| 1. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 2. |
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| 3. |
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| 4. |
- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 5. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 6. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 7. |
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| 8. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 9. |
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| 10. |
- Middeldorp, C. M., et al.
(författare)
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A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts
- 2016
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Ingår i: Journal of the American Academy of Child and Adolescent Psychiatry. - : Elsevier BV. - 0890-8567. ; 55:10
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Method Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. Results SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46× 10−6 and 2.66× 10−6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. Conclusion The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants. © 2016 American Academy of Child and Adolescent Psychiatry
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| 11. |
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| 12. |
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| 13. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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| 14. |
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| 15. |
- Bousquet, J, et al.
(författare)
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Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper
- 2012
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Ingår i: International archives of allergy and immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 158:3, s. 216-231
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Tidskriftsartikel (refereegranskat)abstract
- Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.
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| 16. |
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| 17. |
- Horikoshi, Momoko, et al.
(författare)
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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| 18. |
- Willer, Cristen J., et al.
(författare)
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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
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Tidskriftsartikel (refereegranskat)abstract
- Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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| 19. |
- Artigas Soler, María, et al.
(författare)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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| 20. |
- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 21. |
- Zuberbier, T., et al.
(författare)
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Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA(2)LEN position paper
- 2022
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Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 77:6, s. 1736-1750
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Tidskriftsartikel (refereegranskat)abstract
- Background Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. Methods MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. Results In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. Conclusion Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.
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| 22. |
- Bousquet, J, et al.
(författare)
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GA2LEN (Global Allergy and Asthma European Network) addresses the allergy and asthma 'epidemic'.
- 2009
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 64:7, s. 969-77
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Tidskriftsartikel (refereegranskat)abstract
- Allergic diseases represent a major health problem in Europe. They are increasing in prevalence, severity and costs. The Global Allergy and Asthma European Network (GA(2)LEN), a Sixth EU Framework Program for Research and Technological Development (FP6) Network of Excellence, was created in 2005 as a vehicle to ensure excellence in research bringing together research and clinical institutions to combat fragmentation in the European research area and to tackle allergy in its globality. The Global Allergy and Asthma European Network has benefited greatly from the voluntary efforts of researchers who are strongly committed to this model of pan-European collaboration. The network was organized in order to increase networking for scientific projects in allergy and asthma around Europe and to make GA(2)LEN the world leader in the field. Besides these activities, research has also been carried out and the first papers are being published. Achievements of the Global Allergy and Asthma European Network can be grouped as follows: (i) those for a durable infrastructure built up during the project phase, (ii) those which are project-related and based on these novel infrastructures, and (iii) the development and implementation of guidelines. The major achievements of GA(2)LEN are reported in this paper.
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| 23. |
- Ring, A., et al.
(författare)
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Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer
- 2021
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 125, s. 209-219
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration: ISRCTN 46099296. © 2021, The Author(s).
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| 24. |
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| 25. |
- Barker, Adam, et al.
(författare)
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Association of genetic loci with glucose levels in childhood and adolescence a meta-analysis of over 6,000 children
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 60:6, s. 1805-1812
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011
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| 26. |
- Battisti, N. M. L., et al.
(författare)
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Observational cohort study in older women with early breast cancer: Use of radiation therapy and impact on health-related quality of life and mortality
- 2021
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140. ; 161, s. 166-176
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Tidskriftsartikel (refereegranskat)abstract
- Background: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL). Methods: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires. Results: In 2013–2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months. Conclusion: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient. © 2021 Elsevier B.V.
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| 27. |
- Franceschini, N, et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 5141-
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
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| 28. |
- Klimek, L, et al.
(författare)
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Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemiea, b, c: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H
- 2020
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Ingår i: Allergo Journal : interdisziplinare Zeitschrift fur Allergologie und Umweltmedizin : Organ der Deutschen Gesellschaft fur Allergie- und Immunitatsforschung. - : Springer Science and Business Media LLC. - 0941-8849. ; 29:4, s. 14-27
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Tidskriftsartikel (refereegranskat)
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| 29. |
- Klimek, L, et al.
(författare)
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Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA)A, Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI)B, Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI)D, Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI)E, Österreichische Gesellschaft für Pneumologie (ÖGP)F in co-operation with the German, Austrian, and Swiss ARIA groupsG, and the European Academy of Allergy and Clinical Immunology (EAACI)H
- 2020
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Ingår i: Allergologie select. - 2512-8957. ; 4, s. 53-68
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Tidskriftsartikel (refereegranskat)
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| 30. |
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| 31. |
- Taal, H. Rob, et al.
