| 1. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Brommesson, Peter, et al.
(författare)
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Assessing intrastate shipments from interstate data and expert opinion
- 2021
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Ingår i: Royal Society Open Science. - : Royal Society of Open Science. - 2054-5703. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Live animal shipments are a potential route for transmitting animal diseases between holdings and are crucial when modelling spread of infectious diseases. Yet, complete contact networks are not available in all countries, including the USA. Here, we considered a 10% sample of Interstate Certificate of Veterinary Inspections from 1 year (2009). We focused on distance dependence in contacts and investigated how different functional forms affect estimates of unobserved intrastate shipments. To further enhance our predictions, we included responses from an expert elicitation survey about the proportion of shipments moving intrastate. We used hierarchical Bayesian modelling to estimate parameters describing the kernel and effects of expert data. We considered three functional forms of spatial kernels and the inclusion or exclusion of expert data. The resulting six models were ranked by widely applicable information criterion (WAIC) and deviance information criterion (DIC) and evaluated through within- and out-of-sample validation. We showed that predictions of intrastate shipments were mildly influenced by the functional form of the spatial kernel but kernel shapes that permitted a fat tail at large distances while maintaining a plateau-shaped behaviour at short distances better were preferred. Furthermore, our study showed that expert data may not guarantee enhanced predictions when expert estimates are disparate.
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| 3. |
- Buhnerkempe, Michael G., et al.
(författare)
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The Impact of Movements and Animal Density on Continental Scale Cattle Disease Outbreaks in the United States
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:3, s. 0091724-
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Tidskriftsartikel (refereegranskat)abstract
- Globalization has increased the potential for the introduction and spread of novel pathogens over large spatial scales necessitating continental-scale disease models to guide emergency preparedness. Livestock disease spread models, such as those for the 2001 foot-and-mouth disease (FMD) epidemic in the United Kingdom, represent some of the best case studies of large-scale disease spread. However, generalization of these models to explore disease outcomes in other systems, such as the United Statess cattle industry, has been hampered by differences in system size and complexity and the absence of suitable livestock movement data. Here, a unique database of US cattle shipments allows estimation of synthetic movement networks that inform a near-continental scale disease model of a potential FMD-like (i.e., rapidly spreading) epidemic in US cattle. The largest epidemics may affect over one-third of the US and 120,000 cattle premises, but cattle movement restrictions from infected counties, as opposed to national movement moratoriums, are found to effectively contain outbreaks. Slow detection or weak compliance may necessitate more severe state-level bans for similar control. Such results highlight the role of large-scale disease models in emergency preparedness, particularly for systems lacking comprehensive movement and outbreak data, and the need to rapidly implement multi-scale contingency plans during a potential US outbreak.
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| 4. |
- Gilbertson, Kendra, et al.
(författare)
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The Importance of Livestock Demography and Infrastructure in Driving Foot and Mouth Disease Dynamics
- 2022
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Ingår i: Life. - : MDPI. - 2075-1729. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Transboundary animal diseases, such as foot and mouth disease (FMD) pose a significant and ongoing threat to global food security. Such diseases can produce large, spatially complex outbreaks. Mathematical models are often used to understand the spatio-temporal dynamics and create response plans for possible disease introductions. Model assumptions regarding transmission behavior of premises and movement patterns of livestock directly impact our understanding of the ecological drivers of outbreaks and how to best control them. Here, we investigate the impact that these assumptions have on model predictions of FMD outbreaks in the U.S. using models of livestock shipment networks and disease spread. We explore the impact of changing assumptions about premises transmission behavior, both by including within-herd dynamics, and by accounting for premises type and increasing the accuracy of shipment predictions. We find that the impact these assumptions have on outbreak predictions is less than the impact of the underlying livestock demography, but that they are important for investigating some response objectives, such as the impact on trade. These results suggest that demography is a key ecological driver of outbreaks and is critical for making robust predictions but that understanding management objectives is also important when making choices about model assumptions.
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| 5. |
- Gorsich, Erin E., et al.
(författare)
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Model-guided suggestions for targeted surveillance based on cattle shipments in the US
- 2018
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Ingår i: Preventive Veterinary Medicine. - : ELSEVIER SCIENCE BV. - 0167-5877 .- 1873-1716. ; 150, s. 52-59
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Tidskriftsartikel (refereegranskat)abstract
- Risk-based sampling is an essential component of livestock health surveillance because it targets resources towards sub-populations with a higher risk of infection. Risk-based surveillance in U.S. livestock is limited because the locations of high-risk herds are often unknown and data to identify high-risk herds based on shipments are often unavailable. In this study, we use a novel, data-driven network model for the shipments of cattle in the U.S. (the U.S. Animal Movement Model, USAMM) to provide surveillance suggestions for cattle imported into the U.S. from Mexico. We describe the volume and locations where cattle are imported and analyze their predicted shipment patterns to identify counties that are most likely to receive shipments of imported cattle. Our results suggest that most imported cattle are sent to relatively few counties. Surveillance at 10 counties is predicted to sample 22-34% of imported cattle while surveillance at 50 counties is predicted to sample 43%-61% of imported cattle. These findings are based on the assumption that USAMM accurately describes the shipments of imported cattle because their shipments are not tracked separately from the remainder of the U.S. herd. However, we analyze two additional datasets - Interstate Certificates of Veterinary Inspection and brand inspection data - to ensure that the characteristics of potential post-import shipments do not change on an annual scale and are not dependent on the dataset informing our analyses. Overall, these results highlight the utility of USAMM to inform targeted surveillance strategies when complete shipment information is unavailable.
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| 6. |
- Lindström, Tom, et al.
(författare)
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A Bayesian Approach for Modeling Cattle Movements in the United States: Scaling up a Partially Observed Network
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Networks are rarely completely observed and prediction of unobserved edges is an important problem, especially in disease spread modeling where networks are used to represent the pattern of contacts. We focus on a partially observed cattle movement network in the U.S. and present a method for scaling up to a full network based on Bayesian inference, with the aim of informing epidemic disease spread models in the United States. The observed network is a 10% state stratified sample of Interstate Certificates of Veterinary Inspection that are required for interstate movement; describing approximately 20,000 movements from 47 of the contiguous states, with origins and destinations aggregated at the county level. We address how to scale up the 10% sample and predict unobserved intrastate movements based on observed movement distances. Edge prediction based on a distance kernel is not straightforward because the probability of movement does not always decline monotonically with distance due to underlying industry infrastructure. Hence, we propose a spatially explicit model where the probability of movement depends on distance, number of premises per county and historical imports of animals. Our model performs well in recapturing overall metrics of the observed network at the node level (U.S. counties), including degree centrality and betweenness; and performs better compared to randomized networks. Kernel generated movement networks also recapture observed global network metrics, including network size, transitivity, reciprocity, and assortativity better than randomized networks. In addition, predicted movements are similar to observed when aggregated at the state level (a broader geographic level relevant for policy) and are concentrated around states where key infrastructures, such as feedlots, are common. We conclude that the method generally performs well in predicting both coarse geographical patterns and network structure and is a promising method to generate full networks that incorporate the uncertainty of sampled and unobserved contacts.
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| 7. |
- Lindström, Tom, et al.
(författare)
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A Bayesian Ensemble Approach for Epidemiological Projections
- 2015
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Ingår i: PloS Computational Biology. - : Public Library of Science. - 1553-734X .- 1553-7358. ; 11:4, s. e1004187-
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Tidskriftsartikel (refereegranskat)abstract
- Mathematical models are powerful tools for epidemiology and can be used to compare control actions. However, different models and model parameterizations may provide different prediction of outcomes. In other fields of research, ensemble modeling has been used to combine multiple projections. We explore the possibility of applying such methods to epidemiology by adapting Bayesian techniques developed for climate forecasting. We exemplify the implementation with single model ensembles based on different parameterizations of the Warwick model run for the 2001 United Kingdom foot and mouth disease outbreak and compare the efficacy of different control actions. This allows us to investigate the effect that discrepancy among projections based on different modeling assumptions has on the ensemble prediction. A sensitivity analysis showed that the choice of prior can have a pronounced effect on the posterior estimates of quantities of interest, in particular for ensembles with large discrepancy among projections. However, by using a hierarchical extension of the method we show that prior sensitivity can be circumvented. We further extend the method to include a priori beliefs about different modeling assumptions and demonstrate that the effect of this can have different consequences depending on the discrepancy among projections. We propose that the method is a promising analytical tool for ensemble modeling of disease outbreaks.
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| 8. |
- Lindström, Tom, 1977-
(författare)
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Spatial Spread of Organisms : Modeling ecological and epidemiological processes
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the spread of organisms in both ecological and epidemiological contexts. In most of the studies presented, displacement is modeled with a spatial kernel function, which is characterized by scale and shape. These are measured by the net squared displacement (or kernel variance) and kurtosis, respectively. If organisms disperse by the assumptions of a random walk or correlated random walk, a Gaussian shaped kernel is expected. Empirical studies often report deviations from this, and commonly leptokurtic distributions are found, often as a result of heterogeneity in the dispersal process.In the studies presented in two of the included papers, the importance of the kernel shape is tested, by using a family of kernels where the shape and scale can be separated effectively. Both studies utilize spectral density approaches for modeling the spatial environment. It is concluded that the shape is not important when studying the population distribution in a habitat/matrix context. The shape is however important when looking at the invasion of organisms in a patchy environment, when the arrangement of patches deviates from randomly distributed. The introduced method for generating patch distribution is also compared to empirical distributions of patches (farms and old trees). Here it is concluded that the assumptions used for modeling of the spatial environment are consistent with the observed patterns. These assumptions include fractal properties such that the same aggregational patterns are found at different scales.In a series of papers, movements of animals are considered as vectors for between-herd disease spread. The studies are based on data found in databases held by the Swedish Board of Agricultural (SJV), consisting of reported movements, as well as farm location and characteristics. The first study focuses on the distance related probability of contacts between herds. In the following papers, the analysis is expanded to include production type and herd size. Movement data of pigs (and cattle in Paper I) are analyzed with Bayesian models, implemented with Markov Chain Monte Carlo (MCMC). This is a flexible approach that allows for parameter estimations of complex models, and at the same time includes parameter uncertainty.In Paper IV, the effects of the included factors are investigated. It is shown that all three factors (herd size, production type structure and distance related probability of contacts) are expected to influence disease spread dynamics, however the production type structure is found to be the most important factor. This emphasizes the value of keeping such information in central databases. The models presented can be used as support for risk analysis and disease tracing. However, data reliability is always a problem, and implementation may be improved with better quality data.The thesis also shows that utilizing spatial kernels for description of the spatial spread of organisms is an appropriate approach. However, these kernels must be flexible and flawed assumptions about the shape may lead to erroneous conclusions. Hence, the joint distribution of kernel shape and scale should be estimated. The flexibility of Bayesian analysis, implemented with MCMC techniques, is a good approach for this, and further allows for implementation of more complex models where other factors may be included.
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| 9. |
- Sellman, Stefan, et al.
(författare)
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Modeling nation-wide US swine movement networks at the resolution of the individual premises
- 2022
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Ingår i: Epidemics. - : Elsevier. - 1755-4365 .- 1878-0067. ; 41
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Tidskriftsartikel (refereegranskat)abstract
- The spread of infectious livestock diseases is a major cause for concern in modern agricultural systems. In the dynamics of the transmission of such diseases, movements of livestock between herds play an important role. When constructing mathematical models used for activities such as forecasting epidemic development, evaluating mitigation strategies, or determining important targets for disease surveillance, including between -premises shipments is often a necessity. In the United States (U.S.), livestock shipment data is not routinely collected, and when it is, it is not readily available and mostly concerned with between-state shipments. To bridge this gap in knowledge and provide insight into the complete livestock shipment network structure, we have developed the U.S. Animal Movement Model (USAMM). Previously, USAMM has only existed for cattle shipments, but here we present a version for domestic swine. This new version of USAMM consists of a Bayesian model fit to premises demography, county-level livestock industry variables, and two limited data sets of between-state swine movements. The model scales up the data to simulate nation-wide networks of both within-and between-state shipments at the level of individual premises. Here we describe this shipment model in detail and subsequently explore its usefulness with a rudimentary predictive model of the prevalence of porcine epidemic diarrhea virus (PEDv) across the U.S. Additionally, in order to promote further research on livestock disease and other topics involving the movements of swine in the U.S., we also make 250 synthetic premises-level swine shipment networks with complete coverage of the entire conterminous U.S. freely available to the research community as a useful surrogate for the absent shipment data.
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| 10. |
- Sellman, Stefan, et al.
(författare)
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Modeling US cattle movements until the cows come home: Who ships to whom and how many?
- 2022
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Ingår i: Computers and Electronics in Agriculture. - : ELSEVIER SCI LTD. - 0168-1699 .- 1872-7107. ; 203
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Tidskriftsartikel (refereegranskat)abstract
- Livestock movements between agricultural premises is an important pathway for the spread of infectious disease. Data providing details about the origin and destination of shipments, as well as information about the shipment size is an important component of computer models used to formulate mitigation strategies and design surveillance programs. The United States (U.S.) currently lacks a comprehensive database of farm animal shipments, which hinders such efforts. With the U.S. Animal Movement Model (USAMM), earlier work has successfully scaled up from limited data based on interstate certificates of veterinary inspection (CVI) to comprehensive county-level shipment networks at the national scale. In this work, we present three major improvements to earlier versions of USAMM: (1) increased resolution of the model and simulated networks to the level of individual premises; (2) predictions of shipment sizes; (3) taking into account the types and herd sizes of the premises. We fitted parameters in a Bayesian framework to two sets of CVI data consisting of sub-samples of one years between-state beef and dairy shipments. Through posterior predictive simulation, we then created 1,000 synthetic beef and dairy networks, which we make publicly available to support livestock disease modeling. The simulated networks were validated against summary statistics of the training data as well as out-of-sample CVI data from subsequent years. This new development opens up the possibility of using USAMM in a broader spectrum of applications where information about shipment size and premises identity is necessary and gives novel insights into the U.S. cattle shipment network.
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