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- Berglin, Ewa, MD, PhD, 1955-, et al.
(författare)
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Protein profiling in individuals before onset of anca-associated vasculitis
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79, s. 372-372
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Etiology and pathogenesis of ANCA-associated vasculitis (AAV) is multifactorial and understanding of the processes leading from a healthy immune system to autoimmunity and on to debut of symptoms in AAV is rudimentary.Objectives:To identify inflammatory proteins related to the early processes preceding AAV development, and potential novel biomarkers, using large-scale protein analysesMethods:The Swedish National Patient Register of in-patient carevand the Swedish Cause of Death Register with discharge diagnosis from ICD-9 and-10 for AAV were co-analysed with the registers of 4 different blood biobanks to identify AAV individuals with available samples predating onset of symptom. Of the pre-AAV cases 86 (36 male, 50 female; mean age (SD); 51.9 (16.9) years) were identified with at least one plasma or serum sample (28 plasma, and 100 serum) pre-dating symptom onset (mean (SD); -4.3 (3.1) years), and 14 had 2-3 samples. Serum and plasma control samples matched for sex, age and sampling date were identified (n=198; 82 male, 116 female; mean age (SD); 51.9±15.9 years). The samples were analysed for levels of 92 proteins using proximity extension assay (OLINK inflammation panel, SciLifeLab, Uppsala, Sweden). Data were analysed using routine statistical methods, random forest and Partial Least square-discriminant analysis (PLS-DA).Results:As previously described for the assay significant difference between plasma and serum samples were observed both in pre-AAV individuals and controls. In pre-AAV plasma samples significantly increased concentrations of interleukin (IL)-2, chemokine ligand (CCL)-4, fibroblast growth factor (FGF)21, IL-4 and CCL20 were found closer to symptom onset, (<5 years) than later (> 5 years) and compared with controls. In serum tumor necrosis factor receptor superfamily member (TNFRSF)9, CXCL9, osteoprotegerin and vascular endothelial growth factor-A were significantly increased <5 years before onset vs. later (>5 years) and compared with controls. PLS-DA score scattered plot separated the pre-AAV individuals from healthy controls (R2=0.26), with significantly increased levels of CCL23, CXCL5, and matrix metalloproteinases-1 (MMP-1),transforming growth factor-ß, orosomucoid, en-rage (S100A12) and IL-7 and decreased FGF-19 level in serum. Binary logistic regression analyses comparing tertiles for these proteins confirmed significantly increased odds ratios for disease development of CCL23, CXCL5 and MMP-1. The findings were confirmed in random forest analysis where these factors were among the 20 most discriminatory factors between pre-symptomatic AAV and controls.Conclusion:In serum samples collected years before symptom onset of AAV, proteins involved in immune system activation were increased, suggesting that the inflammatory process is initiated long before clinical manifestations of the disease appear. These findings propose the elevated proteins as novel biomarkers for disease progression.References:[1]Watts et al. Ann Rheum Dis 2007;66:222-22Acknowledgments:Vasculitis Foundation, USADisclosure of Interests:Ewa Berglin: None declared, Anders Esberg: None declared, Johanna Dahlqvist: None declared, Johanna Sjöwall: None declared, Anders Lundquist: None declared, Kristina Lejon: None declared, Ingegerd Johansson: None declared, Aladdin J Mohammad Speakers bureau: lecture fees from Roche and Elli Lilly Sweden, PI (GiACTA study), Solbritt Rantapää Dahlqvist: None declared
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- Gorbach, Tetiana, 1991-
(författare)
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Methods for longitudinal brain imaging studies with dropout
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the challenges in aging research is to understand the brain mechanisms that underlie cognitive development in older adults. Such aging processes are investigated in longitudinal studies, where the within-individual changes over time are observed. However, several methodological issues exist in longitudinal analyses. One of them is loss of participants to follow-up, which occurs when individuals drop out from the study. Such dropout should be taken into account for valid conclusions from longitudinal investigations, and this is the focus of this thesis. The developed methods are used to explore brain aging and its relation to cognition within the Betula longitudinal study of aging.Papers I and II consider the association between changes in brain structure and cognition. In the first paper, regression analysis is used to establish the statistical significance of brain-cognition associations while accounting for dropout. Paper II develops interval estimators directly for an association as measured by partial correlation, when some data are missing. The estimators of Paper II may be used in longitudinal as well as cross-sectional studies and are not limited to brain imaging. Papers III and IV study functional brain connectivity, which is the statistical dependency between the functions of distinct brain regions. Typically, only brain regions with associations stronger than a predefined threshold are considered connected. However, the threshold is often arbitrarily set and does not reflect the individual differences in the overall connectivity patterns. Paper III proposes a mixture model for brain connectivity without explicit thresholding of associations and suggests an alternative connectivity measure. Paper IV extends the mixture modeling of Paper III to a longitudinal setting with dropout and investigates the impact of ignoring the dropout mechanism on the quality of the inferences made on longitudinal connectivity changes.
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| 7. |
- Kissel, Theresa, et al.