(författare)
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Common variants at 12q15 and 12q24 are associated with infant head circumference
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 532-538
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
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| 32. |
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| 33. |
- Lopes, T. S., et al.
(författare)
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Cu(In,Ga)Se2 based ultrathin solar cells the pathway from lab rigid to large scale flexible technology
- 2023
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Ingår i: npj Flexible Electronics. - : Springer Nature. - 2397-4621. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- The incorporation of interface passivation structures in ultrathin Cu(In,Ga)Se2 based solar cells is shown. The fabrication used an industry scalable lithography technique—nanoimprint lithography (NIL)—for a 15 × 15 cm2 dielectric layer patterning. Devices with a NIL nanopatterned dielectric layer are benchmarked against electron-beam lithography (EBL) patterning, using rigid substrates. The NIL patterned device shows similar performance to the EBL patterned device.The impact of the lithographic processes in the rigid solar cells’ performance were evaluated via X-ray Photoelectron Spectroscopy and through a Solar Cell Capacitance Simulator. The device on stainless-steel showed a slightly lower performance than the rigid approach, due to additional challenges of processing steel substrates, even though scanning transmission electron microscopy did not show clear evidence of impurity diffusion. Notwithstanding, time-resolved photoluminescence results strongly suggested elemental diffusion from the flexible substrate. Nevertheless, bending tests on the stainless-steel device demonstrated the mechanical stability of the CIGS-based device.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Wollenberg, A., et al.
(författare)
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ETFAD/EADV Eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children
- 2020
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Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 0926-9959 .- 1468-3083. ; 34:12, s. 2717-2744
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Tidskriftsartikel (refereegranskat)abstract
- Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient’s age and also target flare prevention. Basic therapy includes hydrating and barrier-stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti-inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid-potency corticosteroids are proven agents for proactive therapy, which is defined as the long-term intermittent anti-inflammatory therapy of frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit–risk ratio. The IL-4R-blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side-effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) only have limited effects on AD-related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient-specific, and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. Efficacy-proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Morgan, J. L., et al.
(författare)
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Observational cohort study to determine the degree and causes of variation in the rate of surgery or primary endocrine therapy in older women with operable breast cancer
- 2021
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983. ; 47:2, s. 261-268
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the UK there is variation in the treatment of older women with breast cancer, with up to 40% receiving primary endocrine therapy (PET), which is associated with inferior survival. Case mix and patient choice may explain some variation in practice but clinician preference may also be important. Methods: A multicentre prospective cohort study of women aged >70 with operable breast cancer. Patient characteristics (health status, age, tumour characteristics, treatment allocation and decision-making preference) were analysed to identify whether treatment variation persisted following case-mix adjustment. Expected case-mix adjusted surgery rates were derived by logistic regression using the variables age, co-morbidity, tumour stage and grade. Concordance between patients’ preferred and actual decision-making style was assessed and associations between age, treatment and decision-making style calculated. Results: Women (median age 77, range 70–102) were recruited from 56 UK breast units between 2013 and 2018. Of 2854/3369 eligible women with oestrogen receptor positive breast cancer, 2354 were treated with surgery and 500 with PET. Unadjusted surgery rates varied between hospitals, with 23/56 units falling outside the 95% confidence intervals on funnel plots. Adjusting for case mix reduced, but did not eliminate, this variation between hospitals (10/56 units had practice outside the 95% confidence intervals). Patients treated with PET had more patient-centred decisions compared to surgical patients (42.2% vs 28.4%, p < 0.001). Conclusions: This study demonstrates variation in treatment selection thresholds for older women with breast cancer. Health stratified guidelines on thresholds for PET would help reduce variation, although patient preference should still be respected. © 2020 The Authors
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| 42. |
- Pappa, Irene, et al.
(författare)
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A genome-wide approach to children's aggressive behavior : The EAGLE consortium.
- 2016
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 171:5, s. 562-572
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Tidskriftsartikel (refereegranskat)abstract
- Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.
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| 43. |
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| 44. |
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| 45. |
- van der Harst, Pim, et al.
(författare)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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| 46. |
- Warrington, N M, et al.
