| 1. |
- Cheng, Timothy H T, et al.
(författare)
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Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.
- 2015
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 23:2
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Tidskriftsartikel (refereegranskat)abstract
- The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.
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| 2. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 3. |
- Ebersole, Charles R., et al.
(författare)
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Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability
- 2020
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Ingår i: Advances in Methods and Practices in Psychological Science. - : Sage. - 2515-2467 .- 2515-2459. ; 3:3, s. 309-331
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Tidskriftsartikel (refereegranskat)abstract
- Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3-9; median total sample = 1,279.5, range = 276-3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Delta r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00-.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19-.50).
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| 4. |
- Hayden, Brian, et al.
(författare)
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The HST See Change Program. I. Survey Design, Pipeline, and Supernova Discoveries
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 912:2
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Tidskriftsartikel (refereegranskat)abstract
- The See Change survey was designed to make z > 1 cosmological measurements by efficiently discovering high-redshift Type Ia supernovae (SNe Ia) and improving cluster mass measurements through weak lensing. This survey observed twelve galaxy clusters with the Hubble Space Telescope (HST) spanning the redshift range z = 1.13-1.75, discovering 57 likely transients and 27 likely SNe Ia at z similar to 0.8-2.3. As in similar previous surveys, this proved to be a highly efficient use of HST for supernova observations; the See Change survey additionally tested the feasibility of maintaining, or further increasing, the efficiency at yet higher redshifts, where we have less detailed information on the expected cluster masses and star formation rates. We find that the resulting number of SNe Ia per orbit is a factor of similar to 8 higher than for a field search, and 45% of our orbits contained an active SN Ia within 22 rest-frame days of peak, with one of the clusters by itself yielding 6 of the SNe Ia. We present the survey design, pipeline, and supernova discoveries. Novel features include fully blinded supernova searches, the first random forest candidate classifier for undersampled IR data (with a 50% detection threshold within 0.05 mag of human searchers), real-time forward-modeling photometry of candidates, and semi-automated photometric classifications and follow-up forecasts. We also describe the spectroscopic follow-up, instrumental in measuring host galaxy redshifts. The cosmology analysis of our sample will be presented in a companion paper.
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| 5. |
- Hsieh, Samantha, et al.
(författare)
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Polysaccharide Capsules Equip the Human Symbiont Bacteroides thetaiotaomicron to Modulate Immune Responses to a Dominant Antigen in the Intestine
- 2020
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 204:4, s. 1035-1046
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4+ T cell, BθOM, that is specific for B. thetaiotaomicron and a complete set of single CPS-expressing B. thetaiotaomicron strains, we ask whether CPSs can modify the immune responses to specific bacterial Ags. Acapsular B. thetaiotaomicron, which lacks all B. thetaiotaomicron CPSs, stimulated BθOM T cells more strongly than wild-type B. thetaiotaomicron Despite similar levels of BθOM Ag expression, many single CPS-expressing B. thetaiotaomicron strains were antistimulatory and weakly activated BθOM T cells, but a few strains were prostimulatory and strongly activated BθOM T cells just as well or better than an acapsular strain. B. thetaiotaomicron strains that expressed an antistimulatory CPS blocked Ag delivery to the immune system, which could be rescued by Fc receptor-dependent Ab opsonization. All single CPS-expressing B. thetaiotaomicron strains stimulated the innate immune system to skew toward M1 macrophages and release inflammatory cytokines in an MyD88-dependent manner, with antistimulatory CPS activating the innate immune system in a weaker manner than prostimulatory CPS. The expression of antistimulatory versus prostimulatory CPSs on outer membrane vesicles also regulated immune responses. Moreover, antistimulatory and prostimulatory single CPS-expressing B. thetaiotaomicron strains regulated the activation of Ag-specific and polyclonal T cells as well as clearance of dominant Ag in vivo. These studies establish that the immune responses to specific bacterial Ags can be modulated by a diverse set of CPSs.
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| 6. |
- Johansson, Christian, 1973-
(författare)
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Interaction Between Microgels and Oppositely Charged Proteins
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis reports on interactions between microgels and oppositely charged proteins. Two types of negatively charged microgels are investigated: poly(acrylic acid) microgels of 60-80 µm in diameter, and colloidal poly(NIPAM-co-acrylic acid) microgels of around 1 µm in diameter. The proteins used are lysozyme and cytochrome c, which both have positive net charge. The experimental techniques used in the studies of the larger microgels are mainly micromanipulator-assisted microscopy and confocal microscopy, while the smaller microgels are studied mainly with dynamic light scattering. It is observed that large amounts of protein are absorbed by the microgels, and that the uptake involves a substantial deswelling of the microgel. The uptake generally decreases as the ionic strength is increased, which is characteristic of electrostatic interactions. An ionic strength optimum is however observed in the case of lysozyme and poly(acrylic acid) microgels, where the highest uptake (10 gram lysozyme / gram microgel) is observed at ionic strength 40 mM. Cytochrome c uptake in poly(acrylic acid) microgels results in homogenous cytochrome c distribution throughout the microgel, whereas lysozyme uptake results in core-shell formation; the lysozyme concentration becomes much higher in the shell (outer part of the microgel) than in the core (inner part of the microgel). The shell constitutes a stress-bearing network which is sufficiently porous to allow protein diffusion through the shell. The different protein distributions are associated with different protein-protein interactions; strong protein-protein attraction promotes shell formation. In the case of colloidal microgels, lysozyme uptake decreases the electrophoretic mobility and the colloidal stability of the microgels. The microgels flocculate as the uptake reaches charge ratio 0.6-0.7 (positive lysozyme charges/negative microgel charges), largely independent of ionic strength. Initial experiments on the combination of cytochrome c and colloidal microgels show that colloidal stability is maintained at a range of conditions (ionic strength, protein concentration) where flocculation occurred in the case of lysozyme.
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| 7. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 8. |
- Kaufman, Darrell, et al.
(författare)
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A global database of Holocene paleotemperature records
- 2020
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format.
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| 9. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 10. |
- Mahabal, Ashish, et al.
(författare)
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Machine Learning for the Zwicky Transient Facility
- 2019
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Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 131:997
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Tidskriftsartikel (refereegranskat)abstract
- The Zwicky Transient Facility is a large optical survey in multiple filters producing hundreds of thousands of transient alerts per night. We describe here various machine learning (ML) implementations and plans to make the maximal use of the large data set by taking advantage of the temporal nature of the data, and further combining it with other data sets. We start with the initial steps of separating bogus candidates from real ones, separating stars and galaxies, and go on to the classification of real objects into various classes. Besides the usual methods (e.g., based on features extracted from light curves) we also describe early plans for alternate methods including the use of domain adaptation, and deep learning. In a similar fashion we describe efforts to detect fast moving asteroids. We also describe the use of the Zooniverse platform for helping with classifications through the creation of training samples, and active learning. Finally we mention the synergistic aspects of ZTF and LSST from the ML perspective.
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