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  • 1.
    Andersson, Henrik
    et al.
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Hartmanova (Andersson), Blanka
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Landfors, Mattias
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Matematik och matematisk statistik.
    Noppa, Laila
    FOI, Umeå (Swedish Defence Research Agency).
    Näslund, Linda
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Näslund, A.
    T A microarray analysis of the murine macrophage response to infection with Francisella tularensis LVS2006Inngår i: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 55, nr 8, s. 1023-1033Artikkel i tidsskrift (Fagfellevurdert)
  • 2.
    Andersson, Henrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Hartmanova, Blanka
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Bäck, Erik
    Universitetssjukhuset i Örebro.
    Eliasson, Henrik
    Universitetssjukhuset i Örebro.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Näslund, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Transcriptional profiling of the peripheral blood response during tularemia.2006Inngår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 7, nr 6, s. 503-513Artikkel i tidsskrift (Fagfellevurdert)
  • 3.
    Andersson, Henrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Hartmanova, Blanka
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Kuolee, R.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Conlan, Wayne
    NRC, Kanada.
    Chen, Wang
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Transcriptional profiling of the host responses in mouse lungs following aerosol2006Inngår i: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 55, nr 3, s. 263-271Artikkel i tidsskrift (Fagfellevurdert)
  • 4.
    Andersson-Evelönn, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Källberg, David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Liu, Xijia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Combining epigenetic and clinicopathological variables improves prognostic prediction in clear cell Renal Cell CarcinomaManuskript (preprint) (Annet vitenskapelig)
  • 5.
    Andersson-Evelönn, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Källberg, David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Liu, Xijia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma2020Inngår i: Journal of Translational Medicine, E-ISSN 1479-5876, Vol. 18, nr 1, artikkel-id 435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Metastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis. Almost one-third of patients with non-metastatic tumors at diagnosis will later progress with metastatic disease. These patients need to be identified already at diagnosis, to undertake closer follow up and/or adjuvant treatment. Today, clinicopathological variables are used to risk classify patients, but molecular biomarkers are needed to improve risk classification to identify the high-risk patients which will benefit most from modern adjuvant therapies. Interestingly, DNA methylation profiling has emerged as a promising prognostic biomarker in ccRCC. This study aimed to derive a model for prediction of tumor progression after nephrectomy in non-metastatic ccRCC by combining DNA methylation profiling with clinicopathological variables.

    Methods: A novel cluster analysis approach (Directed Cluster Analysis) was used to identify molecular biomarkers from genome-wide methylation array data. These novel DNA methylation biomarkers, together with previously identified CpG-site biomarkers and clinicopathological variables, were used to derive predictive classifiers for tumor progression.

    Results: The “triple classifier” which included both novel and previously identified DNA methylation biomarkers together with clinicopathological variables predicted tumor progression more accurately than the currently used Mayo scoring system, by increasing the specificity from 50% in Mayo to 64% in our triple classifier at 85% fixed sensitivity. The cumulative incidence of progress (pCIP5yr) was 7.5% in low-risk vs 44.7% in high-risk in M0 patients classified by the triple classifier at diagnosis.

    Conclusions: The triple classifier panel that combines clinicopathological variables with genome-wide methylation data has the potential to improve specificity in prognosis prediction for patients with non-metastatic ccRCC.

    Fulltekst (pdf)
    fulltext
  • 6.
    Bayisa, Fekadu
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Ådahl, Markus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Cronie, Ottmar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Large-scale modelling and forecasting of ambulance calls in northern Sweden using spatio-temporal log-Gaussian Cox processes2020Inngår i: Spatial Statistics, E-ISSN 2211-6753, Vol. 39, artikkel-id 100471Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In order to optimally utilise the resources of a country’s prehospital care system, i.e. ambulance service(s),it is crucial that one is able to spatio-temporally forecast hot-spots, i.e. spatial regions and periods with anincreased risk of seeing a call to the emergency number 112 which results in the dispatch of an ambulance.Such forecasts allow the dispatcher to make strategic decisions regarding e.g. the fleet size and where todirect unoccupied ambulances. In addition, simulations based on forecasts may serve as the startingpoint for different optimal routing strategies. Although the associated data typically comes in the form ofspatio-temporal point patterns, point process based modelling attempts in the literature has been scarce.In this paper, we study a unique set of Swedish spatio-temporal ambulance call data, which consists ofthe spatial (gps) locations of the dispatch addresses and the associated days of occurrence of the calls.The spatial study region is given by the four northernmost regions of Sweden and the study period isJanuary 1, 2014 to December 31, 2018. Motivated by the non-infectious disease nature of the data, wehere employ log-Gaussian Cox processes (LGCPs) for the spatio-temporal modelling and forecasting ofthe calls. To this end, we propose a K-means based bandwidth selection method for the kernel estimationof the spatial component of the separable spatio-temporal intensity function. The temporal componentof the intensity function is modelled by means of Poisson regression, using different calendar covariates,and the spatio-temporal random field component of the random intensity of the LGCP is fitted usingsimulation via the Metropolis-adjusted Langevin algorithm. A study of the spatio-temporal dynamics ofthe data shows that a hot-spot can be found in the south eastern part of the study region, where mostpeople in the region live and our fitted model/forecasts manage to capture this behaviour quite well. Thefitted temporal component of the intensity functions reveals that there is a significant association betweenthe expected number of calls and the day of the week as well as the season of the year. In addition,non-parametric second-order spatio-temporal summary statistic estimates indicate that LGCPs seem tobe reasonable models for the data. Finally, we find that the fitted forecasts generate simulated futurespatial event patterns which quite well resemble the actual future data.

    Fulltekst (pdf)
    fulltext
  • 7.
    Bayisa, Fekadu
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Department of Mathematics and Statistics, Auburn University, AL, Auburn, United States.
    Ådahl, Markus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Cronie, Ottmar
    Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden; School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Regularised semi-parametric composite likelihood intensity modelling of a Swedish spatial ambulance call point pattern2023Inngår i: Journal of Agricultural Biological and Environmental Statistics, ISSN 1085-7117, E-ISSN 1537-2693, Vol. 28, nr 4, s. 664-683Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Motivated by the development of optimal dispatching strategies for prehospital resources, we model the spatial distribution of ambulance call events in the Swedish municipality Skellefteå during 2014–2018 in order to identify important spatial covariates and discern hotspot regions. Our large-scale multivariate data point pattern of call events consists of spatial locations and marks containing the associated priority levels and sex labels. The covariates used are related to road network coverage, population density, and socio-economic status. For each marginal point pattern, we model the associated intensity function by means of a log-linear function of the covariates and their interaction terms, in combination with lasso-like elastic-net regularized composite/Poisson process likelihood estimation. This enables variable selection and collinearity adjustment as well as reduction of variance inflation from overfitting and bias from underfitting. To incorporate mobility adjustment, reflecting people’s movement patterns, we also include a nonparametric (kernel) intensity estimate as an additional covariate. The kernel intensity estimation performed here exploits a new heuristic bandwidth selection algorithm. We discover that hotspot regions occur along dense parts of the road network. A mean absolute error evaluation of the fitted model indicates that it is suitable for designing prehospital resource dispatching strategies. Supplementary materials accompanying this paper appear online.

    Fulltekst (pdf)
    fulltext
  • 8.
    Belyaev, Yu.K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    On Non-Parametric Estimation of Poission Point Processes Related to Failure Stresses of Fibres2000Rapport (Annet vitenskapelig)
    Abstract [en]

    We consider statistical analysis of the reliability of fibres. The problem is to estimate the distribution law of random failure stresses of fibres (i.e. the critical level of stresses that destroy fibres) by using data obtained in a special kind of test, where several fibres are tested until they break. All new pieces resulting from this test will also be tested, if they are long enough. The test ends when all the remaining pieces are too short to be tested further. We refer to these as binary tree structured tests. We assume that the cumulative hazard function (c.h.f.) of the failure stresses of these fibres is continuous, and that the fibres are statistically identical. Under these assumptions we obtain, as the number of tested fibres increases, a strongly consistent Nelson-Aalen type estimator of the c.h.f. The functional central limit resampling theorem in Skorohod space is proved. It justifies the possibility of using resampling for estimating the accuracy of these estimators. The theorem shows that resampling can be used to asymptotically consistently estimate distribution laws of continuous functionals of the random deviations between the estimator and the true c.h.f.. For example, resampling can be used to estimate the distribution law of the maximum distance between estimators and estimands. Numerical examples suggest that resampling works well for a moderate number of tested fibres.

    Fulltekst (pdf)
    fulltext
  • 9.
    Belyaev, Yuri K
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Non-parametric estimators of the distribution of tensile strengths of wires1997Rapport (Annet vitenskapelig)
  • 10.
    Chen, Changchun
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Huang, Bo
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Eliasson, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Byström, Anders S
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Elongator Complex Influences Telomeric Gene Silencing and DNA Damage Response by Its Role in Wobble Uridine tRNA Modification2011Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 7, nr 9, s. e1002258-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elongator complex is required for formation of the side chains at position 5 of modified nucleosides 5-carbamoylmethyluridine (ncm(5)U(34)), 5-methoxycarbonylmethyluridine (mcm(5)U(34)), and 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U(34)) at wobble position in tRNA. These modified nucleosides are important for efficient decoding during translation. In a recent publication, Elongator complex was implicated to participate in telomeric gene silencing and DNA damage response by interacting with proliferating cell nuclear antigen (PCNA). Here we show that elevated levels of tRNA(Lys) (s(2) ) (UUU), tRNA(Gln) (s(2) ) (UUG), and tRNA(Glu) (s(2) ) (UUC), which in a wild-type background contain the mcm(5)s(2)U nucleoside at position 34, suppress the defects in telomeric gene silencing and DNA damage response observed in the Elongator mutants. We also found that the reported differences in telomeric gene silencing and DNA damage response of various elp3 alleles correlated with the levels of modified nucleosides at U(34). Defects in telomeric gene silencing and DNA damage response are also observed in strains with the tuc2Δ mutation, which abolish the formation of the 2-thio group of the mcm(5)s(2)U nucleoside in tRNA(Lys) (mcm(5) (s(2) ) (UUU) ), tRNA(Gln) (mcm(5) (s(2) ) (UUG) ), and tRNA(Glu) (mcm(5) (s(2) ) (UUC) ). These observations show that Elongator complex does not directly participate in telomeric gene silencing and DNA damage response, but rather that modified nucleosides at U(34) are important for efficient expression of gene products involved in these processes. Consistent with this notion, we found that expression of Sir4, a silent information regulator required for assembly of silent chromatin at telomeres, was decreased in the elp3Δ mutants.

    Fulltekst (pdf)
    fulltext
  • 11. De Pascalis, Roberto
    et al.
    Chou, Alicia Y.
    Ryden, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kennett, Nikki J.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Elkins, Karen L.
    Models Derived from In Vitro Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the Francisella tularensis Live Vaccine Strain (LVS)2014Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 5, nr 2, artikkel-id e00936Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Currently, there are no licensed vaccines and no correlates of protection against Francisella tularensis, which causes tularemia. We recently demonstrated that measuring in vitro control of intramacrophage bacterial growth by murine F. tularensis-immune splenocytes, as well as transcriptional analyses, discriminated Francisella vaccines of different efficacies. Further, we identified potential correlates of protection against systemic challenge. Here, we extended this approach by studying leukocytes derived from lungs and livers of mice immunized by parenteral and respiratory routes with F. tularensis vaccines. Liver and lung leukocytes derived from intradermally and intranasally vaccinated mice controlled in vitro Francisella Live Vaccine Strain (LVS) intramacrophage replication in patterns similar to those of splenocytes. Gene expression analyses of potential correlates also revealed similar patterns in liver cells and splenocytes. In some cases (e. g., tumor necrosis factor alpha [TNF-alpha], interleukin 22 [IL-22], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), liver cells exhibited even higher relative gene expression, whereas fewer genes exhibited differential expression in lung cells. In contrast with their strong ability to control LVS replication, splenocytes from intranasally vaccinated mice expressed few genes with a hierarchy of expression similar to that of splenocytes from intradermally vaccinated mice. Thus, the relative levels of gene expression vary between cell types from different organs and by vaccination route. Most importantly, because studies comparing cell sources and routes of vaccination supported the predictive validity of this coculture and gene quantification approach, we combined in vitro LVS replication with gene expression data to develop analytical models that discriminated between vaccine groups and successfully predicted the degree of vaccine efficacy. Thus, this strategy remains a promising means of identifying and quantifying correlative T cell responses.

    IMPORTANCE

    Identifying and quantifying correlates of protection is especially challenging for intracellular bacteria, including Francisella tularensis. F. tularensis is classified as a category A bioterrorism agent, and no vaccines have been licensed in the United States, but tularemia is a rare disease. Therefore, clinical trials to test promising vaccines are impractical. In this report, we further evaluated a novel approach to developing correlates by assessing T cell immune responses in lungs and livers of differentially vaccinated mice; these nonprofessional immune tissues are colonized by Francisella. The relative degree of vaccine efficacy against systemic challenge was reflected by the ability of immune T cells, particularly liver T cells, to control the intramacrophage replication of bacteria in vitro and by relative gene expression of several immunological mediators. We therefore developed analytical models that combined bacterial replication data and gene expression data. Several resulting models provided excellent discrimination between vaccines of different efficacies.

    Fulltekst (pdf)
    fulltext
  • 12. De Pascalis, Roberto
    et al.
    Hahn, Andrew
    Brook, Helen M.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Donart, Nathaniel
    Mittereder, Lara
    Frey, Blake
    Wu, Terry H.
    Elkins, Karen L.
    A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis2018Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 13, nr 5, artikkel-id e0198140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are no defined correlates of protection for any intracellular pathogen, including the bacterium Francisella tularensis, which causes tularemia. Evaluating vaccine efficacy against sporadic diseases like tularemia using field trials is problematic, and therefore alternative strategies to test vaccine candidates like the Francisella Live Vaccine Strain (LVS), such as testing in animals and applying correlate measurements, are needed. Recently, we described a promising correlate strategy that predicted the degree of vaccine-induced protection in mice given parenteral challenges, primarily when using an attenuated Francisella strain. Here, we demonstrate that using peripheral blood lymphocytes (PBLs) in this approach predicts LVS-mediated protection against respiratory challenge of Fischer 344 rats with fully virulent F. tularensis, with exceptional sensitivity and specificity. Rats were vaccinated with a panel of LVS-derived vaccines and subsequently given lethal respiratory challenges with Type A F. tularensis. In parallel, PBLs from vaccinated rats were evaluated for their functional ability to control intramacrophage Francisella growth in in vitro co-culture assays. PBLs recovered from co-cultures were also evaluated for relative gene expression using a large panel of genes identified in murine studies. In vitro control of LVS intramacrophage replication reflected the hierarchy of protection. Further, despite variability between individuals, 22 genes were significantly more up-regulated in PBLs from rats vaccinated with LVS compared to those from rats vaccinated with the variant LVS-R or heat killed LVS, which were poorly protective. These genes included IFN-gamma, IL-21, NOS2, LTA, T-bet, IL-12rβ2, and CCL5. Most importantly, combining quantifications of intramacrophage growth control with 5-7 gene expression levels using multivariate analyses discriminated protected from non-protected individuals with greater than 95% sensitivity and specificity. The results therefore support translation of this approach to non-human primates and people to evaluate new vaccines against Francisella and other intracellular pathogens.