(författare)
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Maternal and fetal genetic contribution to gestational weight gain.
- 2018
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Ingår i: International journal of obesity. - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 42:4, s. 775-84
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Tidskriftsartikel (refereegranskat)abstract
- Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10543 mothers and 16317 offspring of European origin, with replication in 10660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.International Journal of Obesity advance online publication, 21 November 2017; doi:10.1038/ijo.2017.248.
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| 47. |
- Wyld, L., et al.
(författare)
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Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices
- 2021
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 108:5, s. 499-510
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P=0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P=0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P=0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P=0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com). © The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.
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| 48. |
- Wyld, L., et al.
(författare)
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Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life
- 2021
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 142, s. 48-62
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Tidskriftsartikel (refereegranskat)abstract
- Background: Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. Methods: Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. Findings: A total of 3416 women (median age 77, range 69–102) were recruited from 56 breast units—2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23–0.33, P < 0.001). Unmatched breast cancer–specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29–0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53–0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40–1.37, P = 0.34) although at 4–5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance. Interpretation: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4–5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). Trial registration number: ISRCTN: 46099296. © 2020 The Authors
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| 49. |
- Wyld, L., et al.
(författare)
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Improving outcomes for women aged 70 years or above with early breast cancer: Research programme including a cluster RCT
- 2022
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Ingår i: Programme Grants for Applied Research. - 2050-4322. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: In breast cancer management, age-related practice variation is widespread, with older women having lower rates of surgery and chemotherapy than younger women, based on the premise of reduced treatment tolerance and benefit. This may contribute to inferior outcomes. There are currently no age-and fitness-stratified guidelines on which to base treatment recommendations. Aim: We aimed to optimise treatment choice and outcomes for older women (aged > 70 years) with operable breast cancer. Objectives: Our objectives were to (1) determine the age, comorbidity, frailty, disease stage and biology thresholds for endocrine therapy alone versus surgery plus adjuvant endocrine therapy, or adjuvant chemotherapy versus no chemotherapy, for older women with breast cancer; (2) optimise survival outcomes for older women by improving the quality of treatment decision-making; (3) develop and evaluate a decision support intervention to enhance shared decision-making; and (4) determine the degree and causes of treatment variation between UK breast units. Design: A prospective cohort study was used to determine age and fitness thresholds for treatment allocation. Mixed-methods research was used to determine the information needs of older women to develop a decision support intervention. A cluster-randomised trial was used to evaluate the impact of this decision support intervention on treatment choices and outcomes. Health economic analysis was used to evaluate the cost-benefit ratio of different treatment strategies according to age and fitness criteria. A mixed-methods study was used to determine the degree and causes of variation in treatment allocation. Main outcome measures: The main outcome measures were enhanced age-and fitness-specific decision support leading to improved quality-of-life outcomes in older women (aged > 70 years) with early breast cancer. Results: (1) Cohort study: The study recruited 3416 UK women aged > 70 years (median age 77 years). Follow-up was 52 months. (a) The surgery plus adjuvant endocrine therapy versus endocrine therapy alone comparison: 2854 out of 3416 (88%) women had oestrogen-receptor-positive breast cancer, 2354 of whom received surgery plus adjuvant endocrine therapy and 500 received endocrine therapy alone. Patients treated with endocrine therapy alone were older and frailer than patients treated with surgery plus adjuvant endocrine therapy. Unmatched overall survival and breast-cancer-specific survival were higher in the surgery plus adjuvant endocrine therapy group (overall survival: Hazard ratio 0.27, 95% confidence interval 0.23 to 0.33; p < 0.001; breast-cancer-specific survival: Hazard ratio 0.41, 95% confidence interval 0.29 to 0.58; p < 0.001) than in the endocrine therapy alone group. In matched