| 1. |
- 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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| 2. |
- Amundadottir, Laufey, et al.
(författare)
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Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41, s. 986-990
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.
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| 3. |
- Heath, Geoffrey
(författare)
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Performance Management and Rationalityin Public Sector Organisations
- 2019
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract and Keywords The thesis concerns different conceptions of rationality and their implications for organisations, especially in the public sector. The focus is on performance management (as widely defined) within public sector organisations as a subject for exploring these issues. This has long been controversial because seemingly simplistic approaches to performance management persist, despite well recognised shortcomings, such as a tendency to perverse incentives and unintended outcomes. Therefore, in the kappa, I analyse the notion of instrumental rationality, examine the established critique of instrumental rationality from a ‘political’ perspective and present the dilemma that this creates; i.e. how to improve processes of resource allocation and performance evaluation, while recognising organisational realities such as imbalances in power. The potential of communicative rationality as an alternative conceptualisation of rationality in organisations is then discussed. The development of public sector management from the fiscal crises of the 1970s is explained, with the rise of the ‘New Public Management’ based on neo-liberal ideas, and the subsequent opposition to it from ‘New Public Governance’ and ‘New Public Services’ paradigms. These potentially give more scope to participative and deliberative processes of generating performance measurement packages and control systems. Moreover, in practice, particularly interesting examples of participatory approaches have been found in developing countries which align with communicative rationality. A critical position is adopted in the thesis, seeking to challenge ‘managerialist’ orthodoxies. As a theoretical guide to understanding these issues, conceptual frameworks from the management control literature are used. Broadbent and Laughlin’s (2009) conceptual model of performance management systems has been of particular value. They draw on Weber and Habermas to distinguish between instrumental and communicative rationality models and between transactional and relational performance management systems. This enables them to identify two distinct ideal types of ‘rationality clusters’ (instrumental and communicative) to which organisations will incline. They also contend that contingent factors influence where actual organisations are located between these two ideal types. 7 The four papers I have selected for the licentiate from my various publications report on research carried out in three different public sector settings using different methods of investigation. Paper 1 considers the approaches to resource allocation and performance measurement then used by English Health Authorities at the time of writing. In Paper 2 an evaluation carried out at an English police service, utilising cost-consequences analysis, is described and discussed. Papers 3 and 4 concern a performance management regime for the English ambulance service, which became noted for promoting perverse incentives and ‘gaming’, and its subsequent replacement. The first two papers foreground issues of rationality and the last two issues of performance management; but these topics are interrelated and are relevant throughout. It is argued in all the papers that comprehensively ‘rationalistic’ approaches are flawed and that participation, deliberation and dialogue between stakeholders are desirable.
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| 4. |
- Heath, Geoffrey
(författare)
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Performance Management, Rationality and Participation in Public Sector Organisation
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis critically examines the role of performance management in public sector organisations. In particular, it explores how performance management relates to different concepts of rationality (instrumental, value and communicative), including issues around rationality and power, and the relationship between these concepts and various models of participation and democracy. In it, theoretical accounts of public sector management, particularly the New Public Management (NPM) and New Public Governance (NPG) are analysed; theoretical accounts of democracy, including deliberative democracy and agonistic pluralism, are investigated; and conceptual contributions from the accounting and management control literature are discussed.This thesis builds on one for which a Licentiate in Philosophy was awarded in 2019 (Heath, 2019). That thesis concerned the nature of instrumental and communicative rationality and their implications for public sector organisations, especially in connection with performance evaluation. The role of performance management has long been controversial in the public sector because of the prevalence of imposed performance regimes with well-known perverse incentives and unintended consequences; which, nevertheless, are recurring problems. It was concluded that such regimes persist despite their limitations because they seem to legitimise public services through claims to instrumental rationality. However, a more deliberative and participatory approach to performance management, enacting communicative rationality, could have distinct advantages over the more commonly applied methods.The issues raised there are investigated here in greater theoretical depth, with the key ideas advanced further and to a higher level of analysis. In order to do this, the four papers selected for the Licentiate are enhanced by a further three papers, chosen specifically for this doctoral thesis. All the papers referred to are based on research using a range of methods which had been carried out in various public sector settings. Thus the doctoral thesis comprises: Paper A (about higher education); Paper B (about ambulance services) and Paper C (about public services generally but drawing particularly on ambulance services). Paper A concerns the views of HR professionals in UK Universities on how their role contributes to organisational effectiveness and especially to organisational change. Paper B focuses on cultural transformation and perpetuation in ambulance services and explores the relationship between cultures, performance measures and organisational change. Paper C examines performance measurement within the public sector and the problems that can be encountered, with special reference to the English ambulance service. Although all the cases are drawn from England, international research has also been examined in the thesis.Themes of democracy, rationality and power, public governance, and accounting and performance management are explored. The analysis of these themes draws particularly on Broadbent and Laughlin’s (2009) conceptual framework of performance management systems. Their model distinguishes between two ideal types: the instrumental rationality cluster is associated with rational-legal authority and transactional performance management systems and the communicative rationality cluster with reflexive authority and relational performance management systems.Simplistic, imposed performance management regimes are a feature of the NPM, which is seen here as a neo-liberal response to the fiscal and legitimacy crises of the 1970s. This places public sector organisations near the instrumental rationality cluster, but it is proposed that many of them might belong closer to the communicative rationality cluster. This points to attempts to bring participation, deliberation and discourse into public management and accountability. It is contended that, although adopting Deliberative Democracy in a ‘pure’ form may be utopian, combinations of representative and participatory democracy might be developed, reflecting contingent factors and path dependency. Participatory Budgeting is one practical example of this. In addition some forms of the NPG are conducive to it.The papers selected for the two theses are written from a critical-interpretive perspective. This perspective focuses on how accounting affects and is affected by organisational behaviour and political and social institutions, rather than seeing it as a neutral and purely technical instrument. The work anticipates the call of Steccolini (2019) and Steccolini et al. (2020) for interdisciplinary studies in public sector accounting. Moreover, it forms part of the ‘turn’ to social theory in the academic accounting literature identified by Jack (2017). The thesis makes its particular contribution to the literature by demonstrating the potential of democratic and participatory approaches to enhance performance management in the public services; whilst recognising complexity and contingency.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- Petersen, Gloria M, et al.
(författare)
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A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 224-228
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.
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| 9. |
- Robbins, Hilary A., et al.
(författare)
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Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program
- 2023
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Ingår i: Annals of Epidemiology. - : Elsevier. - 1047-2797 .- 1873-2585. ; 77, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
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| 10. |
- Yngve, Agneta, 1953-, et al.
(författare)
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The Women's Health Initiative. What is on trial : nutrition and chronic disease? Or misinterpreted science, media havoc and the sound of silence from peers?
- 2006
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Ingår i: Public Health Nutrition. - 1368-9800 .- 1475-2727. ; 9:2, s. 269-272
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Tidskriftsartikel (refereegranskat)abstract
- The first results of the Women's Health Initiative dietary intervention trial were published in the USA in February. This is a colossal intervention designed to see if diets lower in fat and higher in fruits, vegetables and grains than is usual in high-income countries reduce the incidence of breast cancer, colorectal cancer, heart disease and other chronic diseases, in women aged 50-79 years. As interpreted by US government media releases, the results were unimpressive. As interpreted by a global media blitz, the results indicate that food and nutrition has little or nothing to do with health and disease. But the trial was in key respects not reaching its aims, was methodologically controversial, and in any case has not produced the reported null results. What should the public health nutrition profession do about such messes?
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