One model to rule them all? Modelling approaches across OneHealth for human, animal and plant epidemics

One hundred years after the 1918 influenza outbreak, are we ready for the next pandemic? This paper addresses the need to identify and develop collaborative, interdisciplinary and cross-sectoral approaches to modelling of infectious diseases including the fields of not only human and veterinary medicine, but also plant epidemiology. Firstly, the paper explains the concepts on which the most common epidemiological modelling approaches are based, namely the division of a host population into susceptible, infected and removed (SIR) classes and the proportionality of the infection rate to the size of the susceptible and infected populations. It then demonstrates how these simple concepts have been developed into a vast and successful modelling framework that has been used in predicting and controlling disease outbreaks for over 100 years. Secondly, it considers the compartmental models based on the SIR paradigm within the broader concept of a ‘disease tetrahedron’ (comprising host, pathogen, environment and man) and uses it to review the similarities and differences among the fields comprising the ‘OneHealth’ approach. Finally, the paper advocates interactions between all fields and explores the future challenges facing modellers

Strong position-dependent effects of sequence mismatches on signal ratios measured using long oligonucleotide microarrays

<p>Abstract</p> <p>Background</p> <p>Microarrays are an important and widely used tool. Applications include capturing genomic DNA for high-throughput sequencing in addition to the traditional monitoring of gene expression and identifying DNA copy number variations. Sequence mismatches between probe and target strands are known to affect the stability of the probe-target duplex, and hence the strength of the observed signals from microarrays.</p> <p>Results</p> <p>We describe a large-scale investigation of microarray hybridisations to murine probes with known sequence mismatches, demonstrating that the effect of mismatches is strongly position-dependent and for small numbers of sequence mismatches is correlated with the maximum length of perfectly matched probe-target duplex. Length of perfect match explained 43% of the variance in log₂signal ratios between probes with one and two mismatches. The correlation with maximum length of perfect match does not conform to expectations based on considering the effect of mismatches purely in terms of reducing the binding energy. However, it can be explained qualitatively by considering the entropic contribution to duplex stability from configurations of differing perfect match length.</p> <p>Conclusion</p> <p>The results of this study have implications in terms of array design and analysis. They highlight the significant effect that short sequence mismatches can have upon microarray hybridisation intensities even for long oligonucleotide probes.</p> <p>All microarray data presented in this study are available from the GEO database <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>, under accession number [GEO: GSE9669]</p

Resiliency analysis for complex engineered system design

Resilience is a key driver in the design of systems that must operate in an uncertain operating environment, and is a key metric to assess the capacity for systems to perform within the specified performance envelop despite disturbances to their operating environment. This paper describes a graph spectral approach to calculate the resilience of complex engineered systems. The resilience of the design architecture of complex engineered systems is deduced from graph spectra. This is calculated from adjacency matrix representations of the physical connections between components in complex engineered systems. Furthermore, we propose a new method to identify the most vulnerable components in the design and design architectures that are robust to transmission of failures. Non-linear dynamical system (NLDS) and epidemic spreading models are used to compare the failure propagation mean time transformation. Using these metrics, we present a case study based on the Advanced Diagnostics and Prognostics Testbed (ADAPT), which is an Electrical Power System (EPS) developed at NASA Ames as a subsystem for the Ramp System of an Infantry Fighting Vehicle (IFV).Keywords: Complex System Design, Failure Density, Failure Propagation, Robust Desig

Optimising efficacy of antibiotics against systemic infection by varying dosage quantities and times

Mass production and use of antibiotics has led to the rise of resistant bacteria, a problem possibly exacerbated by inappropriate and non-optimal application. Antibiotic treatment often follows fixed-dose regimens, with a standard dose of antibiotic administered equally spaced in time. But are such fixed-dose regimens optimal or can alternative regimens be designed to increase efficacy? Yet, few mathematical models have aimed to identify optimal treatments based on biological data of infections inside a living host. In addition, assumptions to make the mathematical models analytically tractable limit the search space of possible treatment regimens (e.g. to fixed-dose treatments). Here, we aimed to address these limitations by using experiments in a Galleria mellonella (insect) model of bacterial infection, to create a fully parametrised mathematical model of a systemic Vibrio infection. We successfully validated this model with biological experiments, including treatments unseen by the mathematical model. Then, by applying artificial intelligence, this model was used to determine optimal antibiotic dosage regimens to treat the host to maximise survival while minimising total antibiotic used. As expected, host survival increased as total quantity of antibiotic applied during the course of treatment increased. However, many of the optimal regimens tended to follow a large initial ‘loading’ dose followed by doses of incremental reductions in antibiotic quantity (dose ‘tapering’). Moreover, application of the entire antibiotic in a single dose at the start of treatment was never optimal, except when the total quantity of antibiotic was very low. Importantly, the range of optimal regimens identified was broad enough to allow the antibiotic prescriber to choose a regimen based on additional criteria or preferences. Our findings demonstrate the utility of an insect host to model antibiotic therapies in vivo and the approach lays a foundation for future regimen optimisation for patient and societal benefits

FMDTOOLS: A Fault propagation Toolkit for Resilience Assessment in Early Design

Incorporating resilience in design is important for the long-term viability of complex engineered systems. Complex aerospace systems, for example, must ensure safety in the event of hazards resulting from part failures and external circumstances while maintaining efficient operations. Traditionally, mitigating hazards in early design has involved experts manually creating hazard analyses in a time-consuming process that hinders one’s ability to compare designs. Furthermore, as opposed to reliability-based design, resilience-based design requires using models to determine the dynamic effects of faults to compare recovery schemes. Models also provide design opportunities, since models can be parameterized and optimized and because the resulting hazard analyses can be updated iteratively. While many theoretical frameworks have been presented for early hazard assessment, most currently-available modelling tools are meant for the later stages of design. Given the wide adoption of Python in the broader research community, there is an opportunity to create an environment for researchers to study the resilience of different PHM technologies in the early phases of design. This paper describes fmdtools, an attempt to realize this opportunity with a set of modules which may be used to construct different design models, simulate system behaviors over a set of fault scenarios and analyze the resilience of the resulting simulation results. This approach is demonstrated in the hazard analysis and architecture design of a multi-rotor drone, showing how the toolkit enables a large number of analyses to be performed on a relatively simple model as it progresses through the early design process

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies