| 1. |
- Aarnio, Mikko, et al.
(författare)
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Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
- 2017
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Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter. - 1877-8860 .- 1877-8879. ; 17:1, s. 418-424
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Bäckryd, Emmanuel, et al.
(författare)
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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 controls
- 2017
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 158:12, s. 2487-2495
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Dyhrfort, Philip, et al.
(författare)
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Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care
- 2019
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Ingår i: Journal of Neurotrauma. - : MARY ANN LIEBERT, INC. - 0897-7151 .- 1557-9042. ; 36:20, s. 2872-2885
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) is followed by secondary injury mechanisms strongly involving neuroinflammation. To monitor the complex inflammatory cascade in human TBI, we used cerebral microdialysis (MD) and multiplex proximity extension assay (PEA) technology and simultaneously measured levels of 92 protein biomarkers of inflammation in MD samples every three hours for five days in 10 patients with severe TBI under neurointensive care. One mu L MD samples were incubated with paired oligonucleotide-conjugated antibodies binding to each protein, allowing quantification by real-time quantitative polymerase chain reaction. Sixty-nine proteins were suitable for statistical analysis. We found five different patterns with either early (<48 h; e.g., CCL20, IL6, LIF, CCL3), mid (48-96 h; e.g., CCL19, CXCL5, CXCL10, MMP1), late (>96 h; e.g., CD40, MCP2, MCP3), biphasic peaks (e.g., CXCL1, CXCL5, IL8) or stable (e.g., CCL4, DNER, VEGFA)/low trends. High protein levels were observed for e.g., CXCL1, CXCL10, MCP1, MCP2, IL8, while e.g., CCL28 and MCP4 were detected at low levels. Several proteins (CCL8, -19, -20, -23, CXCL1, -5, -6, -9, -11, CST5, DNER, Flt3L, and SIRT2) have not been studied previously in human TBI. Cross-correlation analysis revealed that LIF and CXCL5 may play a central role in the inflammatory cascade. This study provides a unique data set with individual temporal trends for potential inflammatory biomarkers in patients with TBI. We conclude that the combination of MD and PEA is a powerful tool to map the complex inflammatory cascade in the injured human brain. The technique offers new possibilities of protein profiling of complex secondary injury pathways.
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| 4. |
- Fellström, Bengt, 1947-, et al.
(författare)
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Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females
- 2019
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Ingår i: Journal of Interferon and Cytokine Research. - : Mary Ann Liebert Inc. - 1079-9907 .- 1557-7465. ; 40:2, s. 71-74
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Tidskriftsartikel (refereegranskat)abstract
- There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1α, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.
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| 5. |
- Görgens, Maik, et al.
(författare)
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Bias-correction of the maximum likelihood estimator for the α-Brownian bridge
- 2014
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Ingår i: Statistics and Probability Letters. - : Elsevier BV. - 0167-7152 .- 1879-2103. ; 93, s. 78-86
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Hidman, Josefin, et al.
(författare)
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Increased plasma endostatin and GDF15 in indolent non-Hodgkin lymphoma
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 128
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease.METHODS: Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot.RESULTS: Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls.CONCLUSIONS: The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.
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| 7. |
- Hysing, Eva-Britt, et al.
(författare)
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Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program
- 2019
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Ingår i: Scandinavian Journal of Pain. - : WALTER DE GRUYTER GMBH. - 1877-8860 .- 1877-8879. ; 19:2, s. 235-244
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP).Methods: Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation.Results: Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found.Conclusions: Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved.
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| 8. |
- Khamisi, Selwan, et al.
(författare)
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Increased plasma levels of soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) in patients with Graves' ophthalmopathy in comparison to hyperthyroid patients without Graves' ophthalmopathy.