    Fulltekst (pdf)
    fulltext
  • 13.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evelönn, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keith, W. Nicol
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014Inngår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 7, s. 606-615Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

    Fulltekst (pdf)
    fulltext
  • 14.
    Del Peso-Santos, Teresa
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Skärfstad, Eleonore
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Shingler, Victoria
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Pr is a member of a restricted class of σ70-dependent promoters that lack a recognizable -10 element2012Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr 22, s. 11308-11320Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Pr promoter is the first verified member of a class of bacterial σ(70)-promoters that only possess a single match to consensus within its -10 element. In its native context, the activity of this promoter determines the ability of Pseudomonas putida CF600 to degrade phenolic compounds, which provides proof-of-principle for the significance of such promoters. Lack of identity within the -10 element leads to non-detection of Pr-like promoters by current search engines, because of their bias for detection of the -10 motif. Here, we report a mutagenesis analysis of Pr that reveals strict sequence requirements for its activity that includes an essential -15 element and preservation of non-consensus bases within its -35 and -10 elements. We found that highly similar promoters control plasmid- and chromosomally- encoded phenol degradative systems in various Pseudomonads. However, using a purpose-designed promoter-search algorithm and activity analysis of potential candidate promoters, no bona fide Pr-like promoter could be found in the entire genome of P. putida KT2440. Hence, Pr-like σ(70)-promoters, which have the potential to be a widely distributed class of previously unrecognized promoters, are in fact highly restricted and remain in a class of their own.

    Fulltekst (pdf)
    fulltext
  • 15.
    Desvars, Amélie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Furberg, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Hjertqvist, Marika
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Epidemiology and Ecology of Tularemia in Sweden2015Inngår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, s. 58-58Artikkel i tidsskrift (Annet vitenskapelig)
  • 16.
    Desvars, Amélie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Furberg, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Hjertqvist, Marika
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Rydén, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Epidemiology and Ecology of Tularemia in Sweden, 1984-20122015Inngår i: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 21, nr 1, s. 32-39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The zoonotic disease tularemia is endemic in large areas of the Northern Hemisphere, but research is lacking on patterns of spatial distribution and connections with ecologic factors. To describe the spatial epidemiology of and identify ecologic risk factors for tularemia incidence in Sweden, we analyzed surveillance data collected over 29 years (1984-2012). A total of 4,830 cases were notified, of which 3,524 met all study inclusion criteria. From the first to the second half of the study period, mean incidence increased 10-fold, from 0.26/100,000 persons during 1984-1998 to 2.47/100,000 persons during 1999 2012 (p<0.001). The incidence of tularemia was higher than expected in the boreal and alpine ecologic regions (p<0.001), and incidence was positively correlated with the presence of lakes and rivers (p<0.001). These results provide a comprehensive epidemiologic description of tularemia in Sweden and illustrate that incidence is higher in locations near lakes and rivers.

    Fulltekst (pdf)
    fulltext
  • 17.
    Desvars-Larrive, Amélie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Liu, X.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hjertqvist, M.
    Sjöstedt, A.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Johansson, A.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    High-risk regions and outbreak modelling of tularemia in humans2017Inngår i: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 145, nr 3, s. 482-490Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sweden reports large and variable numbers of human tularemia cases, but the high-risk regions are anecdotally defined and factors explaining annual variations are poorly understood. Here, high-risk regions were identified by spatial cluster analysis on disease surveillance data for 1984-2012. Negative binomial regression with five previously validated predictors (including predicted mosquito abundance and predictors based on local weather data) was used to model the annual number of tularemia cases within the high-risk regions. Seven high-risk regions were identified with annual incidences of 3.8-44 cases/100 000 inhabitants, accounting for 56.4% of the tularemia cases but only 9.3% of Sweden's population. For all high-risk regions, most cases occurred between July and September. The regression models explained the annual variation of tularemia cases within most high-risk regions and discriminated between years with and without outbreaks. In conclusion, tularemia in Sweden is concentrated in a few high-risk regions and shows high annual and seasonal variations. We present reproducible methods for identifying tularemia high-risk regions and modelling tularemia cases within these regions. The results may help health authorities to target populations at risk and lay the foundation for developing an early warning system for outbreaks.

  • 18.
    Dracheva, Elena
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Norinder, Ulf
    Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Engelhardt, Josefin
    Department of Environmental Science, Stockholm University, Stockholm, Sweden.
    Weiss, Jana M.
    Department of Environmental Science, Stockholm University, Stockholm, Sweden.
    Andersson, Patrik L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    In Silico Identification of Potential Thyroid Hormone System Disruptors among Chemicals in Human Serum and Chemicals with a High Exposure Index2022Inngår i: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 56, nr 12, s. 8363-8372Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Data on toxic effects are at large missing the prevailing understanding of the risks of industrial chemicals. Thyroid hormone (TH) system disruption includes interferences of the life cycle of the thyroid hormones and may occur in various organs. In the current study, high-throughput screening data available for 14 putative molecular initiating events of adverse outcome pathways, related to disruption of the TH system, were used to develop 19 in silico models for identification of potential thyroid hormone system-disrupting chemicals. The conformal prediction framework with the underlying Random Forest was used as a wrapper for the models allowing for setting the desired confidence level and controlling the error rate of predictions. The trained models were then applied to two different databases: (i) an in-house database comprising xenobiotics identified in human blood and ii) currently used chemicals registered in the Swedish Product Register, which have been predicted to have a high exposure index to consumers. The application of these models showed that among currently used chemicals, fewer were overall predicted as active compared to chemicals identified in human blood. Chemicals of specific concern for TH disruption were identified from both databases based on their predicted activity.

    Fulltekst (pdf)
    fulltext
  • 19.
    Eneslätt, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Golovliov, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Vaccine-mediated mechanisms controlling replication of Francisella tularensis in human peripheral blood mononuclear cells using a co-culture system2018Inngår i: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, artikkel-id 27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cell-mediated immunity (CMI) is normally required for efficient protection against intracellular infections, however, identification of correlates is challenging and they are generally lacking. Francisella tularensis is a highly virulent, facultative intracellular bacterium and CMI is critically required for protection against the pathogen, but how this is effectuated in humans is poorly understood. To understand the protective mechanisms, we established an in vitro co-culture assay to identify how control of infection of F. tularensis is accomplished by human cells and hypothesized that the model will mimic in vivo immune mechanisms. Non-adherent peripheral blood mononuclear cells (PBMCs) were expanded with antigen and added to cultures with adherent PBMC infected with the human vaccine strain, LVS, or the highly virulent SCHU S4 strain. Intracellular numbers of F. tularensis was followed for 72 h and secreted and intracellular cytokines were analyzed. Addition of PBMC expanded from naïve individuals, i.e., those with no record of immunization to F. tularensis, generally resulted in little or no control of intracellular bacterial growth, whereas addition of PBMC from a majority of F. tularensis-immune individuals executed static and sometimes cidal effects on intracellular bacteria. Regardless of infecting strain, statistical differences between the two groups were significant, P < 0.05. Secretion of 11 cytokines was analyzed after 72 h of infection and significant differences with regard to secretion of IFN-γ, TNF, and MIP-1β was observed between immune and naïve individuals for LVS-infected cultures. Also, in LVS-infected cultures, CD4 T cells from vaccinees, but not CD8 T cells, showed significantly higher expression of IFN-γ, MIP-1β, TNF, and CD107a than cells from naïve individuals. The co-culture system appears to identify correlates of immunity that are relevant for the understanding of mechanisms of the protective host immunity to F. tularensis.

    Fulltekst (pdf)
    fulltext
  • 20.
    Eneslätt, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rietz, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    House, Robert V
    Wolfraim, Lawrence A
    Tärnvik, Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Persistence of cell-mediated immunity three decades after vaccination with the live vaccine strain of Francisella tularensis2011Inngår i: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, nr 4, s. 974-980Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The efficacy of many vaccines against intracellular bacteria depends on the generation of cell-mediated immunity, but studies to determine the duration of immunity are usually confounded by re-exposure. The causative agent of tularemia, Francisella tularensis, is rare in most areas and, therefore, tularemia vaccination is an interesting model for studies of the longevity of vaccine-induced cell-mediated immunity. Here, lymphocyte proliferation and cytokine production in response to F. tularensis were assayed in two groups of 16 individuals, vaccinated 1-3 or 27-34 years previously. As compared to naïve individuals, vaccinees of both groups showed higher proliferative responses and, out of 17 cytokines assayed, higher levels of MIP-1β, IFN-γ, IL-10, and IL-5 in response to recall stimulation. The responses were very similar in the two groups of vaccinees. A statistical model was developed to predict the immune status of the individuals and by use of two parameters, proliferative responses and levels of IFN-γ, 91.1% of the individuals were correctly classified. Using flow cytometry analysis, we demonstrated that during recall stimulation, expression of IFN-γ by CD4(+) CCR7(+) , CD4(+) CD62L(+) , CD8(+) CCR7(+) , and CD8(+) CD62L(+) cells significantly increased in samples from vaccinated donors. In conclusion, cell-mediated immunity was found to persist three decades after tularemia vaccination without evidence of decline.

