| 1. |
- 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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| 2. |
- Gorbach, Tetiana, 1991-, et al.
(författare)
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Contrasting Identifying Assumptions of Average Causal Effects : Robustness and Semiparametric Efficiency
- 2023
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Ingår i: Journal of machine learning research. - : Microtome Publishing. - 1532-4435 .- 1533-7928. ; 24:197, s. 1-65
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Tidskriftsartikel (refereegranskat)abstract
- Semiparametric inference on average causal effects from observational data is based on assumptions yielding identification of the effects. In practice, several distinct identifying assumptions may be plausible; an analyst has to make a delicate choice between these models. In this paper, we study three identifying assumptions based on the potential outcome framework: the back-door assumption, which uses pre-treatment covariates, the front-door assumption, which uses mediators, and the two-door assumption using pre-treatment covariates and mediators simultaneously. We provide the efficient influence functions and the corresponding semiparametric efficiency bounds that hold under these assumptions, and their combinations. We demonstrate that neither of the identification models provides uniformly the most efficient estimation and give conditions under which some bounds are lower than others. We show when semiparametric estimating equation estimators based on influence functions attain the bounds, and study the robustness of the estimators to misspecification of the nuisance models. The theory is complemented with simulation experiments on the finite sample behavior of the estimators. The results obtained are relevant for an analyst facing a choice between several plausible identifying assumptions and corresponding estimators. Our results show that this choice implies a trade-off between efficiency and robustness to misspecification of the nuisance models.
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| 3. |
- Gorbach, Tetiana, 1991-, et al.
(författare)
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Longitudinal association between hippocampus atrophy and episodic-memory decline in non-demented APOE ε4 carriers
- 2020
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Ingår i: Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. - : John Wiley & Sons. - 2352-8729. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for Alzheimer's disease (AD), accelerated cognitive aging, and hippocampal atrophy, but its influence on the association between hippocampus atrophy and episodic-memory decline in non-demented individuals remains unclear.Methods: We analyzed longitudinal (two to six observations) magnetic resonance imaging (MRI)–derived hippocampal volumes and episodic memory from 748 individuals (55 to 90 years at baseline, 50% female) from the European Lifebrain consortium.Results: The change-change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, P = .007; non-carriers: N = 467, r = 0.073,P = .117). The linear relationship was significantly steeper for the carriers [t(629) =2.4, P = .013]. A similar trend toward a stronger change-change relation for carriers was seen in a subsample with more than two assessments.Discussion: These findings provide evidence for a difference in hippocampus-memory association between ε4 carriers and non-carriers, thus highlighting how genetic factors modulate the translation of the AD-related pathophysiological cascade into cognitive deficits.
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| 4. |
- 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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| 5. |
- Lövdén, Martin, 1972, et al.
(författare)
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No moderating influence of education on the association between changes in hippocampus volume and memory performance in aging
- 2023
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.
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| 6. |
- Moosavi, Niloofar, et al.
(författare)
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A note on sensitivity analysis for post-machine learning causal inference
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In Moosavi et al. (2022) a sensitivity analysis method to unobserved confounding was proposed when estimating an average causal effect with a double robust estimator in high dimensional situations. For this purpose, it was assumed that linear models could sparselyapproximate the nuisance functions (treatment assignment and outcome models). In this note, we relax these assumptions making the sensitivity analysis more generally applicable, for instance when nuisance functions are (weakly) consistently estimated with machine learning algorithms. Simulations and a case study illustrate the performance and use of the method.
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| 7. |
- Moosavi, Niloofar, et al.
(författare)
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Valid causal inference: model selection and sensitivity to unobserved confounding in high-dimensional settings
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recently, various methods have been proposed to estimate causal effects with confidence intervals that are uniformly valid over a set of data generating processes, when high-dimensional nuisance models are estimated by post-model selection or machine learning estimators. These methods typically require that all the confounders are observed to ensure identification of the effects. We contribute by showing how valid semiparametric inference can be obtained in the presence of unobserved confounders and high-dimensional nuisance models. We propose uncertainty intervals which allow for unobserved confounding, and show that the resulting inference is valid when the amount of unobserved confounding is small relative to the sample size; the latter is formalized in terms of convergence rates. Simulation experiments illustrate the finite sample properties of the proposed intervals and investigate an alternative procedure that improves the empirical coverage of the intervals when the amount of unobserved confounding is large.
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| 8. |
- Nordin, Kristin, et al.
(författare)
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DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes : A new window into cognitive aging
- 2022
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 100:6, s. 1296-1320
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Tidskriftsartikel (refereegranskat)abstract
- Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain’s structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20–80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.
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| 9. |
- Pedersen, Robin, et al.
(författare)
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When functional blurring becomes deleterious : Reduced system segregation is associated with less white matter integrity and cognitive decline in aging
- 2021
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 242
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Tidskriftsartikel (refereegranskat)abstract
- Healthy aging is accompanied by progressive decline in cognitive performance and concomitant changes in brain structure and functional architecture. Age-accompanied alterations in brain function have been characterized on a network level as weaker functional connections within brain networks along with stronger interactions between networks. This phenomenon has been described as age-related differences in functional network segregation. It has been suggested that functional networks related to associative processes are particularly sensitive to age-related deterioration in segregation, possibly related to cognitive decline in aging. However, there have been only a few longitudinal studies with inconclusive results. Here, we used a large longitudinal sample of 284 participants between 25 to 80 years of age at baseline, with cognitive and neuroimaging data collected at up to three time points over a 10-year period. We investigated age-related changes in functional segregation among two large-scale systems comprising associative and sensorimotor-related resting-state networks. We found that functional segregation of associative systems declines in aging with exacerbated deterioration from the late fifties. Changes in associative segregation were positively associated with changes in global cognitive ability, suggesting that decreased segregation has negative consequences for domain-general cognitive functions. Age-related changes in system segregation were partly accounted for by changes in white matter integrity, but white matter integrity only weakly influenced the association between segregation and cognition. Together, these novel findings suggest a cascade where reduced white-matter integrity leads to less distinctive functional systems which in turn contributes to cognitive decline in aging.
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| 10. |
- Ruotsalainen, Ilona, et al.
(författare)
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Physical activity, aerobic fitness, and brain white matter : Their role for executive functions in adolescence
- 2020
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Ingår i: Developmental Cognitive Neuroscience. - : Elsevier. - 1878-9293 .- 1878-9307. ; 42
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity and exercise beneficially link to brain properties and cognitive functions in older adults, but the findings concerning adolescents remain tentative. During adolescence, the brain undergoes significant changes, which are especially pronounced in white matter. Studies provide contradictory evidence regarding the influence of physical activity or aerobic-exercise on executive functions in youth. Little is also known about the link be- tween both fitness and physical activity with the brain’s white matter during puberty. We investigated the connection between aerobic fitness and physical activity with the white matter in 59 adolescents. We further determined whether white matter interacts with the connection of fitness or physical activity with core executive functions. Our results show that only the level of aerobic fitness, but not of physical activity relates to white matter. Furthermore, the white matter of the corpus callosum and the right superior corona radiata moderates the links of aerobic fitness and physical activity with working memory. Our results suggest that aerobic fitness and physical activity have an unequal contribution to the white matter properties in adolescents. We propose that the differences in white matter properties could underlie the variations in the relationship between either physical activity or aerobic fitness with working memory.
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