| 1. |
- Alexandrov, Ludmil B, et al.
(författare)
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The repertoire of mutational signatures in human cancer
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 94-101
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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| 2. |
- Coenen, Pieter, et al.
(författare)
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Bias and power in group-based epidemiologic studies of low-back pain exposure and outcome : effects of study size and exposure measurement efforts
- 2015
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Ingår i: Annals of Occupational Hygiene. - : Oxford University Press (OUP). - 0003-4878 .- 1475-3162. ; 59:4, s. 439-454
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Exposure-outcome studies, for instance on work-related low-back pain (LBP), often classify workers into groups for which exposures are estimated from measurements on a sample of workers within or outside the specific study. The present study investigated the influence on bias and power in exposure-outcome associations of the sizes of the total study population and the sample used to estimate exposures.Methods: At baseline, lifting, trunk flexion, and trunk rotation were observed for 371 of 1131 workers allocated to 19 a-priori defined occupational groups. LBP (dichotomous) was reported by all workers during three years of follow-up. All three exposures were associated with LBP in this parent study (p<0.01).All 21 combinations of n=10,20,30 workers per group with an outcome, and k=1,2,3,5,10,15,20 workers actually being observed were investigated using bootstrapping, repeating each combination 10,000 times. Odds ratios (OR) with p-values were determined for each of these virtual studies. Average OR and statistical power (p<0.05 and p<0.01) was determined from the bootstrap distributions at each (n,k) combination.Results: For lifting and flexed trunk, studies including n≥20 workers, with k≥5 observed, led to an almost unbiased OR and a power >0.80 (p-level 0.05). A similar performance required n≥30 workers for rotated trunk. Small numbers of observed workers (k) resulted in biased OR, while power was, in general, more sensitive to the total number of workers (n).Conclusions: In epidemiologic studies using a group-based exposure assessment strategy, statistical performance may be sufficient if outcome is obtained from a reasonably large number of workers, even if exposure is estimated from only few workers per group.
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| 3. |
- Coenen, Pieter, et al.
(författare)
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Group-based exposuremeasurement strategies and their effects on trunk rotation and low-back pain exposure-outcome associations
- 2013
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Ingår i: Occupational & Environmental Medicine. - : BMJ Journals. ; , s. A101-A102
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Konferensbidrag (refereegranskat)abstract
- Objectives In epidemiological studies of occupational exposures (e.g. lifting) and low-back pain (LBP), group-based exposure measurement strategies are common. Workers are classified into exposure groups; exposure is measured only in a selection of workers in each group, and their mean exposure is assigned to all workers in the group. Exposure-outcome relationships are then determined by regression, relating exposure estimates with individual LBP data from all subjects. The objective of this study was to assess the effect of different group-based measurement strategies on exposure-outcome associations.Methods 1122 workers, classified into 19 groups on the basis of job-related exposure, participated in this study. In each group, videos were collected from ~25% of the workers (in total, 370 workers), and percentage of the work day spent in trunk rotation was estimated by observation of the videos. This estimate of trunk rotation was significantly associated with self-reported LBP during three years of follow-up (OR:1.43 (1.06–1.93)).Using a bootstrap simulation, workers per group (n = 10, 20, 30, 40) and percentage of observed workers (k = 10, 20, 30, 40, 50%) were varied. For each combination, (nk) workers were selected with replacement in each job group among those observed, and n (100-k) workers among those not observed. The mean exposure of the observed workers was assigned to all group members which was related to individual LBP data. ORs and accompanying p-level was estimated using logistic-regression.Results A group-based measurement protocol led to significant (p < 0.05) ORs when the total number of workers was larger than n = 30 in each job group, and ≥20% was actually observed.Conclusions The proportion of observed workers did have an effect on p-values, but it appeared weaker than that of changing the total group size. These results suggest that it may be sufficient to observe only a minor proportion of workers if the overall size of the population is reasonably large.
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| 4. |
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| 5. |
- Coenen, Pieter, et al.
(författare)
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The effect of the presence and characteristics of an outlying group on exposure-outcome associations
- 2015
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Ingår i: Scandinavian Journal of Work, Environment and Health. - : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 41:1, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Physical exposures (e.g., lifting or bending) are believed to be risk factors for low-back pain (LBP), but the literature is inconsistent. Exposure and LBP prevalence differ considerably between occupations, and so exposure-outcome associations could be severely modified by the presence of particular occupational groups. We aimed at investigating the influence of such outlying groups on the properties of associations between exposure and LBP.Methods: Lifting and trunk flexion were observed for 371 of 1131 workers within 19 groups. LBP was obtained from all workers during three follow-up years. Both exposure variables were associated with LBP (p<0.01) in this parent dataset.By removing the 19 groups one-by-one and performing logistic regressions analysis on the 18 remaining groups, we demonstrated that one group, mainly road workers, with outlying exposures and LBP prevalence substantially affected the exposure-outcome association in the total population. In order to further examine this phenomenon, we assessed, by simulation, the influence of realistic sizes (n=4, 8, 16, 32, 64, 128), mean exposures (e=2000, 3000, 4000 lifts and e=30, 40, 50% trunk flexion time) and LBP prevalences (p=70, 80, 90, 100%) of the outlying group on the strength and certainty of the eventual relationship between exposure and LBP. For each combination of n, e and p, 3000 virtual studies were constructed, including the simulated group together with the other 18 original groups from the parent data-set. Average OR, OR confidence limits, and power (p<0.05) were calculated across these 3,000 studies as measures of the properties of each virtual study design.Results: ORs were attenuated more towards 1 and power decreased with smaller values of n, e and p in the outlying group. Changes in group size and prevalence had a larger influence on OR and power than changes in mean exposure.Conclusions: The size and characteristics of a single group with high exposure and outcome prevalence can strongly influence both the OR point estimate and the likelihood of obtaining significant exposure-outcome associations in studies of large populations. These findings can guide interpretations of prior epidemiological studies and support informed design of future studies.
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| 6. |
- von Scheibler, Emma N.M.M., et al.
(författare)
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Parkinsonism in Genetic Neurodevelopmental Disorders : A Systematic Review
- 2023
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Ingår i: Movement Disorders Clinical Practice. - : Wiley. - 2330-1619. ; 10:1, s. 17-31
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Forskningsöversikt (refereegranskat)abstract
- Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.
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