| 21. |
- Gorbach, Tetiana, 1991-, et al.
(författare)
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A Hierarchical Bayesian Mixture Model Approach for Analysis of Resting-State Functional Brain Connectivity : An Alternative to Thresholding
- 2020
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Ingår i: Brain Connectivity. - : Mary Ann Liebert. - 2158-0014 .- 2158-0022. ; 10:5, s. 202-211
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Tidskriftsartikel (refereegranskat)abstract
- This article proposes a Bayesian hierarchical mixture model to analyze functional brain connectivity where mixture components represent "positively connected" and "non-connected" brain regions. Such an approach provides a data-informed separation of reliable and spurious connections in contrast to arbitrary thresholding of a connectivity matrix. The hierarchical structure of the model allows simultaneous inferences for the entire population as well as for each individual subject. A new connectivity measure, the posterior probability of a given pair of brain regions of a specific subject to be connected given the observed correlation of regions' activity, can be computed from the model fit. The posterior probability reflects the connectivity of a pair of regions relative to the overall connectivity pattern of an individual, which is overlooked in traditional correlation analyses. This article demonstrates that using the posterior probability might diminish the effect of spurious connections on inferences, which is present when a correlation is used as a connectivity measure. In addition, simulation analyses reveal that the sparsification of the connectivity matrix using the posterior probabilities might outperform the absolute thresholding based on correlations. Therefore, we suggest that posterior probability might be a beneficial measure of connectivity compared with the correlation. The applicability of the introduced method is exemplified by a study of functional resting-state brain connectivity in older adults.
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| 22. |
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| 23. |
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| 24. |
- 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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| 25. |
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| 26. |
- Kissel, Theresa, et al.
(författare)
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On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding 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. ; 78:12, s. 1616-1620
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.Methods: ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).Results: V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.Conclusion: Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.
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| 27. |
- 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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| 28. |
- Koch, Elise, et al.
(författare)
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Interactome overlap between schizophrenia and cognition
- 2020
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Ingår i: Schizophrenia Research. - : Elsevier. - 0920-9964 .- 1573-2509. ; 222, s. 167-174
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive impairments constitute a core feature of schizophrenia, and a genetic overlap between schizophrenia and cognitive functioning in healthy individuals has been identified. However, due to the high polygenicity and complex genetic architecture of both traits, overlapping biological pathways have not yet been identified between schizophrenia and normal cognitive ability. Network medicine offers a framework to study underlying biological pathways through protein-protein interactions among risk genes. Here, established network-based methods were used to characterize the biological relatedness of schizophrenia and cognition by examining the genetic link between schizophrenia risk genes and genes associated with cognitive performance in healthy individuals, through the protein interactome. First, network separation showed a profound interactome overlap between schizophrenia risk genes and genes associated with cognitive performance (S-AB = -0.22, z-score = -6.80, p= 5.38e-12). To characterize this overlap, network propagation was thereafter used to identify schizophrenia risk genes that are close to cognition-associated genes in the interactome network space (n = 140, of which 54 were part of the direct genetic overlap). Schizophrenia risk genes close to cognition were enriched for pathways including long-termpotentiation and Alzheimer's disease, and included genes with a role in neurotransmitter systems important for cognitive functioning, such as glutamate and dopamine. These results pinpoint a subset of schizophrenia risk genes that are of particular interest for further examination in schizophrenia patient groups, of which some are druggable genes with potential as candidate targets for cognitive enhancing drugs.
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| 29. |
- Koch, Elise, et al.
(författare)
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Polygenic Risk for Schizophrenia Has Sex-Specific Effects on Brain Activity during Memory Processing in Healthy Individuals
- 2022
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Genetic risk for schizophrenia has a negative impact on memory and other cognitive abilities in unaffected individuals, and it was recently shown that this effect is specific to males. Using functional MRI, we investigated the effect of a polygenic risk score (PRS) for schizophrenia on brain activation during working memory and episodic memory in 351 unaffected participants (167 males and 184 females, 25–95 years), and specifically tested if any effect of PRS on brain activation is sex-specific. Schizophrenia PRS was significantly associated with decreased brain activation in the left dorsolateral prefrontal cortex (DLPFC) during working-memory manipulation and in the bilateral superior parietal lobule (SPL) during episodic-memory encoding and retrieval. A significant interaction effect between sex and PRS was seen in the bilateral SPL during episodic-memory encoding and retrieval, and sex-stratified analyses showed that the effect of PRS on SPL activation was male-specific. These results confirm previous findings of DLPFC inefficiency in schizophrenia, and highlight the SPL as another important genetic intermediate phenotype of the disease. The observed sex differences suggest that the previously shown male-specific effect of schizophrenia PRS on cognition translates into an additional corresponding effect on brain functioning.
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| 30. |
- Koch, Elise, et al.
(författare)
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Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals
- 2021
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Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife, and late-life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25–100 years (N = 1459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the lifespan indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.
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