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  • 1.
    Aarnio, Mikko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wolf, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Linnman, Clas
    Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.2017In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, p. 418-424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

  • 2. Bäckryd, Emmanuel
    et al.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gerdle, Björn
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls2017In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 12, p. 2487-2495Article in journal (Refereed)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

  • 3.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Mathematical Statistics.
    Two simple tests for normality with high power2010Report (Other academic)
    Abstract [en]

    We derive explicit expressions for the correlation coefficients between the sample mean and the sample variance and between the sample mean and the third central sample moment in terms of sample moments. Using these we show that two tests for normality, proposed by Lin and Mudholkar (1980) and Mudholkar et al. (2002), can be simplified by using moment estimators; particularly the sample skewness and kurtosis; rather than the jackknife estimators previously used. In an extensive simulation power study the tests exhibit higher power than some common tests for normality against a wide range of distributions.

  • 4.
    Görgens, Maik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Probability Theory.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    Bias-correction of the maximum likelihood estimator for the α-Brownian bridge2014In: Statistics and Probability Letters, ISSN 0167-7152, E-ISSN 1879-2103, Vol. 93, p. 78-86Article in journal (Refereed)
    Abstract [en]

    The bias of the maximum likelihood estimator of the parameter α in the α-Brownian bridge is derived. A bias-correction which improves the estimator substantially is proposed. The corrected estimator and Bayesian estimators are compared in a simulation study.

  • 5.
    Hysing, Eva-Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Smith, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Karlsten, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Butler, Stephen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic2017In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, no 1, p. 178-185Article in journal (Refereed)
    Abstract [en]

    Background and aims: Patients suffering from chronic nonmalignant pain constitute a heterogeneous population in terms of clinical presentation and treatment results. Few data are available about what distinguishes different groups in this huge population of patients with chronic persistent pain (CPP). A subgroup that is poorly studied, consists of the most severely impaired chronic pain patients. At the Uppsala University Hospital Pain Clinic, there is a specialized department accepting the most complex patients for rehabilitation. In the endeavour to improve and evaluate treatment for this subgroup, a better understanding of the complex nature of the illness is essential. This prospective study aimed to describe the characteristics of this subgroup of patients with CPP.

    Methods: Seventy-two consecutive patients enrolled in the Uppsala programme were evaluated. We collected data on demographics, type of pain and experienced symptoms other than pain using a checklist of 41 possible symptoms. Psychiatric comorbidity was assessed by a psychiatrist using a structured clinical interview. Quality of life (QoL), pain rating and medication/drug/alcohol usage were measured by validated questionnaires: SF-36, NRS, DUDIT and AUDIT. Concerning physical functioning and sick leave, a comparison was made with data from the Swedish Quality Register Registry for pain rehabilitation (SQRP).

    Results: The cohort consisted of 61% women and the average age was 45 (range 20-70) years. For this cohort, 74% reported being on sick leave or disability-pension. In the SQRP 59% were on sick leave at the time they entered the rehabilitation programmes [1]. On average, the study-population reported 22 symptoms other than pain, to be at a high rate of severity. Patients treated in conventional pain rehabilitation programmes reported a mean of 10 symptoms in average. Symptoms reported with the highest frequency (>80%), were lethargy, tiredness, headache and difficulties concentrating. Seventysix percent were diagnosed with a psychiatric disorder. Sixty-nine fulfilled the criteria for depression or depression/anxiety disorder despite that most (65%) were treated with psychotropic medication. Alcohol/drug abuse was minimal. Seventy-one percent were on opioids but the doses were moderate (<100 mg) MEq. The pain rating was >= 7 (out of a maximum of 10) for 60% of the patients.

    Conclusion: This study describes what makes the subgroup of pain patients most affected by their pain special according to associated factors and comorbidity We found that they were distinguished by a high degree of psychiatric comorbidity, low physical functioning and extreme levels of symptom preoccupation/hypervigilance. Many severe symptoms additional to pain (e.g. depression/anxiety, tiredness, disturbed sleep, lack of concentration, constipation) were reported. The group seems hypervigilant, overwhelmed with a multitude of different symptoms on a high severity level.