- 2023
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Ingår i: Cytokine. - : Elsevier. - 1043-4666 .- 1096-0023. ; 169, s. 156269-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Management of Graves' ophthalmopathy (GO) is still a challenge in Graves' disease (GD). Moreover, 40% of GD patients show radiological muscle enlargement without clinically apparent GO. Delayed treatment of GO may lead to deterioration in prognosis.METHODS: Thirty GD patients with overt hyperthyroidism were included in this study, 17 of whom either had GO at diagnosis or developed GO during the study period. Samples were collected at the beginning of the study, at 6 months, and at 24 months. Plasma samples were analyzed for 92 cytokines using the Olink Target 96 inflammation panel.RESULTS: After adjustment for multiplicity testing using the false discovery rate approach, soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) were significantly elevated in GO patients.CONCLUSION: Using a broad cytokine panel we show that patients with Graves' ophthalmopathy have elevated PD-L1 and FGF-23 levels. The findings support previous suggestions that PD-L1 may serve as a treatment target.
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| 9. |
- Persson, Inger, et al.
(författare)
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Multivariate two-sample permutation tests for trials with multiple time-to-event outcomes
- 2019
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Ingår i: Pharmaceutical statistics. - : WILEY. - 1539-1604 .- 1539-1612. ; 18:4, s. 476-485
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Tidskriftsartikel (refereegranskat)abstract
- Clinical trials involving multiple time-to-event outcomes are increasingly common. In this paper, permutation tests for testing for group differences in multivariate time-to-event data are proposed. Unlike other two-sample tests for multivariate survival data, the proposed tests attain the nominal type I error rate. A simulation study shows that the proposed tests outperform their competitors when the degree of censored observations is sufficiently high. When the degree of censoring is low, it is seen that naive tests such as Hotelling's T-2 outperform tests tailored to survival data. Computational and practical aspects of the proposed tests are discussed, and their use is illustrated by analyses of three publicly available datasets. Implementations of the proposed tests are available in an accompanying R package.
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| 10. |
- Sundler Björkman, Linda, et al.
(författare)
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Trends in Treatments With Disease-Specific and Interfering Drugs in Patients With Hereditary Angioedema in Sweden
- 2023
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 2213-2198 .- 2213-2201. ; 11:2, s. 621-628
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hereditary angioedema (HAE) is caused by low levels of or defects in C1 inhibitor. Although disease activity may be modified by prophylaxis, emergency treatment, treatment for comorbidities, and oral contraceptives, the extent of their use is unclear. OBJECTIVE: To investigate trends in the use of disease-specific and interfering drugs in patients with HAE compared with the general population in Sweden. METHODS: In a nationwide, longitudinal study, 239 patients with HAE and 2 383 controls were compared with the Prescribed Drug Register (2005e2019). These data reflect rates of dispensed prescriptions from pharmacies in Sweden. RESULTS: Attenuated androgens were used by approximately 10% of patients with HAE. The number of individuals treated with prophylactic plasma-derived C1 inhibitor increased during this period to reach almost 25% in men and 35% in women in 2019. Tranexamic acid was prescribed to 5% to 15% of patients, primarily children and young adults. Rates of prescriptions for icatibant, an emergency medication, showed a steady increase since its introduction in 2010, in particular among middle-aged women, suggesting poorly controlled disease. The use of di-uretics, calcium channel blockers, and gestagens was more common in patients with HAE than in controls, whereas angiotensin-converting enzyme inhibitors were rarely collected. CONCLUSIONS: Despite concerns regarding side effects, approximately 10% of patients with HAE received attenuated androgens for long-term prophylaxis. The common use of emergency medication also suggests poorly controlled disease in many patients, highlighting the need for increased focus on prophylactic treatment.
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| 11. |
- Thorsell Cederberg, Jenny, et al.
