| 1. |
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| 2. |
- Andersson-Evelönn, Emma, 1983-, et al.
(författare)
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Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma
- 2020
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Bayisa, Fekadu L., et al.
(författare)
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Computed Tomography Image Estimation by Statistical Learning Methods
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There is increasing interest in computed tomography (CT) image estimations from magnetic resonance (MR) images. The estimated CT images canbe utilised for attenuation correction, patient positioning, and dose planningin diagnostic and radiotherapy workflows. This study presents a statisticallearning method for CT image estimation. We have used predefined tissuetype information in a Gaussian mixture model to explore the estimation.The performance of our method was evaluated using cross-validation on realdata. In comparison with the existing model-based CT image estimationmethods, the proposed method has improved the estimation, particularly inbone tissues. Evaluation of our method shows that it is a promising methodto generate CT image substitutes for the implementation of fully MR-basedradiotherapy and PET/MRI applications.
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| 4. |
- Bayisa, Fekadu, et al.
(författare)
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Statistical learning in computed tomography image estimation
- 2018
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Ingår i: Medical physics (Lancaster). - : John Wiley & Sons. - 0094-2405 .- 2473-4209. ; 45:12, s. 5450-5460
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: There is increasing interest in computed tomography (CT) image estimations from magneticresonance (MR) images. The estimated CT images can be utilized for attenuation correction, patientpositioning, and dose planning in diagnostic and radiotherapy workflows. This study aims to introducea novel statistical learning approach for improving CT estimation from MR images and to compare theperformance of our method with the existing model-based CT image estimation methods.Methods: The statistical learning approach proposed here consists of two stages. At the trainingstage, prior knowledge about tissue types from CT images was used together with a Gaussian mixturemodel (GMM) to explore CT image estimations from MR images. Since the prior knowledge is notavailable at the prediction stage, a classifier based on RUSBoost algorithm was trained to estimatethe tissue types from MR images. For a new patient, the trained classifier and GMMs were used topredict CT image from MR images. The classifier and GMMs were validated by using voxel-leveltenfold cross-validation and patient-level leave-one-out cross-validation, respectively.Results: The proposed approach has outperformance in CT estimation quality in comparison withthe existing model-based methods, especially on bone tissues. Our method improved CT image estimationby 5% and 23% on the whole brain and bone tissues, respectively.Conclusions: Evaluation of our method shows that it is a promising method to generate CTimage substitutes for the implementation of fully MR-based radiotherapy and PET/MRI applications
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| 5. |
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| 6. |
- Estévez-Silva, Héctor M., et al.
(författare)
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Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis
- 2022
-
Ingår i: European Journal of Neuroscience. - : John Wiley & Sons. - 0953-816X .- 1460-9568. ; 55:5, s. 1356-1372
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.
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| 7. |
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| 8. |
- Harbs, Justin, et al.
(författare)
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An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples
- 2023
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Ingår i: Epigenetics. - : Taylor & Francis Group. - 1559-2294 .- 1559-2308. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Endogenous sex hormones and DNA methylation both play important roles in various diseases. However, their interplay is largely unknown. A deeper understanding of their interrelationships could provide new insights into the pathology of disease development. We, therefore, investigated associations between circulating sex hormones, sex hormone binding globulin (SHBG), and DNA methylation in blood, using samples from 77 men (65 with repeated samples), from the population-based Northern Sweden Health and Disease Study (NSHDS). DNA methylation was measured in buffy coat using the Infinium Methylation EPIC BeadChip (Illumina). Sex hormone (oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) and SHBG concentrations were measured in plasma using a high-performance liquid chromatography tandem mass spectrometry (LC/MS-MS) method and an enzyme-linked immunoassay, respectively. Associations between sex hormones, SHBG, and DNA methylation were estimated using both linear regression and mixed-effects models. Additionally, we used the comb-p method to identify differentially methylated regions based on nearby P values. We identified one novel CpG site (cg14319657), at which DNA methylation was associated with dehydroepiandrosterone, surpassing a genome-wide significance level. In addition, more than 40 differentially methylated regions were associated with levels of sex hormones and SHBG and several of these mapped to genes involved in hormone-related diseases. Our findings support a relationship between circulating sex hormones and DNA methylation and suggest that further investigation is warranted, both for validation, further exploration and to gain a deeper understanding of the mechanisms and potential consequences for health and disease.
