accessed at https://apps.gerkelab.com/epiTAD/.

genomics↗