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| 3. |
- Dai, Qile, et al.
(författare)
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OTTERS: a powerful TWAS framework leveraging summary-level reference data
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
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| 4. |
- Oresic, Matej, 1967-, et al.
(författare)
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Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury
- 2016
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 12, s. 118-126
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n=22), moderate (moTBI; n=14) or mild TBI (mTBI; n=108) according to Glasgow Coma Scale. The control group (n=28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n=23), moTBI (n=7), mTBI (n=37) patients and controls (n=27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC=0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified 'TBI metabotype' in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new venue for the development of diagnostic and prognostic markers of broad spectrum of TBIs. (C) 2016 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 5. |
- Pappa, Irene, et al.
(författare)
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A genome-wide approach to children's aggressive behavior : The EAGLE consortium.
- 2016
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 171:5, s. 562-572
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Tidskriftsartikel (refereegranskat)abstract
- Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.
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| 6. |
- Posti, Jussi P., et al.
(författare)
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SERUM METABOLITES ASSOCIATE WITH HEAD COMPUTED TOMOGRAPHY FINDINGS FOLLOWING TRAUMATIC BRAIN INJURY
- 2018
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:16, s. A67-A67
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of bio-markers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminalhydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein bio-markers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, thre esugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge pa-tients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.
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| 8. |
- Dickens, Alex Mountfort, et al.
(författare)
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Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury
- 2018
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:22, s. 2673-2683
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Tidskriftsartikel (refereegranskat)abstract
- There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.
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| 10. |
- Farias, Fabiana H. G., et al.
(författare)
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A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers
- 2011
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 42:3, s. 468-474
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Tidskriftsartikel (refereegranskat)abstract
- A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations: however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.
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| 11. |
- Hossain, Iftakher, et al.
(författare)
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Early Levels of Glial Fibrillary Acidic Protein and Neurofilament Light Protein in Predicting the Outcome of Mild Traumatic Brain Injury
- 2019
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Ingår i: Journal of neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 36:10, s. 1551-1560
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Tidskriftsartikel (refereegranskat)abstract
- To correlate the early levels of glial fibrillary acidic protein (GFAP) and neurofilament light protein (NF-L) with outcome in patients with mild traumatic brain injury (mTBI). 107 patients with mTBI [Glasgow Coma Scale (GCS) ≥13] having the blood samples for GFAP and NF-L available within 24 hrs from arrival were included. Patients with mTBI were divided into computed tomography (CT)-positive and CT-negative groups. Glasgow Outcome Scale extended (GOSE) was used to assess the outcome. Outcomes were defined as complete (GOSE 8) vs. incomplete (GOSE <8), and favorable (GOSE 5-8) vs. unfavorable (GOSE 1-4). GFAP and NF-L concentrations in blood were measured using ultrasensitive single molecule array technology. Patients with incomplete recovery had significantly higher levels of NF-L compared to those with complete recovery (p=0.005). The levels of GFAP and NF-L were significantly higher in patients with unfavorable outcome than in patients with favorable outcome (p=0.002 for GFAP and p <0.001 for NF-L). For predicting favorable outcome, the area under the ROC curve for GFAP and NF-L was 0.755 and 0.826, respectively. In a multivariate logistic regression model, the level of NF-L was still a significant predictor for complete recovery (OR=1.008, 95%CI, 1.000-1.016). Moreover, the level of NF-L was a significant predictor for complete recovery in CT-positive patients (OR=1.009, 95%CI, 1.001-1.016). The early levels of GFAP and NF-L are significantly correlated with the outcome in patients with mTBI. The level of NF-L within 24 hrs from arrival has a significant predictive value in mTBI also in a multivariate model.
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| 12. |
- Newnham, D. A., et al.
(författare)
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Observations and Modeling of Increased Nitric Oxide in the Antarctic Polar Middle Atmosphere Associated With Geomagnetic Storm-Driven Energetic Electron Precipitation
- 2018
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 123:7, s. 6009-6025
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) produced in the polar middle and upper atmosphere by energetic particle precipitation depletes ozone in the mesosphere and, following vertical transport in the winter polar vortex, in the stratosphere. Medium-energy electron (MEE) ionization by 30-1,000 keV electrons during geomagnetic storms may have a significant role in mesospheric NO production. However, questions remain about the relative importance of direct NO production by MEE at altitudes similar to 60-90 km versus indirect NO originating from auroral ionization above 90 km. We investigate potential drivers of NO variability in the southern-hemisphere mesosphere and lower thermosphere during 2013-2014. Contrasting geomagnetic activity occurred during the two austral winters, with more numerous moderate storms in the 2013 winter. Ground-based millimeter-wave observations of NO from Halley, Antarctica, are compared with measurements by the Solar Occultation For Ice Experiment (SOFIE) spaceborne spectrometer. NO partial columns over the altitude range 65-140 km from the two observational data sets show large day-to-day variability and significant disagreement, with Halley values on average 49% higher than the corresponding SOFIE data. SOFIE NO number densities, zonally averaged over geomagnetic latitudes -59 degrees to -65 degrees, are up to 3 x 10(8)/cm(3) higher in the winter of 2013 compared to 2014. Comparisons with a new version of the Whole Atmosphere Community Climate Model, which includes detailed D-region ion chemistry (WACCM-SIC) and MEE ionization rates, show that the model underestimates NO in the winter lower mesosphere whereas thermospheric abundances are too high. This indicates the need to further improve and verify WACCM-SIC with respect to MEE ionization, thermospheric NO chemistry, and vertical transport.
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| 13. |
- Nivette, Amy E., et al.
(författare)
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A global analysis of the impact of COVID-19 stay-at-home restrictions on crime
- 2021
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Ingår i: Nature Human Behaviour. - : Nature Publishing Group. - 2397-3374. ; 5, s. 868-877
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Tidskriftsartikel (refereegranskat)abstract
- The implementation of COVID-19 stay-at-home policies was associated with a considerable drop in urban crime in 27 cities across 23 countries. More stringent restrictions over movement in public space were predictive of larger declines in crime. The stay-at-home restrictions to control the spread of COVID-19 led to unparalleled sudden change in daily life, but it is unclear how they affected urban crime globally. We collected data on daily counts of crime in 27 cities across 23 countries in the Americas, Europe, the Middle East and Asia. We conducted interrupted time series analyses to assess the impact of stay-at-home restrictions on different types of crime in each city. Our findings show that the stay-at-home policies were associated with a considerable drop in urban crime, but with substantial variation across cities and types of crime. Meta-regression results showed that more stringent restrictions over movement in public space were predictive of larger declines in crime.
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