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| 9. |
- Harbs, Justin, 1994-
(författare)
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Circulating markers of risk and etiology in colorectal cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Colorectal cancer is the third most commonly diagnosed cancer in men and women. Worldwide around 2 million individuals are diagnosed each year – a number expected to increase as colorectal cancer risk factors become more prevalent. In men and women there is a difference in incidence, which possibly could be explained by inherent differences, including sex hormone profiles. The prognosis of colorectal cancer is highly dependent on the stage at diagnosis, with individuals diagnosed at early stages having the best long-term survival. However, as onset of symptoms can be diffuse, many individuals are diagnosed at later stages when survival rates are significantly poorer. Therefore, screening and prevention strategies to detect colorectal cancer at earlier stages or remove cancer precursors such as polyps may be key to increasing survival. Commonly used screening tools today include fecal blood tests and colonoscopy, but they have modest accuracy or may not be cost-effective. Being able to identify markers in blood, either for early detection, as a complementary or alternative screening method, or for risk stratification, could aid in solving this problem. Aim: The overall of aim of the thesis was to improve our understanding of underlying factors contributing to CRC etiology and to find biomarkers associated with CRC that could aid in the future development of effective risk prediction models. Methods: All studies included in this thesis were based on a case-control cohort nested within the Northern Sweden Health and Disease Study (NSHDS). Additionally in paper I, we also used data from the European Prospective Investigation into Cancer and Nutrition (EPIC), a large multi-center cohort study. In this paper we examined associations between sex hormones, sex hormone binding globulin (SHBG), and colon cancer in men. The study included 690 colon cancer cases and 690 matched controls. Paper II was a longitudinal study, using repeated samples from 80 men, on circulating sex hormones, SHBG, and DNA methylation in white blood cells. Papers III and IV were nested case-control studies on proteins and colorectal cancer risk with Paper III divided into a discovery and a validation phase. In the first phase, which included 69 colorectal cancer case-control pairs with repeated samples, 160 unique proteins related to inflammation and oncology were analyzed. In the second phase, 13 proteins that were significantly associated with colorectal cancer risk, together with 8 proteins identified from the literature, were measured on a custom panel, and validated in a larger material consisting of 1000 case-control pairs. In paper IV, which included 195 colorectal cancer case-control pairs, the protein analysis was extended to include 1536 proteins linked to oncology, inflammation, neurology, and metabolism. In papers using a matched case-control design, conditional i logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations. For longitudinal analyses, mixed effects models were used to estimate associations. Results: In paper I, we observed a statistically significant inverse association between circulating levels of testosterone and colon cancer. For SHBG there was a statistically significant inverse association prior to adjustment of testosterone and estradiol levels. In paper II, we found one novel genome-wide significant association between circulating levels of dehydroepiandrosterone and DNA methylation at the cg14319657 CpG site. In addition, we also identified more than 40 differentially methylated regions associated with levels of sex hormones and SHBG. In paper III, we first identified 13 proteins associated with CRC risk in the discovery phase. In the validation phase, however, none of the proteins remained significantly associated with colorectal cancer. When stratifying by tumor site, FGF-21 and PPY, were statically significant in colon and rectal cancer respectively, and showed some modest increase in predictive performance. In paper IV, we identified 20 proteins surpassing a significance threshold of 0.005. One protein, TFF3 (Trefoil Factor 3), which was positively associated with colorectal, also withstood strict Bonferroni correction. In addition, we validated several proteins, including AREG, CEA, and LGALS4, which were identified as biomarker candidates in previous studies. Conclusions: Our results support the hypothesis that circulating sex hormones play a role in male colon cancer etiology and that this may partly explain the difference in colorectal cancer incidence between men and women. Furthermore, our findings suggest a possible link between circulating sex hormones, SHBG and DNA methylation, which could be of interest in the etiology of colorectal cancer as well as other hormone-dependent diseases. Finally, we also identified several proteins associated with colorectal cancer, some of which have shown potential as screening markers.
