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Search Results: 1 - 10 of 223915 matches for " Robert N Luben "
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Accuracy of death certification and hospital record linkage for identification of incident stroke
Shubhada Sinha, Phyo K Myint, Robert N Luben, Kay-Tee Khaw
BMC Medical Research Methodology , 2008, DOI: 10.1186/1471-2288-8-74
Abstract: We examined a sample of hospital records of incident stroke cases identified by linkage with two routine data sources, death certificates and a national hospital record linkage system (ENCORE), using predefined study criteria. Two senior Specialist Registrars with clinical experience in stroke medicine examined the hospital records and searched for the evidence of stroke recorded in these records between 1993/97–2003.Of 520 incident strokes identified between 1993/1997–2003 using record linkage systems in the EPIC-Norfolk, a sample of 250 medical case notes were examined between March and July 2004. Using the predefined study criteria, there were 191 definite strokes (76%), 20 probable strokes (8%), 11 possible strokes and 11 cases of transient ischaemic attacks (4% each) i.e. 233/250 (93%) with possible or definite stroke or transient ischaemic attacks. Stroke could not be verified using hospital records in 13 cases (5%) and 4 cases (2%) had other diagnoses: 3 cases of vascular dementia and 1 case of benign intracranial hypertension. The diagnosis of stroke in 185 out of 250 cases identified in the EPIC-Norfolk (74.0%) was supported by radiological evidence using WHO criteria.Death certificates and hospital record linkage in this British prospective study have a high accuracy or positive predictive value in correctly identifying incident stroke cases.Deeper insight and better understanding of stroke epidemiology plays an important role in its primary prevention. Large population-based studies with long-term follow-up provide valuable information on prospective relationships between biological, physiological and lifestyle factors and the risk of incident stroke. Most of them rely on self-report and/or death certification data for case ascertainment. Previous validation studies of self-reported prevalent and incident stroke showed high percentages of both false positive and false negative cases that varied between different studies [1-9].Death certification data are
Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study
Adam Naguib, Panagiota N Mitrou, Laura J Gay, James C Cooke, Robert N Luben, Richard Y Ball, Alison McTaggart, Mark J Arends, Sheila A Rodwell
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-99
Abstract: 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations. Diet and lifestyle data were collected prospectively using seven day food diaries.BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p < 0.001). K-ras mutation (mostly in codons 12 and 13) was found in 22.0% of colorectal cancers but at higher frequencies in cancers of more advanced Dukes' stage (p = 0.001), microsatellite stable (MSS) status (p = 0.002) and in individuals with lower blood high-density lipoprotein concentrations (p = 0.04). Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent, however, K-ras mutation was found at higher frequencies in individuals with higher white meat consumption (p < 0.001). Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit (p = 0.02).These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors, acting as mutually exclusive mechanisms of activation of the same signalling pathway.BRAF and K-ras genes both encode proteins that act in the ERK signalling pathway, which mediates cellular responses to growth factors and regulates elements of the cell cycle, apoptosis and differentiation [1]. Activating mutations in both genes have been found in colorectal cancer with mutation frequencies of 4-13% for BRAF [2-9] and of 20-50% for K-ras [10-17] having been reported. BRAF and K-ras mutations are frequently found to be mutually exclusive in colorectal cancer [5,18] and both genes harbour the majority of mutations in distinct hotspots: BRAF at codons 463-468 [19] and 600 [18,19] and K-ras at codons 12 and 13 [20] and also, bu
Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors
Adam Naguib, James C Cooke, Lisa Happerfield, Lucy Kerr, Laura J Gay, Robert N Luben, Richard Y Ball, Panagiota N Mitrou, Alison McTaggart, Mark J Arends
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-123
Abstract: 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires.Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55).These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.The PI3K/AKT signalling pathway affects many cellular processes including cell proliferation, apoptosis and invasion [1]. Signal transduction through this pathway is mediated through conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3) by phosphatidylinositol 3 kinases (PI3K) following their activation, and this reaction is antagonised by phosphatase and tensin homolog, deleted on chromosome ten (PTEN) activity. Of the genes which encode the enzymatic subunit of PI3K heterodimers, the PIK3CA gene, e
Mendelian Randomisation Study of Childhood BMI and Early Menarche
Hannah S. Mumby,Cathy E. Elks,Shengxu Li,Stephen J. Sharp,Kay-Tee Khaw,Robert N. Luben,Nicholas J. Wareham,Ruth J. F. Loos,Ken K. Ong
Journal of Obesity , 2011, DOI: 10.1155/2011/180729
Abstract: To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established “BMI-increasing” genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39–77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI-associated common variants (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2 and SH2B1), and for each individual a “BMI-increasing-allele-score” was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1 kg/m2 increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6–8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche.
Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study
Shengxu Li,Jing Hua Zhao,Jian'an Luan,Ulf Ekelund,Robert N. Luben,Kay-Tee Khaw,Nicholas J. Wareham,Ruth J. F. Loos
PLOS Medicine , 2010, DOI: 10.1371/journal.pmed.1000332
Abstract: Background We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study. Methods and Findings We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39–79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012) kg/m2 (p = 6.73×10?37) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (pinteraction = 0.005) more pronounced in inactive people (0.205 [SE 0.024] kg/m2 [p = 3.62×10?18; 592 g in weight]) than in active people (0.131 [SE 0.014] kg/m2 [p = 7.97×10?21; 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093–1.139, p = 3.37×10?26) in the whole population, but significantly (pinteraction = 0.015) more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118–1.199; p = 1.93×10?16]) than in active individuals (OR = 1.095 (95% CI 1.068–1.123; p = 1.15×10?12]). Consistent with the cross-sectional observations, physical activity modified the association between the genetic predisposition score and change in BMI during follow-up (pinteraction = 0.028). Conclusions Our study shows that living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity, as estimated by the number of risk alleles carried for any of the 12 recently GWAS-identified loci. Please see later in the article for the Editors' Summary
A Latent Variable Partial Least Squares Path Modeling Approach to Regional Association and Polygenic Effect with Applications to a Human Obesity Study
Fuzhong Xue, Shengxu Li, Jian'an Luan, Zhongshang Yuan, Robert N. Luben, Kay-Tee Khaw, Nicholas J. Wareham, Ruth J. F. Loos, Jing Hua Zhao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031927
Abstract: Genetic association studies are now routinely used to identify single nucleotide polymorphisms (SNPs) linked with human diseases or traits through single SNP-single trait tests. Here we introduced partial least squares path modeling (PLSPM) for association between single or multiple SNPs and a latent trait that can involve single or multiple correlated measurement(s). Furthermore, the framework naturally provides estimators of polygenic effect by appropriately weighting trait-attributing alleles. We conducted computer simulations to assess the performance via multiple SNPs and human obesity-related traits as measured by body mass index (BMI), waist and hip circumferences. Our results showed that the associate statistics had type I error rates close to nominal level and were powerful for a range of effect and sample sizes. When applied to 12 candidate regions in data (N = 2,417) from the European Prospective Investigation of Cancer (EPIC)-Norfolk study, a region in FTO was found to have stronger association (rs7204609~rs9939881 at the first intron P = 4.29×10?7) than single SNP analysis (all with P>10?4) and a latent quantitative phenotype was obtained using a subset sample of EPIC-Norfolk (N = 12,559). We believe our method is appropriate for assessment of regional association and polygenic effect on a single or multiple traits.
Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs
Patrick R Benusiglio, Fabienne Lesueur, Craig Luccarini, Joan McIntosh, Robert N Luben, Paula Smith, Alison Dunning, Douglas F Easton, Bruce AJ Ponder, Paul D Pharoah
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-81
Abstract: We used a genetic association study design to determine if common genetic variation (frequency ≥ 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman? in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional.HapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t>g), rs4245443 (IVS7 g>a), rs2513511 (IVS16 a>g), rs2155220 (3'down c>t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a>g) and rs11600501 (IVS10 c>t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population.We found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women.Breast and ovarian cancer are two of the most common causes of cancer in women in the United Kingdom (Office for National Statistics). Together, they account for about a third of all new cancer cases and a quarter of cancer deaths.