(författare)
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Rising ACPA igg variable domain glycosylation pre-disease associates with an increase in autoantibody levels and the development of rheumatoid arthritis
- 2019
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78, s. 249-250
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Anti-citrullinated protein antibodies (ACPA) are present in the majority of rheumatoid arthritis (RA) patients (60-70%) and play a pivotal role in disease development1. ACPA IgGs are unique in a way that they are abundantly N-glycosylated within their variable regions2. These variable domain (V-domain) glycans are found on over 90% of ACPAs present in sera from RA-patients3. To undergo N-linked glycosylation, a consensus sequence in the protein backbone is required (N-X-S/T, where X ≠ P)4. Recently, it was shown that the N-linked glycosylation sites in ACPA-IgG V-domains are introduced during somatic hypermutation and that the introduction of such sites likely conveys a selective advantage to ACPA expressing B-cells5. However, it is currently unknown, whether ACPA-expressing B-cells already introduced glycosylation-sites into their V-domains before disease onset or when ACPA-V-domain glycosylation occurs.Objectives: Investigate the appearance of ACPA V-domain glycosylation in pre-symptomatic individuals and RA patients.Methods In a case-control study, individuals (n=201) from the Medical Biobank, who were sampled before onset of symptoms (mean±SEM predating time; 5.8±0.3 years) (140 aCCP+ and 61 aCCP-), and after diagnosis of RA (n=99, 94 aCCP+ and 5 aCCP-) and randomly selected control samples (n=43, 3 aCCP+ and 40 aCCP-) were analyzed for their ACPA IgG V-domain glycosylation levels. ACPA IgGs were affinity purified, N-linked glycans released, and 2-AA labeled for further analysis using UHPLC6. Data calibration and integration was performed and a cut-off defined. Samples below the cut-off were determined as non-detectable and excluded from the analysis. The percentage V-domain glycosylation was calculated as described previously3. Statistical calculations were performed using SPSS.Results: Our data indicated that ACPA IgG V-domain glycans are already present years before symptom onset, in pre-symptomatic individuals who subsequently will develop RA. Analysis of matched pairs showed a significant increase of ACPA V-domain glycosylation in RA patients compared to individuals pre-disease (p<0.001). The results showed that ACPA N-glycosylation was correlated with anti-CCP concentrations pre-disease (rs =0.504, p<0.001), while no such association can be found after RA onset. Further, V-domain glycosylation levels increase closer to symptom onset.
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- Koch, Elise, 1980-
(författare)
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The genetics of schizophrenia : sex, drugs, and cognition
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cognitive impairment constitutes an important predictor of general functional outcomes in schizophrenia. Polygenic risk for schizophrenia has been linked to cognitive ability as well as brain activation during cognitive processing. Although sex differences have long been observed in schizophrenia patients, it is not known if genetic effects on cognitive phenotypes differ between males and females. Despite attempts to develop drugs that address the cognitive symptoms in schizophrenia or to investigate existing drugs with potential procognitive effects, there are currently no available medications that efficiently treat these symptoms in schizophrenia. The aim of this PhD project was to explore the genetic underpinnings of cognitive symptoms in schizophrenia, and to identify existing drugs that potentially could be used for repurposing to address these symptoms. We identified male-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning as well as brain activation during cognitive processing. Within gene networks, we identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance, and identified novel schizophrenia risk genes that are related to cognitive functioning. Utilizing gene networks incorporating gene expression data, we identified eight existing drugs that could potentially be used for repurposing to address the cognitive symptoms in schizophrenia, most of which have anti-inflammatory and neuroprotective effects. Using sex-specific gene expression data, we identified different repurposing candidates for male and female schizophrenia patients. In conclusion, the findings of this PhD project indicate that the effects of schizophrenia genetics on cognitive functioning are dependent on biological processes that differ between the sexes, and suggest that the cognitive symptoms in schizophrenia should be addressed by sex-specific pharmacological treatments.
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| 9. |
- Lundquist, Anders, 1978-
(författare)
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A note on choosing sampling probabilities for conditional Poisson sampling
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- For conditional Poisson sampling the sampling probabilities and the achieved inclusion probabilities are not identical, which is a problem. We present a general method for choosing the sampling probabilities, which uses only the desired inclusion probabilities and transformations of them. We compare the performance of this new method to other reasonable choices of sampling probabilities.
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- Lundquist, Anders, 1978-
(författare)
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Balanced unequal probability sampling with maximum entropy
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This paper investigates how to perform balanced unequal probability sampling with maximum entropy. Focus is on balancing conditions having the form of known marginal sums in a cross-stratification table. Since only marginal sums are fixed, the sample sizes for one or more cells in the table are random. The probability distribution for those sample sizes can be expressed explicitly but there are computational difficulties except for very small cases. Markov Chain Monte Carlo methods are proposed for obtaining good distribution approximations, as well as sample selection. Some large-sample Gaussian approximations are also considered. Iterative procedures for obtaining sampling probabilities yielding specified inclusion probabilities are discussed.
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