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| 10. |
- Harbs, Justin, et al.
(författare)
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Circulating Sex Hormone Levels and Colon Cancer Risk in Men : A Nested Case–Control Study and Meta-Analysis
- 2022
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 31:4, s. 793-803
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Tidskriftsartikel (refereegranskat)abstract
- Background: Endogenous sex hormones may contribute to higher colorectal cancer incidence rates in men compared with women, but despite an increased number of studies, clear evidence is lacking.Methods: We conducted a comprehensive nested case–control study of circulating concentrations of sex hormones, sex hormone precursors, and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid LC/MS-MS in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men.Results: Circulating levels of testosterone (OR, 0.68; 95% CI, 0.51–0.89) and SHBG (OR, 0.77; 95% CI, 0.62–0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR, 0.83; 95% CI, 0.58–1.18). In a dose–response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone [relative risks (RR) per 100 ng/dL ¼ 0.98; 95% CI, 0.96–1.00; I2 ¼ 22%] and free testosterone (RR per 1 ng/dL ¼ 0.98; 95% CI, 0.95–1.00; I2 ¼ 0%).Conclusions: Our results provide suggestive evidence for the association between testosterone, SHBG, and male colon cancer development.Impact: Additional support for the involvement of sex hormones in male colon cancer.
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| 11. |
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| 12. |
- Harlid, Sophia, 1978-, et al.
(författare)
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A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed. Using prospectively collected plasma samples from the population-based Northern Sweden Health and Disease Study, we evaluated protein biomarkers in relation to colorectal cancer risk. Applying a two-tiered approach, we analyzed 160 proteins in matched sequential samples from 58 incident colorectal cancer case–control pairs. Twenty-one proteins selected from both this discovery phase and the literature were then analyzed in a validation set of 450 case–control pairs. Odds ratios were estimated by conditional logistic regression. LASSO regression and ROC analysis were used for multi-marker analyses. In the main validation analysis, no proteins retained statistical significance. However, exploratory subgroup analyses showed associations between FGF-21 and colon cancer risk (multivariable OR per 1 SD: 1.23 95% CI 1.03–1.47) as well as between PPY and rectal cancer risk (multivariable OR per 1 SD: 1.47 95% CI 1.12–1.92). Adding protein markers to basic risk predictive models increased performance modestly. Our results highlight the challenge of developing biomarkers that are effective in the asymptomatic, prediagnostic window of opportunity for early detection of colorectal cancer. Distinguishing between cancer subtypes may improve prediction accuracy. However, single biomarkers or small panels may not be sufficient for effective precision screening.
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| 13. |
- Ignatov, Dmitriy, et al.
(författare)
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An mRNA-mRNA Interaction Couples Expression of a Virulence Factor and Its Chaperone in Listeria monocytogenes
- 2020
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Ingår i: Cell Reports. - : cell press. - 2211-1247. ; 30:12, s. 4027-
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial pathogens often employ RNA regulatory elements located in the 5' untranslated regions (UTRs) to control gene expression. Using a comparative structural analysis, we examine the structure of 5' UTRs at a global scale in the pathogenic bacterium Listeria monocytogenes under different conditions. In addition to discovering an RNA thermoswitch and detecting simultaneous interaction of ribosomes and small RNAs with mRNA, we identify structural changes in the 5' UTR of an mRNA encoding the post-translocation chaperone PrsA2 during infection conditions. We demonstrate that the 5' UTR of the prsA2 mRNA base pairs with the 3' UTR of the full-length hly mRNA encoding listeriolysin O, thus preventing RNase J1-mediated degradation of the prsA2 transcript. Mutants lacking the hly-prsA2 interaction exhibit reduced virulence properties. This work highlights an additional level of RNA regulation, where the mRNA encoding a chaperone is stabilized by the mRNA encoding its substrate.