  • 21.
    Evengård, Birgitta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Destouni, G.
    Department of Physical Geography, And Bolin Centre for Climate Research, Stockholm University, Stockholm, Sweden.
    Kalantari, Z.
    Department of Physical Geography, And Bolin Centre for Climate Research, Stockholm University, Stockholm, Sweden; Dept. of Sustainable Devmt., Environ. Sci. and Engineering, Sustainability Assessment and Management, KTH Royal Institute of Technology, Stockholm, Sweden.
    Albihn, A.
    Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute, Uppsala, Sweden.
    Björkman, C.
    Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Bylund, H.
    Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Jenkins, E.
    Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, SK, Saskatoon, Canada.
    Koch, A.
    Greenland Center for Health Research, Ilisimatusarfik-University of Greenland, Nuuk, Greenland; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
    Kukarenko, N.
    Department of Philosophy and Sociology, Northern Arctic Federal University, Arkhangelsk, Russian Federation.
    Leibovici, D.
    School of Mathematics and Statistics, University of Sheffield, Sheffield, United Kingdom.
    Lemmityinen, J.
    Finnish Meteorological Institute, Helsinki, Finland.
    Menshakova, M.
    Department of Natural Sciences, Murmansk Arctic State University, Murmansk, Russian Federation.
    Mulvad, G.
    Greenland Center for Health Research, Ilisimatusarfik-University of Greenland, Nuuk, Greenland.
    Nilsson, Lena Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för epidemiologi och global hälsa. Umeå universitet, Humanistiska fakulteten, Várdduo – Centrum för samisk forskning.
    Omazic, A.
    Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute, Uppsala, Sweden.
    Pshenichnaya, N.
    Central Research Institute of Epidemiology, Moscow, Russian Federation.
    Quegan, S.
    School of Mathematics and Statistics, University of Sheffield, Sheffield, United Kingdom.
    Rautio, A.
    Arctic Health, Faculty of Medicine, University of Oulu, Oulu, Finland; Thule Institute, University of the Arctic, Oulu, Finland.
    Revich, B.
    Institute of Economic Forecasting, Russian Academy of Science, Moscow, Russian Federation.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Tokarevich, N.
    Laboratory of Zoonoses, St Petersburg Pasteur Institute, St Petersburg, Russian Federation.
    Thierfelder, T.
    Department of Energy and Technology, Swedish University of Agricultural Sciences SLU, Uppsala, Sweden.
    Orlov, D.
    Faculty of Geography, Lomonosov Moscow State University, Moscow, Russian Federation.
    Healthy ecosystems for human and animal health: Science diplomacy for responsible development in the Arctic2021Inngår i: Polar Record, ISSN 0032-2474, E-ISSN 1475-3057, Vol. 57, artikkel-id e39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Climate warming is occurring most rapidly in the Arctic, which is both a sentinel and a driver of further global change. Ecosystems and human societies are already affected by warming. Permafrost thaws and species are on the move, bringing pathogens and vectors to virgin areas. During a five-year project, the CLINF - a Nordic Center of Excellence, funded by the Nordic Council of Ministers, has worked with the One Health concept, integrating environmental data with human and animal disease data in predictive models and creating maps of dynamic processes affecting the spread of infectious diseases. It is shown that tularemia outbreaks can be predicted even at a regional level with a manageable level of uncertainty. To decrease uncertainty, rapid development of new and harmonised technologies and databases is needed from currently highly heterogeneous data sources. A major source of uncertainty for the future of contaminants and infectious diseases in the Arctic, however, is associated with which paths the majority of the globe chooses to follow in the future. Diplomacy is one of the most powerful tools Arctic nations have to influence these choices of other nations, supported by Arctic science and One Health approaches that recognise the interconnection between people, animals, plants and their shared environment at the local, regional, national and global levels as essential for achieving a sustainable development for both the Arctic and the globe.

    Fulltekst (pdf)
    fulltext
  • 22.
    Fahlén, Jessica
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Freyhult, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Bylesjö, Max
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hvidsten, Torgeir
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bioinformatics strategies for cDNA-microarray data processing2009Inngår i: Batch effects and noise in microarray experiments: sources and solutions / [ed] Scherer, Andreas, Wiley and Sons , 2009, 1, , s. 272s. 61-74Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    

    Pre-processing plays a vital role in cDNA-microarray data analysis. Without proper pre-processing it is likely that the biological conclusions will be misleading. However, there are many alternatives and in order to choose a proper pre-processing procedure it is necessary to understand the effect of different methods. This chapter discusses several pre-processing steps, including image analysis, background correction, normalization, and filtering. Spike-in data are used to illustrate how different procedures affect the analytical ability to detect differentially expressed genes and estimate their regulation. The result shows that pre-processing has a major impact on both the experiment’s sensitivity andits bias. However, general recommendations are hard to give, since pre-processing consists of several actions that are highly dependent on each other. Furthermore, it is likely that pre-processing have a major impact on downstream analysis, such as clustering and classification, and pre-processing methods should be developed and evaluated with this in mind.

    Fulltekst (pdf)
    FULLTEXT01
  • 23.
    Fahlén, Jessica
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Rentoft, Matilda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    MicroRNA-microarray data analysis in the precence of FFPE storage time effects2010Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: The standard method for preserving patient samples for diagnostic purposes is fixation in formalin followed by embedding in paraffin (FFPE). The use of FFPE blocks makes it possible to include a large number of patients in the experimental studies since millions of FFPE blocks are stored around the world. However, FFPE storage can cause degradation and modifi­cations of nucleic acids. In order to draw reliable biological conclusions it is therefore important to know what effect FFPE-storage have on the tissues and to have procedures that normalize this effect. In this paper, we study the effect that FFPE-storage has on microRNA-microarray data from tongue-cancer patients and propose a novel procedure for normalizing the bias intro­duced by FFPE-storage.

    Results: MicroRNA-microarray data from 21 tongue-cancer patients and 8 control patients were used. The samples were stored in FFPE blocks and had been in storage for up to 11 years. The data contained a large amount of biological relevant variation, yet the largest variation was due to the samples storage times. The storage effect was shown to be significant and some results suggested that it may be causal. Moreover, the microRNAs were unequally affected by storage and this could partially be explained by sequence characteristics. The novel normaliza­tion procedure was shown to have a large impact in the analysis ability to identify differentially expressed microRNAs between young and old cancer patients as well as between cancer and control patients. The p-values for the top microRNAs candidates were much lower for the pro­posed novel normalization compared to a standard normalization procedure which suggested that the novel normalization made the analysis more efficient.

    Conclusions: MicroRNA-microarray data can be seriously affected by FFPE-storage and the introduced variation cannot be removed by standard normalizations. The proposed normaliza­tion removes the bias introduced by FFPE-storage and gives higher sensitivity than the standard normalization.

  • 24.
    Freyhult, Eva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Önskog, Jenny
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Hvidsten, Torgeir R.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Challenges in microarray class discovery: a comprehensive examination of normalization, gene selection and clustering2010Inngår i: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 11, artikkel-id 503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Cluster analysis, and in particular hierarchical clustering, is widely used to extract information from gene expression data. The aim is to discover new classes, or sub-classes, of either individuals or genes. Performing a cluster analysis commonly involve decisions on how to; handle missing values, standardize the data and select genes. In addition, pre processing, involving various types of filtration and normalization procedures, can have an effect on the ability to discover biologically relevant classes. Here we consider cluster analysis in a broad sense and perform a comprehensive evaluation that covers several aspects of cluster analyses, including normalization.