(författare)
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Child and Parent Risk and Resilience Factors as Predictors of Long-term Recovery in Youth Undergoing Spinal Fusion Surgery
- 2024
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Ingår i: The Clinical Journal of Pain. - : Wolters Kluwer. - 0749-8047 .- 1536-5409. ; 40:5, s. 278-287
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Undertreated pediatric postsurgical pain negatively affects health-related quality of life (HRQOL) and functioning and may lead to chronic postsurgical pain (CPSP). Predictors of recovery have been identified but more research is needed, particularly regarding resilience, social factors, and long-term effects. The aim of the present study was to investigate child and parent risk and resilience factors as predictors of long-term postsurgical recovery for adolescents.Methods: Participants were patients with Adolescent Idiopathic Scoliosis (AIS), 12 to 18 years old, undergoing spinal fusion, and their parents. Recruitment occurred at the orthopedic units at 4 hospitals in Belgium. Data were collected before surgery (T0), at 3 (T1) and 6 weeks (T2), 6 months (T3), and 1 year (T4) post surgery. Multiple regression models were used to evaluate the predictive effect of pain intensity, pain catastrophizing, psychological flexibility, and pain acceptance on long-term functioning, HRQOL, and pain.Results: The sample comprised 100 adolescents and 61 parents. Pain at T0, T1, and T3 and adolescent pain catastrophizing (T0) predicted health-related quality of life, functioning, and pain at T4 (while pain at T2 predicted HRQOL and pain). Parent pain catastrophizing predicted pain at T4. Adolescent and parental psychological flexibility predicted HRQOL, and parent psychological flexibility also predicted pain at T4. Adolescent acceptance at T1 predicted pain, and acceptance at T2 predicted HRQOL, at T4.Discussion: The study identified pain and adolescent pain catastrophizing as risk factors, and adolescent and parental psychological flexibility and adolescent pain acceptance as resilience factors, for long-term recovery in youths undergoing spinal fusion. Postsurgical pain management targeting these factors may therefore promote recovery for these adolescents.
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| 12. |
- Thulin, Elisabeth, et al.
(författare)
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Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.
- 2017
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 23, s. 111-118
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 13. |
- Thulin, Måns, 1986-
(författare)
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A high-dimensional two-sample test for the mean using random subspaces
- 2014
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Ingår i: Computational Statistics & Data Analysis. - : Elsevier BV. - 0167-9473 .- 1872-7352. ; 74, s. 26-38
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 14. |
- Thulin, Måns, 1986-
(författare)
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Coverage-adjusted confidence intervals for a binomial proportion
- 2014
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Ingår i: Scandinavian Journal of Statistics. - : Wiley. - 0303-6898 .- 1467-9469. ; 41:2, s. 291-300
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 15. |
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| 16. |
- Thulin, Måns, 1986-, et al.
(författare)
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Exact confidence intervals and hypothesis tests for parameters of discrete distributions
- 2017
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Ingår i: Bernoulli. - 1350-7265 .- 1573-9759. ; 23:1, s. 479-502
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 17. |
- Thulin, Måns, 1986-
(författare)
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On Confidence Intervals and Two-Sided Hypothesis Testing
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 18. |
- Thulin, Måns, 1986-
(författare)
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On split sample and randomized confidence intervals for binomial proportions
- 2014
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Ingår i: Statistics and Probability Letters. - : Elsevier BV. - 0167-7152 .- 1879-2103. ; 92, s. 65-71
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 19. |
- Thulin, Måns, 1986-
(författare)
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The cost of using exact confidence intervals for a binomial proportion
- 2014
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Ingår i: Electronic Journal of Statistics. - 1935-7524. ; 8, s. 817-840
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Thulin, Måns, 1986-
(författare)
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Two-sample tests and one-way MANOVA for multivariate biomarker data with nondetects
- 2016
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Ingår i: Statistics in Medicine. - : Wiley. - 0277-6715 .- 1097-0258. ; 35:20, s. 3623-3644
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 21. |
- Tigchelaar, Celien, et al.