    Implications: When treating this complex group, the expressions of the illness can act as obstacles to achieve successful treatment outcomes. The study provides evidence based information, for a better understanding of the needs concerning these pain patients. Our result indicates that parallel assessment and treatment of psychiatric comorbidities and sleep disorders combined with traditional rehabilitation, i.e. physical activation and cognitive reorganization are imperative for improved outcomes.

  • 6.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The effects of age and gender on plasma levels of 63 cytokines2015In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 425, p. 58-61Article in journal (Refereed)
    Abstract [en]

    Cytokines play important roles as regulators of cell functions, and over the last decades a number of cytokine assays have been developed. The aim of the present study was to investigate the effects of age and gender on a large number of cytokines. Plasma samples were collected from 33 healthy blood donors. The samples were analyzed using the multiplex proximity extension assay (PEA) allowing simultaneous measurement of 92 cytokines and four technical controls. Biomarkers with less than 80% quantitative results were excluded leaving 63 cytokines that were analyzed for the effects of gender and age. The plasma level of three of the investigated biomarkers (DNER, MCP-4 and MMP-10) were found to be significantly different for the two genders (adjusted p-value <0.05), and 15 of the biomarkers (CCL11, CCL25, CDCP1, CSF-1, CXCL11, CXCL9, FGF-23, Flt3L, HGF, IL-10RB, MCP-3, MCP-4, MMP-10, OPG, VEGF-A) were significantly associated with age. This study reveals the effects of age and gender on a large number of cytokine assays. CXCL5 and TNFB were significantly higher in females, while the other markers with significant gender-dependent differences were higher in males. For the markers that were significantly associated with age, only CXCL6 was found to decrease with age, while the other biomarkers increased with age.

  • 7.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bodolea, Constantin
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid2015In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, no 2, p. 514-518Article in journal (Refereed)
    Abstract [en]

    Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.

  • 8.
    Moen, Aurora
    et al.
    Natl Inst Occupat Hlth, N-0033 Oslo, Norway.;Oslo Univ Hosp, Dept Phys Med & Rehabil, N-0424 Oslo, Norway..
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Roe, Cecilie
    Oslo Univ Hosp, Dept Phys Med & Rehabil, N-0424 Oslo, Norway.;Univ Oslo, Fac Med, N-0316 Oslo, Norway..
    Gjerstad, Johannes
    Natl Inst Occupat Hlth, N-0033 Oslo, Norway.;Oslo Univ Hosp, Dept Phys Med & Rehabil, N-0424 Oslo, Norway.;Univ Oslo, Dept Mol Biosci, N-0371 Oslo, Norway..
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation2016In: INTERNATIONAL JOURNAL OF INFLAMMATION, ISSN 2090-8040, article id UNSP 3874964Article in journal (Refereed)
    Abstract [en]

    Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ulleval, Norway, during the period 2007-2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 (CXCM5; 217% increase), epidermal growth factor (EGF; 142% increase), and monocyte chemotactic protein 4 (MCP-4; 70% increase). Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation.

  • 9.
    Rydfjord, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fagrell, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Temperature measurements with two different IR sensors in a continuous-flow microwave heated system2013In: Beilstein Journal of Organic Chemistry, ISSN 2195-951X, E-ISSN 1860-5397, Vol. 9, p. 2079-2087Article in journal (Refereed)
    Abstract [en]

    In a continuous-flow system equipped with a nonresonant microwave applicator we have investigated how to best assess the actual temperature of microwave heated organic solvents with different characteristics. This is non-trivial as the electromagnetic field will influence most traditional methods of temperature measurement. Thus, we used a microwave transparent fiber optic probe, capable of measuring the temperature inside the reactor, and investigated two different IR sensors as non-contact alternatives to the internal probe. IR sensor 1 measures the temperature on the outside of the reactor whilst IR sensor 2 is designed to measure the temperature of the fluid through the borosilicate glass that constitutes the reactor wall. We have also, in addition to the characterization of the before mentioned IR sensors, developed statistical models to correlate the IR sensor reading to a correct value of the inner temperature (as determined by the internal fiber optic probe), thereby providing a non-contact, indirect, temperature assessment of the heated solvent. The accuracy achieved with these models lie well within the range desired for most synthetic chemistry applications.