Mendelian Randomisation Study of Childhood BMI and Early Menarche
Hannah S. Mumby,Cathy E. Elks,Shengxu Li,Stephen J. Sharp,Kay-Tee Khaw,Robert N. Luben,Nicholas J. Wareham,Ruth J. F. Loos,Ken K. Ong
Journal of Obesity , 2011, DOI: 10.1155/2011/180729
Abstract: To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established “BMI-increasing” genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39–77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI-associated common variants (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2 and SH2B1), and for each individual a “BMI-increasing-allele-score” was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1?kg/ increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6–8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche. 1. Introduction Early age at menarche, the onset of menstrual periods in girls, is associated with increased risks of adverse health outcomes such as breast, ovarian, and endometrial cancer, hypertension, type 2 diabetes, and cardiovascular disease [1, 2]. Earlier age at menarche is also associated with increased risk for a number of psychosocial outcomes in adolescence including depression, eating disorders, substance abuse, sexual risk-taking and teenage pregnancy [3]. It has been suggested that childhood BMI has a causal effect on the risk for early menarche and there are a number of strongly plausible biological mechanisms [4, 5]. However, discordant secular trends in obesity and age at menarche have raised doubts about the causal nature of these associations. In developed countries, a long-term trend towards earlier menarche has been observed from the late 1800s to the mid 1900s [6]. In many countries these trends appear to have slowed or even stopped since around 1950 [6] while the prevalence of childhood overweight and obesity has increased since the 1980s [7]. It is possible, therefore, that the apparent association between higher BMI and earlier age at menarche might be confounded by other factors such as diet or exposure to endocrine disruptors [8]. The association could also be explained by reverse causality
Socioeconomic position and risk of short-term weight gain: Prospective study of 14,619 middle-aged men and women
Lisa R Purslow, Elizabeth H Young, Nicholas J Wareham, Nita Forouhi, Eric J Brunner, Robert N Luben, Ailsa A Welch, Kay-Tee Khaw, Shelia A Bingham, Manjinder S Sandhu
BMC Public Health , 2008, DOI: 10.1186/1471-2458-8-112
Abstract: We analysed data on 14,619 middle-aged men and women (aged between 40–75 at baseline) with repeated objective measures of weight and height at baseline (1993–1997) and follow up (1998–2000).During follow up 5,064 people gained more than 2.5 kg. Compared with the highest social class, individuals in the lowest social class had around a 30% greater risk of gaining more than 2.5 kg (OR 1.29; 95% CI 1.11–1.51; p for trend = 0.002). This association remained statistically significant following adjustment for sex, age, baseline BMI, smoking, and follow up time (OR 1.25; CI 1.07–1.46; p for trend <0.001). We also found no material difference between unadjusted models and those including all confounders and potential mediators.Individuals of low socioeconomic position are at greatest risk of gaining weight during middle age, which is not explained by classical correlates of socioeconomic position and risk factors for obesity.Across the UK there has been a rapid increase in the prevalence of obesity in recent decades [1]. Since obesity is associated with a greater risk of morbidity and mortality [2], identifying the determinants of weight gain and obesity is fundamental to the development of preventative strategies at the individual and societal level. Social inequalities in health are well recognised, and several studies suggest that adverse socioeconomic position is associated with obesity [3-5]. However, the association between socioeconomic position in middle age and risk of subsequent, short-term weight gain is unknown [5]. Additionally, few studies have attempted to investigate the mechanisms underlying the associations between socioeconomic position and weight gain [5,6]. We therefore investigated this association in a prospective population based study of 14,619 middle-aged men and women.We used data from the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk cohort. The study was approved by the Norfolk Health District Ethics Committee and f
Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk
Caroline Baynes, Catherine S Healey, Karen A Pooley, Serena Scollen, Robert N Luben, Deborah J Thompson, Paul DP Pharoah, Douglas F Easton, Bruce AJ Ponder, Alison M Dunning, the SEARCH breast cancer study
Breast Cancer Research , 2007, DOI: 10.1186/bcr1669
Abstract: We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene.No significant breast cancer associations were detected with any individual or combination of tag SNPs.It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.Four of the genes which lie in the DNA damage-recognition and repair pathway, ATM, BRCA1, BRCA2 and TP53, have mutations that are recognised to increase breast cancer susceptibility with moderate to high penetrance. Such mutations are very rare, and most probably of recent origin. A fifth gene, CHEK2, in the same pathway, has a deletion (1100delC) that reaches polymorphic frequencies (>0.01) in some European countries and doubles the risk of breast cancer in female carriers [1]. Together these mutations account for only a small proportion (2% to 5%) of all breast cancer incidences [2,3]. Breast cancer is, however, a common disease and genetic epidemiological data suggest that there is a low-penetrance genetic contribution to most cases [4,5]. It is likely that at least a part of breast cancer aetiology will fit the common disease-common variant hypothesis, which states that patients with a common, complex disease are likely to share some common, low-penetrance alleles that increase their susceptibility to that disease. This raises the question of whether such common, polymorphic susceptibility alleles exist within these five genes in addition t
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