| 51. |
- Brazel, David M., et al.
(författare)
-
Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
- 2019
-
Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 85:11, s. 946-955
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
|
|
| 52. |
- Ellinor, Patrick T., et al.
(författare)
-
Meta-analysis identifies six new susceptibility loci for atrial fibrillation
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:6, s. 88-670
-
Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death(1). We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 x 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
|
|
| 53. |
- Lanza, Nina L., et al.
(författare)
-
Oxidation of manganese in an ancient aquifer, Kimberley formation, Gale crater, Mars
- 2016
-
Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:14, s. 7398-7407
-
Tidskriftsartikel (refereegranskat)abstract
- The Curiosity rover observed high Mn abundances (>25wt % MnO) in fracture-filling materials that crosscut sandstones in the Kimberley region of Gale crater, Mars. The correlation between Mn and trace metal abundances plus the lack of correlation between Mn and elements such as S, Cl, and C, reveals that these deposits are Mn oxides rather than evaporites or other salts. On Earth, environments that concentrate Mn and deposit Mn minerals require water and highly oxidizing conditions; hence, these findings suggest that similar processes occurred on Mars. Based on the strong association between Mn-oxide deposition and evolving atmospheric dioxygen levels on Earth, the presence of these Mn phases on Mars suggests that there was more abundant molecular oxygen within the atmosphere and some groundwaters of ancient Mars than in the present day
|
|
| 54. |
- Levis, Brooke, et al.
(författare)
-
Comparison of major depression diagnostic classification probability using the SCID, CIDI, and MINI diagnostic interviews among women in pregnancy or postpartum : An individual participant data meta-analysis
- 2019
-
Ingår i: International Journal of Methods in Psychiatric Research. - : WILEY. - 1049-8931 .- 1557-0657. ; 28:4
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: A previous individual participant data meta-analysis (IPDMA) identified differences in major depression classification rates between different diagnostic interviews, controlling for depressive symptoms on the basis of the Patient Health Questionnaire-9. We aimed to determine whether similar results would be seen in a different population, using studies that administered the Edinburgh Postnatal Depression Scale (EPDS) in pregnancy or postpartum.Methods: Data accrued for an EPDS diagnostic accuracy IPDMA were analysed. Binomial generalised linear mixed models were fit to compare depression classification odds for the Mini International Neuropsychiatric Interview (MINI), Composite International Diagnostic Interview (CIDI), and Structured Clinical Interview for DSM (SCID), controlling for EPDS scores and participant characteristics.Results Among fully structured interviews, the MINI (15 studies, 2,532 participants, 342 major depression cases) classified depression more often than the CIDI (3 studies, 2,948 participants, 194 major depression cases; adjusted odds ratio [aOR] = 3.72, 95% confidence interval [CI] [1.21, 11.43]). Compared with the semistructured SCID (28 studies, 7,403 participants, 1,027 major depression cases), odds with the CIDI (interaction aOR = 0.88, 95% CI [0.85, 0.92]) and MINI (interaction aOR = 0.95, 95% CI [0.92, 0.99]) increased less as EPDS scores increased.Conclusion Different interviews may not classify major depression equivalently.
|
|
| 55. |
- Rajaraman, Preetha, et al.
(författare)
-
Genome-wide association study of glioma and meta-analysis
- 2012
-
Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 131:12, s. 1877-1888
-
Tidskriftsartikel (refereegranskat)abstract
- Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
|
|
| 56. |
- Rice, Gillian I, et al.
(författare)
-
Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.
- 2017
-
Ingår i: Neuropediatrics. - : Georg Thieme Verlag KG. - 1439-1899 .- 0174-304X. ; 48:3, s. 166-184
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
|
|
| 57. |
- Sofer, Tamar, et al.
(författare)
-
A fully adjusted two-stage procedure for rank-normalization in genetic association studies
- 2019
-
Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 43:3, s. 263-275
-
Tidskriftsartikel (refereegranskat)abstract
- When testing genotype–phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. Because genotypes are expected to have small effects (if any) investigators now routinely use a two‐stage method, in which they first regress the trait on covariates, obtain residuals, rank‐normalize them, and then use the rank‐normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice, no further adjustment is done in the second stage. Here, we show that this widely used approach can lead to tests with undesirable statistical properties, due to both combination of a mis‐specified mean–variance relationship and remaining covariate associations between the rank‐normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome‐wide and whole‐genome sequencing association studies. We further propose and evaluate an alternative fully adjusted two‐stage approach that adjusts for covariates both when residuals are obtained and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.
|
|
| 58. |
- Steadman, Randolph H., et al.
(författare)
-
Screen-Based Simulation for Training and Automated Assessment of Teamwork Skills Comparing 2 Modes With Different Interactivity
- 2021
-
Ingår i: Simulation in Healthcare. - : LIPPINCOTT WILLIAMS & WILKINS. - 1559-2332 .- 1559-713X. ; 16:5, s. 318-326
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The need for teamwork training is well documented; however, teaching these skills is challenging given the logistics of assembling individual team members together to train in person. We designed 2 modes of screen-based simulation for training teamwork skills to assess whether interactivity with nonplayer characters was necessary for in-game performance gains or for player satisfaction with the experience. Methods: Mixed, randomized, repeated measures study with licensed healthcare providers block-stratified and randomized to evaluation-participant observes and evaluates the team player in 3 scenarios-and game play-participant is immersed as the leader in the same 3 scenarios. Teamwork construct scores (leadership, communication, situation monitoring, mutual support) from an ontology-based, Bayesian network assessment model were analyzed using mixed randomized repeated measures analyses of variance to compare performance, across scenarios and modes. Learning was measured by pretest and posttest quiz scores. User experience was evaluated using chi(2) analyses. Results: Among 166 recruited and randomized participants, 120 enrolled in the study and 109 had complete data for analysis. Mean composite teamwork Bayesian network scores improved for successive scenarios in both modes, with evaluation scores statistically higher than game play for every teamwork construct and scenario (r = 0.73, P = 0.000). Quiz scores improved from pretest to posttest (P = 0.004), but differences between modes were not significant. Conclusions: For training teamwork skills using screen-based simulation, interactivity of the player with the nonplayer characters is not necessary for in-game performance gains or for player satisfaction with the experience.
|
|
| 59. |
- Ulmert, David, et al.
(författare)
-
Imaging androgen receptor signaling with a radiotracer targeting free prostate-specific antigen.
- 2012
-
Ingår i: Cancer Discovery. - 2159-8274. ; 2:4, s. 320-327
-
Tidskriftsartikel (refereegranskat)abstract
- Despite intense efforts to develop radiotracers to detect cancers or monitor treatment response, few are widely used as a result of challenges with demonstrating clear clinical use. We reasoned that a radiotracer targeting a validated clinical biomarker could more clearly assess the advantages of imaging cancer. The virtues and shortcomings of measuring secreted prostate-specific antigen (PSA), an androgen receptor (AR) target gene, in patients with prostate cancer are well documented, making it a logical candidate for assessing whether a radiotracer can reveal new (and useful) information beyond that conferred by serum PSA. Therefore, we developed (89)Zr-labeled 5A10, a novel radiotracer that targets "free" PSA. (89)Zr-5A10 localizes in an AR-dependent manner in vivo to models of castration-resistant prostate cancer, a disease state in which serum PSA may not reflect clinical outcomes. Finally, we demonstrate that (89)Zr-5A10 can detect osseous prostate cancer lesions, a context where bone scans fail to discriminate malignant and nonmalignant signals.
|
|