  • 10. Stehlik, M.
    et al.
    Strelec, L.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    On robust testing for normality in chemometrics2014In: Chemometrics and Intelligent Laboratory Systems, ISSN 0169-7439, E-ISSN 1873-3239, Vol. 130, p. 98-108Article in journal (Refereed)
    Abstract [en]

    The assumption that the data has been generated by a normal distribution underlies many statistical methods used in chemometrics. While such methods can be quite robust to small deviations from normality, for instance caused by a small number of outliers, common tests for normality are not and will often needlessly reject normality. It is therefore better to use tests from the little-known class of robust tests for normality. We illustrate the need for robust normality testing in chemometrics with several examples, review a class of robustified omnibus Jarque-Bera tests and propose a new class of robustified directed Lin-Mudholkar tests. The robustness and power of several tests for normality are compared in a large simulation study. The new tests are robust and have high power in comparison with both classic tests and other robust tests. A new graphical method for assessing normality is also introduced.

  • 11.
    Thulin, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 23, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Mecillinam (amdinocillin) is a β-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (Mec(R)) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were Mec(R) due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, Mec(R)E. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the Mec(R) mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as Mec(R) in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting Mec(R)E. coli strain and thereby increase treatment efficiency.

  • 12.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    A high-dimensional two-sample test for the mean using random subspaces2014In: Computational Statistics & Data Analysis, ISSN 0167-9473, E-ISSN 1872-7352, Vol. 74, p. 26-38Article in journal (Refereed)
    Abstract [en]

    A common problem in genetics is that of testing whether a set of highly dependent gene expressions differ between two populations, typically in a high-dimensional setting where the data dimension is larger than the sample size. Most high-dimensional tests for the equality of two mean vectors rely on naive diagonal or trace estimators of the covariance matrix, ignoring dependences between variables. A test using random subspaces is proposed, which offers higher power when the variables are dependent and is invariant under linear transformations of the marginal distributions. The p-values for the test are obtained using permutations. The test does not rely on assumptions about normality or the structure of the covariance matrix. It is shown by simulation that the new test has higher power than competing tests in realistic settings motivated by microarray gene expression data. Computational aspects of high-dimensional permutation tests are also discussed and an efficient R implementation of the proposed test is provided.

  • 13.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Coverage-adjusted confidence intervals for a binomial proportion2014In: Scandinavian Journal of Statistics, ISSN 0303-6898, E-ISSN 1467-9469, Vol. 41, no 2, p. 291-300Article in journal (Refereed)
    Abstract [en]

    We consider the classic problem of interval estimation of a proportion p based on binomial sampling. The ‘exact’ Clopper–Pearson confidence interval for p is known to be unnecessarily conservative. We propose coverage adjustments of the Clopper–Pearson interval that incorporate prior or posterior beliefs into the interval. Using heatmap-type plots for comparing confidence intervals, we show that the coverage-adjusted intervals have satisfying coverage and shorter expected lengths than competing intervals found in the literature.

  • 14.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Decision-theoretic justifications for Bayesian hypothesis testing using credible sets2014In: Journal of Statistical Planning and Inference, ISSN 0378-3758, E-ISSN 1873-1171, Vol. 146, p. 133-138Article in journal (Refereed)
    Abstract [en]

    In Bayesian statistics the precise point-null hypothesis theta=theta(0) can be tested by checking whether theta(0) is contained in a credible set. This permits testing of theta=theta(0) without having to put prior probabilities on the hypotheses. While such inversions of credible sets have a long history in Bayesian inference, they have been criticized for lacking decision-theoretic justification. We argue that these tests have many advantages over the standard Bayesian tests that use point-mass probabilities on the null hypothesis. We present a decision-theoretic justification for the inversion of central credible intervals, and in special case HPD sets, by studying a three-decision problem with directional conclusions. Interpreting the loss function used in the justification, we discuss when tests based on credible sets are applicable. We then give some justifications for using credible sets when testing composite hypotheses, showing that tests based on credible sets coincide with standard tests in this setting. 