    Result: We evaluated 2780 cluster analysis methods on seven publicly available 2-channel microarray data sets with common reference designs. Each cluster analysis method differed in data normalization (5 normalizations were considered), missing value imputation (2), standardization of data (2), gene selection (19) or clustering method (11). The cluster analyses are evaluated using known classes, such as cancer types, and the adjusted Rand index. The performances of the different analyses vary between the data sets and it is difficult to give general recommendations. However, normalization, gene selection and clustering method are all variables that have a significant impact on the performance. In particular, gene selection is important and it is generally necessary to include a relatively large number of genes in order to get good performance. Selecting genes with high standard deviation or using principal component analysis are shown to be the preferred gene selection methods. Hierarchical clustering using Ward's method, k-means clustering and Mclust are the clustering methods considered in this paper that achieves the highest adjusted Rand. Normalization can have a significant positive impact on the ability to cluster individuals, and there are indications that background correction is preferable, in particular if the gene selection is successful. However, this is an area that needs to be studied further in order to draw any general conclusions.

    Conclusions: The choice of cluster analysis, and in particular gene selection, has a large impact on the ability to cluster individuals correctly based on expression profiles. Normalization has a positive effect, but the relative performance of different normalizations is an area that needs more research. In summary, although clustering, gene selection and normalization are considered standard methods in bioinformatics, our comprehensive analysis shows that selecting the right methods, and the right combinations of methods, is far from trivial and that much is still unexplored in what is considered to be the most basic analysis of genomic data.

    Fulltekst (pdf)
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  • 25.
    Fries, Niklas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    A comparison of local explanation methods for high-dimensional industrial data: a simulation study2022Inngår i: Expert systems with applications, ISSN 0957-4174, E-ISSN 1873-6793, Vol. 207, artikkel-id 117918Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prediction methods can be augmented by local explanation methods (LEMs) to perform root cause analysis for individual observations. But while most recent research on LEMs focus on low-dimensional problems, real-world datasets commonly have hundreds or thousands of variables. Here, we investigate how LEMs perform for high-dimensional industrial applications. Seven prediction methods (penalized logistic regression, LASSO, gradient boosting, random forest and support vector machines) and three LEMs (TreeExplainer, Kernel SHAP, and the conditional normal sampling importance (CNSI)) were combined into twelve explanation approaches. These approaches were used to compute explanations for simulated data, and real-world industrial data with simulated responses. The approaches were ranked by how well they predicted the contributions according to the true models. For the simulation experiment, the generalized linear methods provided best explanations, while gradient boosting with either TreeExplainer or CNSI, or random forest with CNSI were robust for all relationships. For the real-world experiment, TreeExplainer performed similarly, while the explanations from CNSI were significantly worse. The generalized linear models were fastest, followed by TreeExplainer, while CNSI and Kernel SHAP required several orders of magnitude more computation time. In conclusion, local explanations can be computed for high-dimensional data, but the choice of statistical tools is crucial.

    Fulltekst (pdf)
    fulltext
  • 26.
    Fries, Niklas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    A simulation framework for evaluating statistical methods for quality control in manufacturingManuskript (preprint) (Annet vitenskapelig)
  • 27.
    Fries, Niklas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Concordance and resampling for assessing the robustness of local explanation methodsManuskript (preprint) (Annet vitenskapelig)
  • 28.
    Fries, Niklas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Data-driven process adjustment policies for quality improvement2024Inngår i: Expert systems with applications, ISSN 0957-4174, E-ISSN 1873-6793, Vol. 237, artikkel-id 121524Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Common objectives in machine learning research are to predict the output quality of manufacturing processes, to perform root cause analysis in case of reduced quality, and to propose intervention strategies. The cost of reduced quality must be weighed against the cost of the interventions, which depend on required downtime, personnel costs, and material costs. Furthermore, there is a risk of false negatives, i.e., failure to identify the true root causes, or false positives, i.e., adjustments that further reduce the quality. A policy for process adjustments describes when and where to perform interventions, and we say that a policy is worthwhile if it reduces the expected operational cost. In this paper, we describe a data-driven alarm and root cause analysis framework, that given a predictive and explanatory model trained on high-dimensional process and quality data, can be used to search for a worthwhile adjustment policy. The framework was evaluated on large-scale simulated process and quality data. We find that worthwhile adjustment policies can be derived also for problems with a large number of explanatory variables. Interestingly, the performance of the adjustment policies is almost exclusively driven by the quality of the model fits. Based on these results, we discuss key areas of future research, and how worthwhile adjustment policies can be implemented in real world applications.

    Fulltekst (pdf)
    fulltext
  • 29. Griffin, Robert M.
    et al.
    Dean, Rebecca
    Grace, Jaime L.
    Ryden, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Friberg, Urban
    The Shared Genome Is a Pervasive Constraint on the Evolution of Sex-Biased Gene Expression2013Inngår i: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 30, nr 9, s. 2168-2176Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Males and females share most of their genomes, and differences between the sexes can therefore not evolve through sequence divergence in protein coding genes. Sexual dimorphism is instead restricted to occur through sex-specific expression and splicing of gene products. Evolution of sexual dimorphism through these mechanisms should, however, also be constrained when the sexes share the genetic architecture for regulation of gene expression. Despite these obstacles, sexual dimorphism is prevalent in the animal kingdom and commonly evolves rapidly. Here, we ask whether the genetic architecture of gene expression is plastic and easily molded by sex-specific selection, or if sexual dimorphism evolves rapidly despite pervasive genetic constraint. To address this question, we explore the relationship between the intersexual genetic correlation for gene expression (r(MF)), which captures how independently genes are regulated in the sexes, and the evolution of sex-biased gene expression. Using transcriptome data from Drosophila melanogaster, we find that most genes have a high r(MF) and that genes currently exposed to sexually antagonistic selection have a higher average r(MF) than other genes. We further show that genes with a high r(MF) have less pronounced sex-biased gene expression than genes with a low r(MF) within D. melanogaster and that the strength of the r(MF) in D. melanogaster predicts the degree to which the sex bias of a gene's expression has changed between D. melanogaster and six other species in the Drosophila genus. In sum, our results show that a shared genome constrains both short- and long-term evolution of sexual dimorphism.

  • 30.
    Jonsson, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Byström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sandgren, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 4, s. 463-473Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 31.
    Kellgren, Therese
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Dwibedi, Chinmay Kumar
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Widerström, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Monsen, Tor J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    The emergence of an antimicrobial resistant Staphylococcus epidermidis clone in Northern EuropeManuskript (preprint) (Annet vitenskapelig)
  • 32.
    Kellgren, Therese
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Dwibedi, Chinmay Kumar
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Widerström, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sundell, David
    Division of CBRN Defence and Security, Swedish Defense Research Agency, SE, Umeå, Sweden.
    Öhrman, Caroline
    Division of CBRN Defence and Security, Swedish Defense Research Agency, SE, Umeå, Sweden.
    Sjödin, Andreas
    Division of CBRN Defence and Security, Swedish Defense Research Agency, SE, Umeå, Sweden.
    Monsen, Tor J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Completed genome and emergence scenario of the multidrug-resistant nosocomial pathogen Staphylococcus epidermidis ST2152024Inngår i: BMC Microbiology, E-ISSN 1471-2180, Vol. 24, nr 1, artikkel-id 215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: A multidrug-resistant lineage of Staphylococcus epidermidis named ST215 is a common cause of prosthetic joint infections and other deep surgical site infections in Northern Europe, but is not present elsewhere. The increasing resistance among S. epidermidis strains is a global concern. We used whole-genome sequencing to characterize ST215 from healthcare settings.