(författare)
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Cerebrospinal fluid and plasma concentrations of the inflammatory marker soluble CD27 in a large surgical population
- 2024
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Ingår i: iScience. - : Elsevier. - 2589-0042. ; 27:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Soluble CD27 (sCD27) has the potential to serve as a biomarker for diseases involving immune system dysfunction. To inform interpretation of assay results, reference values are needed. So far, analysis of cerebrospinal fluid (CSF) sCD27 has mostly been performed in cohorts of patients with neuroinflammatory disorders, and general control data is missing. The aim of this study was therefore to determine reference ranges and to investigate the influence of factors such as age, comorbidity, blood-CSF-barrier (BCB) function (as assessed by the CSF/plasma albumin quotient (Qalb)) and inflammatory status markers, on CSF and plasma sCD27 concentrations in a relatively neurologically healthy surgical population. Methods: CSF and blood were collected from 486 patients undergoing spinal anaesthesia for elective surgery. Patient demographics, clinical data and the results of routine laboratory analyses were analysed for associations with sCD27 levels in CSF and plasma using a univariable and multivariable model. A healthy sub-cohort was selected based on an American Society of Anesthesiologists (ASA) physical status of I or II (healthy patient or with mild systemic disease), and inter alia, no history of cancer, immunological or neurological disorders, heavy tobacco use, or alcohol abuse. For the whole cohort, and the subpopulation of healthy patients we calculated reference intervals as the central 95% of the data.Results: In the total study group (age range 18 – 92 years, 57% male), median [range] CSF sCD27 concentration was 163 [<50 to 7474] pg/mL and median [range] plasma sCD27 concentration was 4624 [1830 to >400,000] pg/mL. In a multivariable model, plasma sCD27 concentration, age and Qalb were identified as most important for explaining the variability of CSF sCD27 levels. Reference sCD27 concentration intervals in the healthy sub-cohort were < 50 pg/mL – 419 pg/mL for CSF (n=125) and 2344 – 36422 pg/mL for plasma (n=158). Conclusions: Our data from a large group of patients reflecting a broad selection from the general population show that CSF sCD27 concentrations correlate with age and Qalb. These findings provide a solid foundation for interpreting sCD27 as clinical biomarker against a background of multiple socio-demographic and physiological aspects that may influence levels. Further studies to establish clinical CSF sCD27 cut-offs for central nervous system diseases should also account for the influence of age and blood-CSF-barrier function.
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| 22. |
- Vikman, Sofia, et al.
(författare)
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Increased levels of a subset of angiogenesis-related plasma proteins in essential thrombocythemia
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 128
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Increased local angiogenesis is important for the growth and dissemination of cancer. The myeloproliferative neoplasm essential thrombocythemia (ET) is known to involve increased bone marrow angiogenesis. Blood levels of several angiogenesis-related proteins are increased in different types of cancer. The aim of this study was to investigate whether a subset of such proteins was elevated in treatment-naïve ET patients.METHODS: Blood plasma from 41 ET patients and 43 healthy aged-matched controls was analyzed for eight different angiogenesis-related proteins.RESULTS: The ET cohort displayed a more homogenous expression pattern of these proteins compared with controls. Five of the eight proteins were significantly increased in ET patients.CONCLUSION: Increased plasma levels of matrix metallopeptidase 9 (MMP9) and endostatin have not previously been reported in ET. In our patients, MMP9 levels correlated positively with Janus kinase 2 (JAK2) V617F allele burden and leukocyte count.
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| 23. |
- Wu, Di, et al.
(författare)
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Profiling surface proteins on individual exosomes using a proximity barcoding assay
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Exosomes have been implicated in numerous biological processes, and they may serve as important disease markers. Surface proteins on exosomes carry information about their tissues of origin. Because of the heterogeneity of exosomes it is desirable to investigate them individually, but this has so far remained impractical. Here, we demonstrate a proximity-dependent barcoding assay to profile surface proteins of individual exosomes using antibody-DNA conjugates and next-generation sequencing. We first validate the method using artificial streptavidin-oligonucleotide complexes, followed by analysis of the variable composition of surface proteins on individual exosomes, derived from human body fluids or cell culture media. Exosomes from different sources are characterized by the presence of specific combinations of surface proteins and their abundance, allowing exosomes to be separately quantified in mixed samples to serve as markers for tissue-specific engagement in disease.
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