  • 15.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    On Confidence Intervals and Two-Sided Hypothesis Testing2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis consists of a summary and six papers, dealing with confidence intervals and two-sided tests of point-null hypotheses.

    In Paper I, we study Bayesian point-null hypothesis tests based on credible sets. A decision-theoretic justification for tests based on central credible intervals is presented.

    Paper II is concerned with a new two-sample test for the difference of mean vectors, in the high-dimensional setting where the number of variables is greater than the sample size. A simulation study indicates that the proposed test yields higher power when the variables are correlated. Computational aspects of the test are discussed.

    In Paper III, we discuss randomized confidence intervals for a binomial proportion. How some classical intervals fare is compared to how a recently proposed interval fares, in terms of coverage, length and sensitivity to the randomization.

    In Paper IV, a level-adjustment of the Clopper-Pearson interval for a binomial proportion is proposed. The adjusted interval is shown to have good coverage properties and short expected length.

    In Paper V we study the cost of using the exact Clopper-Pearson interval rather than shorter approximate intervals, in terms of the increase in expected length and the increase in sample size required to obtain a given length. Comparisons are made using asymptotic expansions.

    Paper VI deals with exact confidence intervals and point-null hypothesis tests for parameters of a class of discrete distributions. A large class of intervals are shown to lack strict nestedness and to have bounds that are not strictly monotone and typically also discontinuous. The p-values of the corresponding hypothesis test are shown to lack desirable continuity properties, and to typically also lack certain monotonicity properties.

    List of papers
    1. Decision-theoretic justifications for Bayesian hypothesis testing using credible sets
    Open this publication in new window or tab >>Decision-theoretic justifications for Bayesian hypothesis testing using credible sets
    2014 (English)In: Journal of Statistical Planning and Inference, ISSN 0378-3758, E-ISSN 1873-1171, Vol. 146, p. 133-138Article in journal (Refereed) Published
    Abstract [en]

    In Bayesian statistics the precise point-null hypothesis theta=theta(0) can be tested by checking whether theta(0) is contained in a credible set. This permits testing of theta=theta(0) without having to put prior probabilities on the hypotheses. While such inversions of credible sets have a long history in Bayesian inference, they have been criticized for lacking decision-theoretic justification. We argue that these tests have many advantages over the standard Bayesian tests that use point-mass probabilities on the null hypothesis. We present a decision-theoretic justification for the inversion of central credible intervals, and in special case HPD sets, by studying a three-decision problem with directional conclusions. Interpreting the loss function used in the justification, we discuss when tests based on credible sets are applicable. We then give some justifications for using credible sets when testing composite hypotheses, showing that tests based on credible sets coincide with standard tests in this setting. 

    Keywords
    Bayesian inference, Credible set, Decision theory, Directional conclusion, Hypothesis testing, Three-decision problem
    National Category
    Mathematics
    Identifiers
    urn:nbn:se:uu:diva-216025 (URN)10.1016/j.jspi.2013.09.014 (DOI)000328593200012 ()
    Available from: 2014-01-20 Created: 2014-01-17 Last updated: 2017-12-06Bibliographically approved
    2. A high-dimensional two-sample test for the mean using random subspaces
    Open this publication in new window or tab >>A high-dimensional two-sample test for the mean using random subspaces
    2014 (English)In: Computational Statistics & Data Analysis, ISSN 0167-9473, E-ISSN 1872-7352, Vol. 74, p. 26-38Article in journal (Refereed) Published
    Abstract [en]