analysis, surgery plus adjuvant endocrine therapy was still associated with better overall survival (hazard ratio 0.72, 95% confidence interval 0.53 to 0.98; p = 0.04) than endocrine therapy alone, but not with better breast-cancer-specific survival (hazard ratio 0.74, 95% confidence interval 0.40 to 1.37; p = 0.34) or progression-free-survival (hazard ratio 1.11, 95% confidence interval 0.55 to 2.26; p = 0.78). (b) The adjuvant chemotherapy versus no chemotherapy comparison: 2811 out of 3416 (82%) women received surgery plus adjuvant endocrine therapy, of whom 1520 (54%) had high-recurrence-risk breast cancer [grade 3, node positive, oestrogen receptor negative or human epidermal growth factor receptor-2 positive, or a high Oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA) score of > 25]. In this high-risk population, there were no differences according to adjuvant chemotherapy use in overall survival or breast-cancer-specific survival after propensity matching. Adjuvant chemotherapy was associated with a lower risk of metastatic recurrence than no chemotherapy in the unmatched (adjusted hazard ratio 0.36, 95% confidence interval 0.19 to 0.68; p = 0.002) and propensity-matched patients (adjusted hazard ratio 0.43, 95% confidence interval 0.20 to 0.92; p = 0.03). Adjuva t chemotherapy improved the overall survival and breast-cancer-specific survival of patients with oestrogen-receptor-negative disease. (2) Mixed-methods research to develop a decision support intervention: An iterative process was used to develop two decision support interventions (each comprising a brief decision aid, a booklet and an online tool) specifically for older women facing treatment choices (endocrine therapy alone or surgery plus adjuvant endocrine therapy, and adjuvant chemotherapy or no chemotherapy) using several evidence sources (expert opinion, literature and patient interviews). The online tool was based on models developed using registry data from 23,842 patients and validated on an external data set of 14,526 patients. Mortality rates at 2 and 5 years differed by < 1% between predicted and observed values. (3) Cluster-randomised clinical trial of decision support tools: 46 UK breast units were randomised (intervention, n = 21; usual care, n = 25), recruiting 1339 women (intervention, n = 670; usual care, n = 669). There was no significant difference in global quality of life at 6 months post baseline (difference-0.20, 95% confidence interval-2.7 to 2.3; p = 0.90). In women offered a choice of endocrine therapy alone or surgery plus adjuvant endocrine therapy, knowledge about treatments was greater in the intervention arm than the usual care arm (94% vs. 74%; p = 0.003). Treatment choice was altered, with higher rates of endocrine therapy alone than of surgery in the intervention arm. Similarly, chemotherapy rates were lower in the intervention arm (endocrine therapy alone rate: Intervention sites 21% vs. usual-care sites 15%, difference 5.5%, 95% confidence interval 1.1% to 10.0%; p = 0.02; adjuvant chemotherapy rate: Intervention sites 10% vs. usual-care site 15%, difference 4.5%, 95% confidence interval 0.0% to 8.0%; p = 0.013). Survival was similar in both arms. (4) Health economic analysis: A probabilistic economic model was developed using registry and cohort study data. For most health and fitness strata, surgery plus adjuvant endocrine therapy had lower costs and returned more quality-adjusted life-years than endocrine therapy alone. However, for some women aged > 90 years, surgery plus adjuvant endocrine therapy was no longer cost-effective and generated fewer quality-adjusted life-years than endocrine therapy alone. The incremental benefit of surgery plus adjuvant endocrine therapy reduced with age and comorbidities. (5) Variation in practice: analysis of rates of surgery plus adjuvant endocrine therapy or endocrine therapy alone between the 56 breast units in the cohort study demonstrated significant variation in rates of endocrine therapy alone that persisted after adjustment for age, fitness and stage. Clinician preference was an important determinant of treatment choice. Conclusions: This study demonstrates that, for older women with oestrogen-receptor-positive breast cancer, there is a cohort of women with a life expectancy of < 4 years for whom surgery plus adjuvant endocrine therapy may offer little benefit and simply have a negative impact on quality of life. The Age Gap decision tool may help make this shared decision. Similarly, although adjuvant chemotherapy offers little benefit and has a negative impact on quality of life for the majority of older women with oestrogen-receptor-positive breast cancer, for women with oestrogen-receptor-negative breast cancer, adjuvant chemotherapy is beneficial. The negative impacts of adjuvant chemotherapy on quality of life, although significant, are transient. This implies that, for the majority of fitter women aged > 70 years, standard care should be offered. Limitations: As with any observational study, despite detailed propensity score matching, residual bias cannot be excluded. Follow-up was at median 52 months for the cohort analysis. Longer-term follow-up will be required to validate these findings owing to the slow time course of oestrogen-receptor-positive breast cancer. Future work: The online algorithm is now available (URL: Https://ag gap.shef.ac.uk/; accessed May 2022). There are plans to validate the tool and incorprate quality-of-life and 10-year survival outcomes.
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| 50. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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