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| 14. |
- Lindgren, Helena, 1969-, et al.
(författare)
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Francisella tularensis-specific antibody levels in sera from Swedish patients with suspected tularemia during a 13-year period
- 2024
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: For a majority of tularemia patients, serology is the basis for the diagnosis. The aim of this study was to perform an analysis of the samples analyzed at a Swedish reference laboratory for the presence of Francisella tularensis-specific antibody levels in sera from individuals with suspected tularemia. Annual and monthly variations of the total number of samples and proportions of positive samples were analyzed, as well as the influence of age and gender.Methods: We performed a retrospective analysis of the presence of F. tularensis-specific antibodies in serological samples from patients with suspected tularemia analyzed during the period 2010 - 2022 at the University Hospital of Umeå in Sweden, a national reference laboratory, by use of various statistical methods. In total, some 15,100 serum samples had been analyzed for the presence of IgG and IgM antibodies by ELISA during the 13-year period.Results: Overall, there were higher number of samples with IgG positive or borderline titers, 2,522 and 921, respectively, than with IgM positive or borderline titers, 1,802 and 409, respectively. Repeated samples were obtained from some 1,930 individuals and approximately a third of the cases, which were initially seronegative, had seroconverted when resampled. Peak number of monthly samples were recorded in August and September, > 3,000. Annual numbers varied greatly and peak numbers were observed in 2015 and 2019, 1,832 and 2,250, respectively, whereas some other years the numbers were 700 – 800. There was also much variation in the annual and monthly percentages of positive samples and they varied between less than 10% to greater than 20%. The highest percentages of positive samples were recorded in September and October. IgG and IgM titers declined with age and these differences were highly significant for IgG titers, with decreasing average titers for each 20-year interval.Discussion: Collectively, the data demonstrate the marked annual and seasonal variations in tularemia sampling occurring in Sweden. Also, the proportion of positive samples increased during months and years with peak number of samples. Another notable finding was that average antibody titers decreased with increased age.
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| 15. |
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| 16. |
- Liu, Xijia, et al.
(författare)
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Dyadic diagonalization of positive definite band matrices and efficient B-spline orthogonalization
- 2022
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Ingår i: Journal of Computational and Applied Mathematics. - : Elsevier. - 0377-0427 .- 1879-1778. ; 414
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Tidskriftsartikel (refereegranskat)abstract
- A dyadic algorithm for diagonalizing an arbitrary positive definite band matrix, referred to as a band Gramian, is obtained to efficiently orthogonalize the B-splines. The algorithm can be also used as a fast inversion method for a band Gramian characterized by remarkable sparsity of the diagonalizing matrix. There are two versions of the algorithm: the first one is more efficient and is applicable to a Toeplitz band Gramian while the second one is more general, works with any Gramian matrix, but is more computationally intensive. In the context of the B-splines, these two cases result in new symmetric orthogonalization procedures and correspond to equally and arbitrarily spaced knots, respectively. In the algorithm, the sparsity of a band Gramian is utilized to produce a natural dyadic net of orthogonal splines, rather than a sequence of them. Such a net is thus naturally referred to as a splinet. The splinets exploit “near-orthogonalization” of the B-splines and feature locality expressed through a small size of the total support set and computational efficiency that is a result of a small number of inner product evaluations needed for their construction. These and other efficiencies are formally quantified by upper bounds and asymptotic rates with respect to the number of splines in a splinet. An additional assessment is provided through numerical experiments. They suggest that the theoretical bounds are rather conservative and the method is even more efficient than the bounds indicate. The dyadic net-like structures and the locality bear some resemblance to wavelets but in fact, the splinets are fundamentally different because they do not aim at capturing the resolution scales. The orthogonalization method together with efficient spline algebra and calculus has been implemented in R-package Splinets available on CRAN.