    A common problem in genetics is that of testing whether a set of highly dependent gene expressions differ between two populations, typically in a high-dimensional setting where the data dimension is larger than the sample size. Most high-dimensional tests for the equality of two mean vectors rely on naive diagonal or trace estimators of the covariance matrix, ignoring dependences between variables. A test using random subspaces is proposed, which offers higher power when the variables are dependent and is invariant under linear transformations of the marginal distributions. The p-values for the test are obtained using permutations. The test does not rely on assumptions about normality or the structure of the covariance matrix. It is shown by simulation that the new test has higher power than competing tests in realistic settings motivated by microarray gene expression data. Computational aspects of high-dimensional permutation tests are also discussed and an efficient R implementation of the proposed test is provided.

    National Category
    Probability Theory and Statistics
    Research subject
    Mathematical Statistics; Statistics
    Identifiers
    urn:nbn:se:uu:diva-224136 (URN)10.1016/j.csda.2013.12.003 (DOI)000333781500003 ()
    Available from: 2014-05-05 Created: 2014-05-05 Last updated: 2017-12-05Bibliographically approved
    3. On split sample and randomized confidence intervals for binomial proportions
    Open this publication in new window or tab >>On split sample and randomized confidence intervals for binomial proportions
    2014 (English)In: Statistics and Probability Letters, ISSN 0167-7152, E-ISSN 1879-2103, Vol. 92, p. 65-71Article in journal (Refereed) Published
    Abstract [en]

    We study randomized confidence intervals for binomial proportions, comparing coverage, length and the impact of the randomization. It is seen that the recently proposed split sample intervals can be improved upon in various ways. Criticisms of randomized intervals are discussed.

    National Category
    Probability Theory and Statistics
    Identifiers
    urn:nbn:se:uu:diva-226502 (URN)10.1016/j.spl.2014.05.005 (DOI)000340313200010 ()
    Available from: 2014-06-17 Created: 2014-06-17 Last updated: 2017-12-05Bibliographically approved
    4. Coverage-adjusted confidence intervals for a binomial proportion
    Open this publication in new window or tab >>Coverage-adjusted confidence intervals for a binomial proportion
    2014 (English)In: Scandinavian Journal of Statistics, ISSN 0303-6898, E-ISSN 1467-9469, Vol. 41, no 2, p. 291-300Article in journal (Refereed) Published
    Abstract [en]

    We consider the classic problem of interval estimation of a proportion p based on binomial sampling. The ‘exact’ Clopper–Pearson confidence interval for p is known to be unnecessarily conservative. We propose coverage adjustments of the Clopper–Pearson interval that incorporate prior or posterior beliefs into the interval. Using heatmap-type plots for comparing confidence intervals, we show that the coverage-adjusted intervals have satisfying coverage and shorter expected lengths than competing intervals found in the literature.

    National Category
    Probability Theory and Statistics
    Research subject
    Statistics; Mathematical Statistics
    Identifiers
    urn:nbn:se:uu:diva-224408 (URN)10.1111/sjos.12021 (DOI)000335388400002 ()
    Available from: 2014-05-12 Created: 2014-05-12 Last updated: 2017-12-05Bibliographically approved
    5. The cost of using exact confidence intervals for a binomial proportion
    Open this publication in new window or tab >>The cost of using exact confidence intervals for a binomial proportion
    2014 (English)In: Electronic Journal of Statistics, ISSN 1935-7524, E-ISSN 1935-7524, Vol. 8, p. 817-840Article in journal (Refereed) Published
    Abstract [en]

    When computing a confidence interval for a binomial proportion p one must choose between using an exact interval, which has a coverage probability of at least 1 a for all values of p, and a shorter approximate interval, which may have lower coverage for some p but that on average has coverage equal to 1 a. We investigate the cost of using the exact one and two-sided Clopper-Pearson confidence intervals rat her than shorter approximate intervals, first in terms of increased expected length and then in terms of the increase in sample size required to obtain a desired expected length. Using asymptotic expansions, we also give a closed-form formula for determining the sample size for the exact Clopper-Pearson methods. For two-sided intervals, our investigation reveals an interesting connection between the frequentist Clopper-Pearson interval and Bayesian intervals based on noninformative priors.