    Results: We completed the genome of a ST215 isolate from a Swedish hospital using short and long reads, resulting in a circular 2,676,787 bp chromosome and a 2,326 bp plasmid. The new ST215 genome was placed in phylogenetic context using 1,361 finished public S. epidermidis reference genomes. We generated 10 additional short-read ST215 genomes and 11 short-read genomes of ST2, which is another common multidrug-resistant lineage at the same hospital. We studied recombination’s role in the evolution of ST2 and ST215, and found multiple recombination events averaging 30–50 kb. By comparing the results of antimicrobial susceptibility testing for 31 antimicrobial drugs with the genome content encoding antimicrobial resistance in the ST215 and ST2 isolates, we found highly similar resistance traits between the isolates, with 22 resistance genes being shared between all the ST215 and ST2 genomes. The ST215 genome contained 29 genes that were historically identified as virulence genes of S. epidermidis ST2. We established that in the nucleotide sequence stretches identified as recombination events, virulence genes were overrepresented in ST215, while antibiotic resistance genes were overrepresented in ST2.

    Conclusions: This study features the extensive antibiotic resistance and virulence gene content in ST215 genomes. ST215 and ST2 lineages have similarly evolved, acquiring resistance and virulence through genomic recombination. The results highlight the threat of new multidrug-resistant S. epidermidis lineages emerging in healthcare settings.

    Fulltekst (pdf)
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  • 33.
    Kellgren, Therese
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Experimental designs for finding disease-causing mutations in rare diseasesManuskript (preprint) (Annet vitenskapelig)
  • 34. Kheir, Sahar M.
    et al.
    Kafi, Shamsoun K.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Elbir, Haitham
    Soliman, Mohammed A.
    Ali, Shima
    Abulikailik, Ramy
    Ahamed, Khadega
    Abu-Aisha, Hasan
    Results of application of the ISPD guidelines to the management of peritoneal dialysis in a single center in Sudan2017Inngår i: Journal of Infection and Public Health, ISSN 1876-0341, E-ISSN 1876-035X, Vol. 10, nr 3, s. 348-352Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The culture negative peritonitis in Sudan 2010 was 46% exceeding 20% of the recommended ISPD (International Society for Peritoneal Dialysis) guidelines. This study reports an update after applying the standard ISPD protocol. The routine method was replaced by ISPD protocol. The culture negative rate using the ISPD guidelines dropped from 46% in the year 2010, to 39% in the year 2011, to 5% in the 2012 and to zero percent in the year 2013. Bacterial and fungal species represent (86.76%) and (13.23%) of infection and most isolates showed low resistance rate to antibiotics. Touch contamination added significantly (p = 0.0006) to the risk of contracting Peritonitis. The risk of contracting Peritonitis was 1.53 times higher in the group exposed by touch contamination. None of the other risk factors contributed significantly to Peritonitis. The study highlights the importance of implementing high hygiene practice. (C) 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Limited. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  • 35. Kurtz, Sherry L.
    et al.
    Gardina, Paul J.
    Myers, Timothy G.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Elkins, Karen L.
    Whole genome profiling refines a panel of correlates to predict vaccine efficacy against Mycobacterium tuberculosis2020Inngår i: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 120, artikkel-id 101895Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    New vaccines are needed to combat the public health threat posed by M. tuberculosis (M. tb), but no correlates have been defined to aid vaccine development. Using mouse models, we previously developed an in vitro system that measures the ability of M. tb-immune lymphocytes to control bacterial replication during co-culture with M. tb-infected macrophages. We demonstrated that the degree of in vitro growth control by lymphocytes from mice given vaccines of varying efficacy reflected the relative degree of in vivo protection against lethal challenge. Further, using targeted analyses of gene expression in lymphocytes recovered from co-cultures, we found mediators whose relative expression also correlated with in vitro and in vivo outcomes. Here we advanced those findings by employing genome-wide expression analyses. We first screened splenocytes recovered from co-cultures by microarray, revealing additional genes whose expression correlated with protection. After applying pathway analyses to down-select gene candidates, we used both splenocytes and peripheral blood lymphocytes to validate microarray findings by qRT-PCR. We then subjected data from top candidates to rigorous statistical analyses. Resulting correlate candidates, including CXCL9, IFN-γ, and CCL5, significantly predicted protection with high specificity. These findings therefore refine and extend a panel of relevant immune correlates to advance vaccine development.

  • 36.
    Kurtz, Sherry L.
    et al.
    Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Elkins, Karen L.
    Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
    Transcriptional signatures measured in whole blood correlate with protection against tuberculosis in inbred and outbred mice2023Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 18, nr 8, artikkel-id e0289358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although BCG has been used for almost 100 years to immunize against Mycobacterium tuberculosis, TB remains a global public health threat. Numerous clinical trials are underway studying novel vaccine candidates and strategies to improve or replace BCG, but vaccine development still lacks a well-defined set of immune correlates to predict vaccine-induced protection against tuberculosis. This study aimed to address this gap by examining transcriptional responses to BCG vaccination in C57BL/6 inbred mice, coupled with protection studies using Diversity Outbred mice. We evaluated relative gene expression in blood obtained from vaccinated mice, because blood is easily accessible, and data can be translated to human studies. We first determined that the average peak time after vaccination is 14 days for gene expression of a small subset of immune-related genes in inbred mice. We then performed global transcriptomic analyses using whole blood samples obtained two weeks after mice were vaccinated with BCG. Using comparative bioinformatic analyses and qRT-PCR validation, we developed a working correlate panel of 18 genes that were highly correlated with administration of BCG but not heat-killed BCG. We then tested this gene panel using BCG-vaccinated Diversity Outbred mice and revealed associations between the expression of a subset of genes and disease outcomes after aerosol challenge with M. tuberculosis. These data therefore demonstrate that blood-based transcriptional immune correlates measured within a few weeks after vaccination can be derived to predict protection against M. tuberculosis, even in outbred populations.

    Fulltekst (pdf)
    fulltext
  • 37.
    Källberg, David
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Belyaev, Yuri
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    A moment-distance hybrid method for estimating a mixture of two symmetric densities2018Inngår i: Modern Stochastics: Theory and Applications, ISSN 2351-6054, Vol. 5, nr 1, s. 1-36Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In clustering of high-dimensional data a variable selection is commonly applied to obtain an accurate grouping of the samples. For two-class problems this selection may be carried out by fitting a mixture distribution to each variable. We propose a hybrid method for estimating a parametric mixture of two symmetric densities. The estimator combines the method of moments with the minimum distance approach. An evaluation study including both extensive simulations and gene expression data from acute leukemia patients shows that the hybrid method outperforms a maximum-likelihood estimator in model-based clustering. The hybrid estimator is flexible and performs well also under imprecise model assumptions, suggesting that it is robust and suited for real problems.

    Fulltekst (pdf)
    fulltext
  • 38.
    Källberg, David
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Comparison of Methods for Feature Selection in Clustering of High-Dimensional RNA-Sequencing Data to Identify Cancer Subtypes2021Inngår i: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 12, artikkel-id 632620Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer subtype identification is important to facilitate cancer diagnosis and select effective treatments. Clustering of cancer patients based on high-dimensional RNA-sequencing data can be used to detect novel subtypes, but only a subset of the features (e.g., genes) contains information related to the cancer subtype. Therefore, it is reasonable to assume that the clustering should be based on a set of carefully selected features rather than all features. Several feature selection methods have been proposed, but how and when to use these methods are still poorly understood. Thirteen feature selection methods were evaluated on four human cancer data sets, all with known subtypes (gold standards), which were only used for evaluation. The methods were characterized by considering mean expression and standard deviation (SD) of the selected genes, the overlap with other methods and their clustering performance, obtained comparing the clustering result with the gold standard using the adjusted Rand index (ARI). The results were compared to a supervised approach as a positive control and two negative controls in which either a random selection of genes or all genes were included. For all data sets, the best feature selection approach outperformed the negative control and for two data sets the gain was substantial with ARI increasing from (−0.01, 0.39) to (0.66, 0.72), respectively. No feature selection method completely outperformed the others but using the dip-rest statistic to select 1000 genes was overall a good choice. The commonly used approach, where genes with the highest SDs are selected, did not perform well in our study.