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| 17. |
- Liu, Xijia, et al.
(författare)
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Measure of location-based estimators in simple linear regression
- 2016
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Ingår i: Journal of Statistical Computation and Simulation. - : Taylor & Francis. - 0094-9655 .- 1563-5163. ; 86:9, s. 1771-1784
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Tidskriftsartikel (refereegranskat)abstract
- In this note we consider certain measure of location-based estimators (MLBEs) for the slope parameter in a linear regression model with a single stochastic regressor. The median-unbiased MLBEs are interesting as they can be robust to heavy-tailed samples and, hence, preferable to the ordinary least squares estimator (LSE). Two different cases are considered as we investigate the statistical properties of the MLBEs. In the first case, the regressor and error is assumed to follow a symmetric stable distribution. In the second, other types of regressions, with potentially contaminated errors, are considered. For both cases the consistency and exact finite-sample distributions of the MLBEs are established. Some results for the corresponding limiting distributions are also provided. In addition, we illustrate how our results can be extended to include certain heteroskedastic and multiple regressions. Finite-sample properties of the MLBEs in comparison to the LSE are investigated in a simulation study.
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| 18. |
- Liu, Xijia, et al.
(författare)
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Measure of location-based sestimators in simple linear regression
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- In this paper we consider certain measure of location-based estimators (MLBEs)for the slope parameter in a linear regression model with a single stochastic regressor. Themedian-unbiased MLBEs are interesting as they can be robust to heavy-tailed samples and,hence, preferable to the ordinary least squares estimator (LSE). Two dierent cases are consideredas we investigate the statistical properties of the MLBEs. In the rst case, the regressorand error are assumed to follow a symmetric stable distribution. In the second, other typesof regressions, with potentially contaminated errors, are considered. For both cases the consistencyand exact nite-sample distributions of the MLBEs are established. Some results for thecorresponding limiting distributions are also provided. In addition, we illustrate how our resultscan be extended to include certain heteroscedastic regressions. Finite-sample properties of theMLBEs in comparison to the LSE are investigated in a simulation study.
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| 19. |
- Liu, Xijia, 1983-
(författare)
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On Non Parametric Regression and Panel Unit Root Testing
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, two different issues in econometrics are studied, the estimation of regression coefficients and the non-stationartiy analysis in a panel setting.Regarding the first topic, we study a set of measure of location-based estimators (MLBEs) for the slope parameter in a linear regression model with a single stochastic regressor. The median-unbiased MLBEs are interesting as they can be robust to heavy-tailed and, hence, preferable to the ordinary least squares estimator (LSE) in such situations. Two cases, symmetric stable regression and contaminated normal regression, are considered as we investigate the statistical properties of the MLBEs. In addition, we illustrate how our results can be extended to include certain heteroscedastic regressions.There are three papers concerning the second part. In the first paper, we propose a novel way to test the unit roots in the panel setting. The new tests are based on the observation that the trajectory of the cross sectional sample variance behaves differently for stationary than for non-stationary processes. Three different test statistics are proposed. The limiting distributions are derived and the small sample properties are studied by simulations. In the remaining papers, we focus on the studies of the block bootstrap panel unit root tests proposed by Palm, Smeekes and Urbain (2011) which aims at dealing with a rather general cross-sectional dependency structure. One paper studies the robustness of PSU tests by a comparison with two representative tests from the second generation panel unit root tests. In another paper, we generalized the block bootstrap panel unit root tests in the sense of considering the deterministic terms in the model. Two different methods to deal with the deterministic terms are proposed and the asymptotic validity of bootstrap tests under the main null hypothesis is theoretically checked. The small sample properties are studied by simulations.