    Keywords
    Asymptotic expansion, binomial distribution, confidence interval, expected length, sample size determination, proportion
    National Category
    Probability Theory and Statistics
    Identifiers
    urn:nbn:se:uu:diva-226501 (URN)10.1214/14-EJS909 (DOI)000338327100001 ()
    Available from: 2014-06-17 Created: 2014-06-17 Last updated: 2017-12-05Bibliographically approved
    6. Exact confidence intervals and hypothesis tests for parameters of discrete distributions
    Open this publication in new window or tab >>Exact confidence intervals and hypothesis tests for parameters of discrete distributions
    2017 (English)In: Bernoulli, ISSN 1350-7265, E-ISSN 1573-9759, Vol. 23, no 1, p. 479-502Article in journal (Refereed) Published
    Abstract [en]

    We study exact confidence intervals and two-sided hypothesis tests for univariate parameters of stochastically increasing discrete distributions, such as the binomial and Poisson distributions. It is shown that several popular methods for constructing short intervals lack strict nestedness, meaning that accepting a lower confidence level not always will lead to a shorter confidence interval. These intervals correspond to a class of tests that are shown to assign differing p-values to indistinguishable models. Finally, we show that among strictly nested intervals, fiducial intervals, including the Clopper-Pearson interval for a binomial proportion and the Garwood interval for a Poisson mean, are optimal.

    Keywords
    binomial distribution, confidence interval, expected length, fiducial interval, hypothesis test, Poisson distribution
    National Category
    Probability Theory and Statistics
    Identifiers
    urn:nbn:se:uu:diva-229398 (URN)10.3150/15-BEJ750 (DOI)000389565500017 ()
    Available from: 2014-08-06 Created: 2014-08-06 Last updated: 2017-12-05Bibliographically approved
  • 16.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    On split sample and randomized confidence intervals for binomial proportions2014In: Statistics and Probability Letters, ISSN 0167-7152, E-ISSN 1879-2103, Vol. 92, p. 65-71Article in journal (Refereed)
    Abstract [en]

    We study randomized confidence intervals for binomial proportions, comparing coverage, length and the impact of the randomization. It is seen that the recently proposed split sample intervals can be improved upon in various ways. Criticisms of randomized intervals are discussed.

  • 17.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Mathematical Statistics.
    On two classic problems in statistics2012Licentiate thesis, comprehensive summary (Other academic)
  • 18.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Tests for multivariate normality based on canonical correlations2014In: Statistical Methods and Applications, ISSN 1618-2510, Vol. 23, no 2, p. 189-208Article in journal (Refereed)
    Abstract [en]

    We propose new affine invariant tests for multivariate normality, based on independence characterizations of the sample moments of the normal distribution. The test statistics are obtained using canonical correlations between sets of sample moments in a way that resembles the construction of Mardia's skewness measure and generalizes the Lin-Mudholkar test for univariate normality. The tests are compared to some popular tests based on Mardia's skewness and kurtosis measures in an extensive simulation power study and are found to offer higher power against many of the alternatives.

  • 19.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    Tests for multivariate normality based on canonical correlations2014In: Statistical Methods & Applications, ISSN 1618-2510, Vol. 23, no 2, p. 189-208Article in journal (Refereed)
  • 20.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    The cost of using exact confidence intervals for a binomial proportion2014In: Electronic Journal of Statistics, ISSN 1935-7524, E-ISSN 1935-7524, Vol. 8, p. 817-840Article in journal (Refereed)
    Abstract [en]

    When computing a confidence interval for a binomial proportion p one must choose between using an exact interval, which has a coverage probability of at least 1 a for all values of p, and a shorter approximate interval, which may have lower coverage for some p but that on average has coverage equal to 1 a. We investigate the cost of using the exact one and two-sided Clopper-Pearson confidence intervals rat her than shorter approximate intervals, first in terms of increased expected length and then in terms of the increase in sample size required to obtain a desired expected length. Using asymptotic expansions, we also give a closed-form formula for determining the sample size for the exact Clopper-Pearson methods. For two-sided intervals, our investigation reveals an interesting connection between the frequentist Clopper-Pearson interval and Bayesian intervals based on noninformative priors.