  • 39.
    Källberg, David
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Comparison of methods for variable selection in clustering of high-dimensional RNA-sequencing data to identify cancer subtypesManuskript (preprint) (Annet vitenskapelig)
  • 40.
    Landfors, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Fahlén, Jessica
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Rydén, Patrik
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    MC-normalization: a novel method for dye-normalization of two-channel microarray data2009Inngår i: Statistical Applications in Genetics and Molecular Biology, ISSN 1544-6115, E-ISSN 1544-6115, Vol. 8, nr 1, s. 42-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Motivation: Pre-processing plays a vital role in two-color microarray data analysis. An analysis is characterized by its ability to identify differentially expressed genes (its sensitivity) and its ability to provide unbiased estimators of the true regulation (its bias). It has been shown that microarray experiments regularly underestimate the true regulation of differentially expressed genes. We introduce the MC-normalization, where C stands for channel-wise normalization, with considerably lower bias than the commonly used standard methods.

    Methods: The idea behind the MC-normalization is that the channels’ individual intensities determine the correction, rather than the average intensity which is the case for the widely used MA-normalization. The two methods were evaluated using spike-in data from an in-house produced cDNA-experiment and a public available Agilent-experiment. The methods were applied on background corrected and non-background corrected data. For the cDNA-experiment the methods were either applied separately on data from each of the print-tips or applied on the complete array data. Altogether 24 analyses were evaluated. For each analysis the sensitivity, the bias and two variance measures were estimated.

    Results: We prove that the MC-normalization has lower bias than the MA-normalization. The spike-in data confirmed the theoretical result and suggest that the difference is significant. Furthermore, the empirical data suggest that the MC-and MA-normalization have similar sensitivity. A striking result is that print-tip normalizations did have considerably higher sensitivity than analyses using the complete array data.

  • 41.
    Landfors, Mattias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Philip, Philge
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Stenberg, Per
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Normalization of high dimensional genomics data where the distribution of the altered variables is skewed2011Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 6, nr 11, s. e27942-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide analysis of gene expression or protein binding patterns using different array or sequencing based technologies is now routinely performed to compare different populations, such as treatment and reference groups. It is often necessary to normalize the data obtained to remove technical variation introduced in the course of conducting experimental work, but standard normalization techniques are not capable of eliminating technical bias in cases where the distribution of the truly altered variables is skewed, i.e. when a large fraction of the variables are either positively or negatively affected by the treatment. However, several experiments are likely to generate such skewed distributions, including ChIP-chip experiments for the study of chromatin, gene expression experiments for the study of apoptosis, and SNP-studies of copy number variation in normal and tumour tissues. A preliminary study using spike-in array data established that the capacity of an experiment to identify altered variables and generate unbiased estimates of the fold change decreases as the fraction of altered variables and the skewness increases. We propose the following work-flow for analyzing high-dimensional experiments with regions of altered variables: (1) Pre-process raw data using one of the standard normalization techniques. (2) Investigate if the distribution of the altered variables is skewed. (3) If the distribution is not believed to be skewed, no additional normalization is needed. Otherwise, re-normalize the data using a novel HMM-assisted normalization procedure. (4) Perform downstream analysis. Here, ChIP-chip data and simulated data were used to evaluate the performance of the work-flow. It was found that skewed distributions can be detected by using the novel DSE-test (Detection of Skewed Experiments). Furthermore, applying the HMM-assisted normalization to experiments where the distribution of the truly altered variables is skewed results in considerably higher sensitivity and lower bias than can be attained using standard and invariant normalization methods.

    Fulltekst (pdf)
    fulltext
  • 42.
    Larsson, Miriam
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Uvell, Hanna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sandström, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Selth, Luke A.
    Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Functional studies of the yeast Med5, Med15 and Med16 mediator tail subunits2013Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 8, artikkel-id e73137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature-sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when Med5/15 or Med15/16 are inactivated together. We identify 25 genes in each double mutant that show a significant change in expression when compared to the corresponding single mutants and to the wild type strain. Importantly, 13 of the 25 identified genes are common for both double mutants. We also find that all strains in which MED15 is inactivated show down-regulation of genes that have been identified as targets for the Ace2 transcriptional activator protein, which is important for progression through the G1 phase of the cell cycle. Supporting this observation, we demonstrate that loss of Med15 leads to a G1 arrest phenotype. Collectively, these findings provide insight into the function of the Mediator Tail module.

    Fulltekst (pdf)
    fulltext
  • 43.
    Law, Simon R
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Björk, Rafael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keech, Olivier
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Centralization Within Sub-Experiments Enhances the Biological Relevance of Gene Co-expression Networks: A Plant Mitochondrial Case Study2020Inngår i: Frontiers in Plant Science, E-ISSN 1664-462X, Vol. 11, artikkel-id 524Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gene co-expression networks (GCNs) can be prepared using a variety of mathematical approaches based on data sampled across diverse developmental processes, tissue types, pathologies, mutant backgrounds, and stress conditions. These networks are used to identify genes with similar expression dynamics but are prone to introducing false-positive and false-negative relationships, especially in the instance of large and heterogenous datasets. With the aim of optimizing the relevance of edges in GCNs and enhancing global biological insight, we propose a novel approach that involves a data-centering step performed simultaneously per gene and per sub-experiment, called centralization within sub-experiments (CSE). Using a gene set encoding the plant mitochondrial proteome as a case study, our results show that all CSE-based GCNs assessed had significantly more edges within the majority of the considered functional sub-networks, such as the mitochondrial electron transport chain and its complexes, than GCNs not using CSE; thus demonstrating that CSE-based GCNs are efficient at predicting canonical functions and associated pathways, here referred to as the core gene network. Furthermore, we show that correlation analyses using CSE-processed data can be used to fine-tune prediction of the function of uncharacterized genes; while its use in combination with analyses based on non-CSE data can augment conventional stress analyses with the innate connections underpinning the dynamic system being examined. Therefore, CSE is an effective alternative method to conventional batch correction approaches, particularly when dealing with large and heterogenous datasets. The method is easy to implement into a pre-existing GCN analysis pipeline and can provide enhanced biological relevance to conventional GCNs by allowing users to delineate a core gene network. Author Summary Gene co-expression networks (GCNs) are the product of a variety of mathematical approaches that identify causal relationships in gene expression dynamics but are prone to the misdiagnoses of false-positives and false-negatives, especially in the instance of large and heterogenous datasets. In light of the burgeoning output of next-generation sequencing projects performed on a variety of species, and developmental or clinical conditions; the statistical power and complexity of these networks will undoubtedly increase, while their biological relevance will be fiercely challenged. Here, we propose a novel approach to generate a "core" GCN with enhanced biological relevance. Our method involves a data-centering step that effectively removes all primary treatment/tissue effects, which is simple to employ and can be easily implemented into pre-existing GCN analysis pipelines. The gain in biological relevance resulting from the adoption of this approach was assessed using a plant mitochondrial case study.

    Fulltekst (pdf)
    fulltext
  • 44.
    Lindgren, Helena
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Eneslätt, Kjell
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Golovliov, Igor
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Gelhaus, Carl
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Wu, Terry
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Vaccine-Mediated Mechanisms Controlling Francisella tularensis SCHU S4 Growth in a Rat Co-Culture System2020Inngår i: Pathogens, E-ISSN 2076-0817, Vol. 9, nr 5, artikkel-id 338Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Francisella tularensis causes the severe disease tularemia. In the present study, the aim was to identify correlates of protection in the rat co-culture model by investigating the immune responses using two vaccine candidates conferring distinct degrees of protection in rat and mouse models. The immune responses were characterized by use of splenocytes from naive or Live vaccine strain- (LVS) or clpB/wbtC-immunized Fischer 344 rats as effectors and bone marrow-derived macrophages infected with the highly virulent strain SCHU S4. A complex immune response was elicited, resulting in cytokine secretion, nitric oxide production, and efficient control of the intracellular bacterial growth. Addition of LVS-immune splenocytes elicited a significantly better control of bacterial growth than clpB/wbtC splenocytes. This mirrored the efficacy of the vaccine candidates in the rat model. Lower levels of IFN-gamma, TNF, fractalkine, IL-2, and nitrite were present in the co-cultures with clpB/wbtC splenocytes than in those with splenocytes from LVS-immunized rats. Nitric oxide was found to be a correlate of protection, since the levels inversely correlated to the degree of protection and inhibition of nitric oxide production completely reversed the growth inhibition of SCHU S4. Overall, the results demonstrate that the co-culture assay with rat-derived cells is a suitable model to identify correlates of protection against highly virulent strains of F. tularensis