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| 20. |
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| 21. |
- Liu, Xijia
(författare)
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Panel unit root tests based on sample variance
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- In this paper, we propose a novel way to test for unit root in a panel setting.The new tests are based on the observation that the trajectory of the cross sectional samplevariance behaves dierently for stationary than for non-stationary processes. Three dierenttest statistics are considered and their limiting distributions are derived. Interestingly, oneof the statistics has a non-standard limiting distribution which can be described in terms offunctionals of a Gaussian process. A small scale simulation study indicates that our proposedtests have good power properties, quite close to the test of Levin, Lin and Chu (2002)(LLC).However, the empirical size of one of our tests is better than LLC when T is small and N islarge, and this suggest a good property for unit root tests in micro panels. In addition, the studyalso suggests that our tests are robust to cross section dependence for a particular covariancestructure.
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| 22. |
- Liu, Xijia, et al.
(författare)
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Utility of Borrelia-specific IgM and IgG antibody titer determinations during a 12-year period : results from a clinical laboratory in Northern Sweden
- 2023
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Interpretation of serological findings in suspected Lyme borreliosis (LB) is challenging and IgM reactivities may have low predictive value. Therefore, if used indiscriminately, there is a risk for incorrect diagnosis of LB. To evaluate the usefulness of IgM titer determination, we performed a study of the prevalence of Borrelia-specific antibodies in serological samples from patients with suspected LB analyzed during the period 2010 - 2021 at the University Hospital of Umeå in Sweden. In total, 19,335 samples had been analyzed for the presence of IgG and IgM antibodies. Overall, there were higher percentages of IgM positive or borderline titers, 1,847 (9.6%) and 905 (4.7%), respectively, than IgG positive or borderline titers, 959 (5.0%) and 406 (2.1%), respectively. Peak number of samples were recorded 2012 - 2013, exceeding 1,800, whereas there were around 1,200 during 2020 - 2021. The peak number of positive IgG and/or positive IgM samples were observed during the period 2015 - 2017 with close to, or above 400, and concomitantly, the proportion of IgG positive samples increased markedly. For IgG positive samples, the increase followed a positive linear time trend (P< 0.001). Peak monthly numbers were observed during August, September, and October. This seasonal increase was significant for the IgG positive group (P< 0.05), but not for the IgM positive/IgG negative group. Repeated samples were obtained from 3,188 individuals and of the initial samples 2,817 were (88%) IgG negative and 2,315 (72%) were IgM negative and of these, 130 (4%) showed IgG seroconversion and 300 (9%) IgM seroconversion. Collectively, the data demonstrate that IgG and/or IgM positive samples represented a minority of all samples, even when repeated sampling had occurred, and IgM positive samples were much more common than IgG positive samples. Thus, the accuracy of the clinical suspicion was low and this will lead to a low predictive value of the analysis, in particular of IgM. These findings question the use of IgM titer determination as a routine analysis.
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| 23. |
- Meyer, Lena, et al.