  • 21.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Two-sample tests and one-way MANOVA for multivariate biomarker data with nondetects2016In: Statistics in Medicine, ISSN 0277-6715, E-ISSN 1097-0258, Vol. 35, no 20, p. 3623-3644Article in journal (Refereed)
    Abstract [en]

    Testing whether the mean vector of a multivariate set of biomarkers differs between several populations is an increasingly common problem in medical research. Biomarker data is often left censored because some measurements fall below the laboratory's detection limit. We investigate how such censoring affects multivariate two-sample and one-way multivariate analysis of variance tests. Type I error rates, power and robustness to increasing censoring are studied, under both normality and non-normality. Parametric tests are found to perform better than non-parametric alternatives, indicating that the current recommendations for analysis of censored multivariate data may have to be revised.

  • 22.
    Thulin, Måns
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Zwanzig, Silvelyn
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied Mathematics and Statistics.
    Exact confidence intervals and hypothesis tests for parameters of discrete distributions2017In: Bernoulli, ISSN 1350-7265, E-ISSN 1573-9759, Vol. 23, no 1, p. 479-502Article in journal (Refereed)
    Abstract [en]

    We study exact confidence intervals and two-sided hypothesis tests for univariate parameters of stochastically increasing discrete distributions, such as the binomial and Poisson distributions. It is shown that several popular methods for constructing short intervals lack strict nestedness, meaning that accepting a lower confidence level not always will lead to a shorter confidence interval. These intervals correspond to a class of tests that are shown to assign differing p-values to indistinguishable models. Finally, we show that among strictly nested intervals, fiducial intervals, including the Clopper-Pearson interval for a binomial proportion and the Garwood interval for a Poisson mean, are optimal.

  • 23.
    Åberg Lindell, Matilda
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Grape, Sophie
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Hellesen, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Håkansson, Ane
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Discrimination of irradiated MOX fuel from UOX fuel by multivariate statistical analysis of simulated activities of gamma-emitting isotopes2018In: Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, ISSN 0168-9002, E-ISSN 1872-9576, Vol. 885, p. 67-78Article in journal (Refereed)
    Abstract [en]

    This paper investigates how concentrations of certain fission products and their related gamma-ray emissions can be used to discriminate between uranium oxide (UOX) and mixed oxide (MOX) type fuel. Discrimination of irradiated MOX fuel from irradiated UOX fuel is important in nuclear facilities and for transport of nuclear fuel, for purposes of both criticality safety and nuclear safeguards. Although facility operators keep records on the identity and properties of each fuel, tools for nuclear safeguards inspectors that enable independent verification of the fuel are critical in the recovery of continuity of knowledge, should it be lost. A discrimination methodology for classification of UOX and MOX fuel, based on passive gamma-ray spectroscopy data and multivariate analysis methods, is presented. Nuclear fuels and their gamma-ray emissions were simulated in the Monte Carlo code Serpent, and the resulting data was used as input to train seven different multivariate classification techniques. The trained classifiers were subsequently implemented and evaluated with respect to their capabilities to correctly predict the classes of unknown fuel items. The best results concerning successful discrimination of UOX and MOX-fuel were acquired when using non-linear classification techniques, such as the k nearest neighbors method and the Gaussian kernel support vector machine. For fuel with cooling times up to 20 years, when it is considered that gamma-rays from the isotope  134Cs can still be efficiently measured, success rates of 100% were obtained. A sensitivity analysis indicated that these methods were also robust.

1 - 23 of 23
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