| 1. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 2. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 4. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 5. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 6. |
- Adelani, David Ifeoluwa, et al.
(författare)
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MasakhaNER 2.0: Africa-centric Transfer Learning for Named Entity Recognition
- 2022
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Ingår i: Proceedings of the 2022 Conference on Empirical Methods in Natural Language Processing. - : Association for Computational Linguistics (ACL). ; , s. 4488-4508
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Konferensbidrag (refereegranskat)abstract
- African languages are spoken by over a billion people, but are underrepresented in NLP research and development. The challenges impeding progress include the limited availability of annotated datasets, as well as a lack of understanding of the settings where current methods are effective. In this paper, we make progress towards solutions for these challenges, focusing on the task of named entity recognition (NER). We create the largest human-annotated NER dataset for 20 African languages, and we study the behavior of state-of-the-art cross-lingual transfer methods in an Africa-centric setting, demonstrating that the choice of source language significantly affects performance. We show that choosing the best transfer language improves zero-shot F1 scores by an average of 14 points across 20 languages compared to using English. Our results highlight the need for benchmark datasets and models that cover typologically-diverse African languages.
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| 7. |
- Adelani, David Ifeoluwa, et al.
(författare)
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MasakhaNER: Named Entity Recognition for African Languages
- 2021
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Ingår i: Transactions of the Association for Computational Linguistics. - : MIT Press. - 2307-387X. ; 9, s. 1116-1131
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Tidskriftsartikel (refereegranskat)abstract
- We take a step towards addressing the under-representation of the African continent in NLP research by bringing together different stakeholders to create the first large, publicly available, high-quality dataset for named entity recognition (NER) in ten African languages. We detail the characteristics of these languages to help researchers and practitioners better understand the challenges they pose for NER tasks. We analyze our datasets and conduct an extensive empirical evaluation of state-of-the-art methods across both supervised and transfer learning settings. Finally, we release the data, code, and models to inspire future research on African NLP.
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| 8. |
- Mezza, D., et al.
(författare)
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Calibration methods for charge integrating detectors
- 2022
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 1024
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Tidskriftsartikel (refereegranskat)abstract
- Since the introduction of the extremely intense X-ray free electron lasers, the need for low noise, high dynamic range and potentially fast charge integrating detectors has increased significantly. Among all the problems that research and development groups have to face in the development of such detectors, their calibration represents one of the most challenging and the collaboration between the detector development and user groups is of fundamental importance. The main challenge is to develop a calibration suite that is capable to test the detector over a wide dynamic range, with a high granularity and a very high linearity, together with a certain radiation tolerance and the possibility to well define the timings and the synchronization with the detector. Practical considerations have also to be made like the possibility to calibrate the detector in a reasonable time, the availability of the calibration source at the experimental place and so on. Such a calibration test suite is often not represented by a single source but by several sources that can cover different parts of the dynamic range and that need to be cross calibrated to have a final calibration curve. In this respect an essential part of the calibration is also to develop a mathematical model that allows calibrating the entire dynamic range, taking into account features that are calibration source and/or detector specific. The aim of this contribution is to compare the calibration for the AGIPD detector using several calibration sources such as internal current source, backside pulsing, IR pulsed laser, LED light and mono-energetic protons. The mathematical procedure used to calibrate the different sources will be discussed in great detail showing how to take into account a few shortcomings (like pixel coupling) that are common for many charge integrating detectors. This work has been carried out in the frame of the AGIPD project for the European X-ray Free Electron Laser.
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| 9. |
- Mezza, D., et al.
(författare)
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Characterization of the AGIPD1.1 readout chip and improvements with respect to AGIPD1.0
- 2019
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 945
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Tidskriftsartikel (refereegranskat)abstract
- AGIPD, the Adaptive Gain Integrating Pixel Detector, is a hybrid detector with a frame rate of 4.5 MHz, a dynamic range up to 104⋅ 12.4 keV photons, as well as single photon resolution, developed for the European XFEL (Eu.XFEL). The final 1 Mpixel detector system consists of 16 tiled modules each one with 16 readout chips. The single ASIC is 64 x 64 pixels, each with a size of 200 x 200 μm2. Each pixel can store up to 352 images. This work is focused on the characterization of AGIPD1.1, the second version of the full scale ASIC, and the improvements with respect to AGIPD1.0. From the measurements presented in this paper we show that the flaws observed in AGIPD1.0 (i.e. ghosting, crosstalk, slow readout speed) have been fixed in AGIPD1.1. In addition the main performance parameters such as noise, dynamic range and so on were measured for the new version of the ASIC and will be summarized.
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| 10. |
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