    Fulltekst (pdf)
    fulltext
  • 45.
    Monsen, Tor
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå university hospital.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    A new concept and a comprehensive evaluation of SYSMEX UF-1000i flow cytometer to identify culture-negative urine specimens in patients with UTI2017Inngår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 36, nr 9, s. 1691-1703Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Urinary tract infections (UTIs) are among the most common bacterial infections in men and urine culture is gold standard for diagnosis. Considering the high prevalence of culture-negative specimens, any method that identifies such specimens is of interest. The aim was to evaluate a new screening concept for flow cytometry analysis (FCA). The outcomes were evaluated against urine culture, uropathogen species and three conventional screening methods. A prospective, consecutive study examined 1,312 urine specimens, collected during January and February 2012. The specimens were analyzed using the Sysmex UF1000i FCA. Based on the FCA data culture negative specimens were identified in a new model by use of linear discriminant analysis (FCA-LDA). In total 1,312 patients were included. In- and outpatients represented 19.6% and 79.4%, respectively; 68.3% of the specimens originated from women. Of the 610 culture-positive specimens, Escherichia coli represented 64%, enterococci 8% and Klebsiella spp. 7%. Screening with FCA-LDA at 95% sensitivity identified 42% (552/1312) as culture negative specimens when UTI was defined according to European guidelines. The proposed screening method was either superior or similar in comparison to the three conventional screening methods. In conclusion, the proposed/suggested and new FCA-LDA screening method was superior or similar to three conventional screening methods. We recommend the proposed screening method to be used in clinic to exclude culture negative specimens, to reduce workload, costs and the turnaround time. In addition, the FCA data may add information that enhance handling and support diagnosis of patients with suspected UTI pending urine culture.

    Fulltekst (pdf)
    fulltext
  • 46.
    Monsen, Tor
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Flow Cytometry Analysis Using Sysmex UF-1000i Classifies Uropathogens Based on Bacterial, Leukocyte, and Erythrocyte Counts in Urine Specimens among Patients with Urinary Tract Infections2015Inngår i: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, nr 2, s. 539-545Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Urinary tract infections (UTIs) are the second most common bacterial infection. Urine culture is the gold standard for diagnosis, but new techniques, such as flow cytometry analysis (FCA), have been introduced. The aim of the present study was to evaluate FCA characteristics regarding bacteriuria, leukocyturia, and erythrocyturia in relation to cultured uropathogens in specimens from patients with a suspected UTI. We also wanted to evaluate whether the FCA characteristics can identify uropathogens prior to culture. From a prospective study, 1,587 consecutive urine specimens underwent FCA prior to culture during January and February 2012. Outpatients and inpatients (79.6% and 19.4%, respectively) were included, of whom women represented 67.5%. In total, 620 specimens yielded growth, of which Escherichia coli represented 65%, Enterococcus spp.8%, Klebsiella spp. 7%, and Staphylococcus spp. 5%. For the uropathogens, the outcome of FCA was compared against the results for specimens with E. coli and those with a negative culture. E. coli had high bacterial (median, 17,914/mu l), leukocyte (median, 348/mu l), and erythrocyte (median, 23/mu l) counts. With the exception of Klebsiella spp., the majority of the uropathogens had considerable or significantly lower bacterial counts than that of E. coli. High leukocyte counts were found in specimens with Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and group C streptococci. Elevated erythrocyte counts were found for P. vulgaris, P. aeruginosa, and group C streptococci, as well as for Staphylococcus saprophyticus. In essence, FCA adds new information about the bacterial, leukocyte, and erythrocyte counts in urine specimens for different uropathogens. Based on FCA characteristics, uropathogens can be classified and identified prior to culture. E. coli and Klebsiella spp. have similar FCA characteristics.

  • 47.
    Rentoft, Matilda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Fahlén, Jessica
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Coates, PJ
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Sjöström, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    miRNA analysis of formalin-fixed squamous cell carcinomas of the tongue is affected by age of the samples2011Inngår i: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 38, nr 1, s. 61-69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Global miRNA expression arrays were used for analysis of 836 miRNAs in formalin-fixed paraffin-embedded samples from 21 tongue cancer patients and 8 controls. Samples had been stored for one to eleven years. Results separated tumour samples from controls, however, the largest variation was correlated to sample storage time, detectable already after one year. With the use of a linear regression model we could adjust for the storage-dependent effect, leading to the identification of 54 differentially expressed miRNAs in tongue cancer, compared to 16 when using standard normalization, including up-regulation of a novel miRNA, miR-424.

  • 48.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Matematisk statistik.
    Estimation of the reliability of systems described by the Daniels Load-Sharing Model1999Licentiatavhandling, monografi (Annet vitenskapelig)
    Abstract [en]

    We consider the problem of estimating the failure stresses of bundles (i.e. the tensile forces that destroy the bundles), constructed of several statisti-cally similar fibres, given a particular kind of censored data. Each bundle consists of several fibres which have their own independent identically dis-tributed failure stresses, and where the force applied on a bundle at any moment is distributed equally between the unbroken fibres in the bundle. A bundle with these properties is an example of an equal load-sharing sys-tem, often referred to as the Daniels failure model. The testing of several bundles generates a special kind of censored data, which is complexly struc-tured. Strongly consistent non-parametric estimators of the distribution laws of bundles are obtained by applying the theory of martingales, and by using the observed data. It is proved that random sampling, with replace-ment from the statistical data related to each tested bundle, can be used to obtain asymptotically correct estimators for the distribution functions of deviations of non-parametric estimators from true values. In the case when the failure stresses of the fibres are described by a Weibull distribution, we obtain strongly consistent parametric maximum likelihood estimators of the distribution functions of failure stresses of bundles, by using the complexly structured data. Numerical examples illustrate the behavior of the obtained estimators.

    Fulltekst (pdf)
    fulltext
  • 49.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Matematisk statistik.
    Statistical analysis and simulation methods related to load-sharing models.2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    We consider the problem of estimating the reliability of bundles constructed of several fibres, given a particular kind of censored data. The bundles consist of several fibres which have their own independent identically dis-tributed failure stresses (i.e.the forces that destroy the fibres). The force applied to a bundle is distributed between the fibres in the bundle, accord-ing to a load-sharing model. A bundle with these properties is an example of a load-sharing system. Ropes constructed of twisted threads, compos-ite materials constructed of parallel carbon fibres, and suspension cables constructed of steel wires are all examples of load-sharing systems. In par-ticular, we consider bundles where load-sharing is described by either the Equal load-sharing model or the more general Local load-sharing model.

    In order to estimate the cumulative distribution function of failure stresses of bundles, we need some observed data. This data is obtained either by testing bundles or by testing individual fibres. In this thesis, we develop several theoretical testing methods for both fibres and bundles, and related methods of statistical inference.

    Non-parametric and parametric estimators of the cumulative distribu-tion functions of failure stresses of fibres and bundles are obtained from different kinds of observed data. It is proved that most of these estimators are consistent, and that some are strongly consistent estimators. We show that resampling, in this case random sampling with replacement from sta-tistically independent portions of data, can be used to assess the accuracy of these estimators. Several numerical examples illustrate the behavior of the obtained estimators. These examples suggest that the obtained estimators usually perform well when the number of observations is moderate.

    Fulltekst (pdf)
    fulltext
  • 50.
    Rydén, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Björk, Rafael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Schäfer, Martina L
    Lundström, Jan O
    Petersén, Bodil
    Lindblom, Anders
    Forsman, Mats
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence2012Inngår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 205, nr 2, s. 297-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data.

    Methods. A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden.

    Results. Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks.

    Conclusions. This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.

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