(författare)
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Microinjection of Francisella tularensis and Listeria monocytogenes reveals the importance of bacterial and host factors for successful replication
- 2015
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 83:8, s. 3233-3242
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Certain intracellular bacteria use the host cell cytosol as the replicative niche. Although it has been hypothesized that the successful exploitation of this compartment requires a unique metabolic adaptation, supportive evidence is lacking. For Francisella tularensis, many genes of the Francisella pathogenicity island (FPI) are essential for intracellular growth, and therefore, FPI mutants are useful tools for understanding the prerequisites of intracytosolic replication. We compared the growth of bacteria taken up by phagocytic or nonphagocytic cells with that of bacteria microinjected directly into the host cytosol, using the live vaccine strain (LVS) of F. tularensis; five selected FPI mutants thereof, i.e., Delta iglA, Delta iglC, Delta iglG, Delta iglI, and Delta pdpE strains; and Listeria monocytogenes. After uptake in bone marrow-derived macrophages (BMDM), ASC(-/-) BMDM, MyD88(-/-) BMDM, J774 cells, or HeLa cells, LVS, Delta pdpE and Delta iglG mutants, and L. monocytogenes replicated efficiently in all five cell types, whereas the Delta iglA and Delta iglC mutants showed no replication. After microinjection, all 7 strains showed effective replication in J774 macrophages, ASC(-/-) BMDM, and HeLa cells. In contrast to the rapid replication in other cell types, L. monocytogenes showed no replication in MyD88(-/-) BMDM and LVS showed no replication in either BMDM or MyD88(-/-) BMDM after microinjection. Our data suggest that the mechanisms of bacterial uptake as well as the permissiveness of the cytosolic compartment per se are important factors for the intracytosolic replication. Notably, none of the investigated FPI proteins was found to be essential for intracytosolic replication after microinjection.
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| 24. |
- Wang, Jianfeng, et al.
(författare)
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Contrast Agent Quantification by Using Spatial Information in Dynamic Contrast Enhanced MRI
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The purpose of this study is to investigate a method, using simulations, to improve contrast agent quantification in Dynamic Contrast Enhanced MRI. Bayesian hierarchical models (BHMs) are applied to smaller images (10×10×10) such that spatial information can be incorporated. Then exploratory analysis is done for larger images (64×64×64) by using maximum a posteriori (MAP).For smaller images: the estimators of proposed BHMs show improvements in terms of the root mean squared error compared to the estimators in existing method for a noise level equivalent of a 12-channel head coil at 3T. Moreover, Leroux model outperforms Besag models. For larger images: MAP estimators also show improvements by assigning Leroux prior.
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| 25. |
- Wu, Wendy Yi-Ying, et al.
(författare)
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Overdiagnosis in the population-based organized breast cancer screening program estimated by a non-homogeneous multi-state model : a cohort study using individual data with long-term follow-up
- 2018
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Overdiagnosis, defined as the detection of a cancer that would not become clinically apparent in a woman’s lifetime without screening, has become a growing concern. Similar underlying risk of breast cancer in the screened and control groups is a prerequisite for unbiased estimates of overdiagnosis, but a contemporary control group is usually not available in organized screening programs.Methods: We estimated the frequency of overdiagnosis of breast cancer due to screening in women 50–69 years old by using individual screening data from the population-based organized screening program in Stockholm County 1989–2014. A hidden Markov model with four latent states and three observed states was constructed to estimate the natural progression of breast cancer and the test sensitivity. Piecewise transition rates were used to consider the time-varying transition rates. The expected number of detected non-progressive breast cancer cases was calculated.Results: During the study period, 2,333,153 invitations were sent out; on average, the participation rate in the screening program was 72.7% and the average recall rate was 2.48%. In total, 14,648 invasive breast cancer cases were diagnosed; among the 8305 screen-detected cases, the expected number of non-progressive breast cancer cases was 35.9, which is equivalent to 0.43% (95% confidence interval (CI) 0.10%–2.2%) overdiagnosis. The corresponding estimates for the prevalent and subsequent rounds were 15.6 (0.87%, 95% CI 0.20%–4.3%) and 20.3 (0.31%, 95% CI 0.07%–1.6%), respectively. The likelihood ratio test showed that the non-homogeneous model fitted the data better than an age-homogeneous model (P<0.001).Conclusions: Our findings suggest that overdiagnosis in the organized biennial mammographic screening for women 50–69 in Stockholm County is a minor phenomenon. The frequency of overdiagnosis in the prevalent screening round was higher than that in subsequent rounds. The non-homogeneous model performed better than the simpler, traditional homogeneous model.
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