Biomedical subjects

N E Day

Publications and source records attributed to N E Day.

At least 37 records · Page 2Linked to original sources

PubMed2003

The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease.

We aimed to quantify the benefits of detecting ductal carcinoma in situ (DCIS) and of downwards stage-shifting within invasive tumours in mammographic screening. Using data from the Swedish Two-County Trial of breast cancer screening, we examined the 20-year death rates from invasive tumours of stage II or worse, invasive tumours of stage I and DCIS. We then used these rates and their respective incidences in invited (active study population, ASP) and control (passive study population, PSP) arms of the trial, to estimate the numbers of deaths avoided by downward stage-shifting the larger stage II or worse tumours to stage I and the stage I cancers to DCIS. We also studied the association between the mortality reduction achieved and the proportion of DCIS cases detected in the randomised trials of breast cancer screening. In the Swedish Two County Trial, 141 breast cancer deaths were avoided in the ASP compared with the PSP at approximately 20 years of follow-up. Of these, 65% (91/141) were avoided as a result of stage-shifting from invasive stage II or worse to invasive stage I, and 5% (7/141) as a result of stage-shifting from invasive stage I to DCIS. If we assumed that 10% of stage II or worse tumours avoided were shifted not to stage I, but to DCIS, the estimated number of deaths prevented by shifting from invasive disease to in situ was 17, which is 12% of all deaths prevented. When the results of all the randomised trials of breast cancer screening were reviewed, there was no clear association between the percentage of DCIS cases diagnosed and the observed mortality reduction. We conclude that compared with downward stage-shifting of invasive tumours, detection of DCIS plays a small part in saving lives from breast cancer. Treatment decisions in DCIS, as in invasive carcinoma, should take full account of histopathological, clinical and radiological attributes of the tumour.

Adult↗

PubMed2003

LDL cholesterol is associated with small abdominal aortic aneurysms.

OBJECTIVE: To examine the relationship between serum lipids and abdominal aortic aneurysms (AAA). METHODS: Two hundred and six males (>50 years) with AAA (> or =30 mm) detected in a population based screening programme were compared with 252 age-matched male controls in a nested case-control study. Smoking status, previous medical and family histories, height, weight, blood pressure, ankle brachial pressure index (ABPI) and non-fasting lipid profile were recorded. RESULTS: Cases were found to have significantly higher LDL cholesterol than controls. LDL cholesterol was an independent predictor of the risk for aneurysms in a logistic regression model adjusting for smoking status, family history of AAA, history of ischaemic heart disease, presence of peripheral vascular disease, use of lipid lowering medication and treatment for hypertension. There was a linear effect with increased levels of LDL cholesterol increasing the risk of having a small aneurysm (test for trend p=0.03). CONCLUSION: The highly significant association between LDL cholesterol and small aneurysms suggests that LDL, possibly acting via inflammatory mediated matrix degeneration, could be an initiating factor in the development of AAA. The ability of statin therapy to prevent AAA formation requires further investigation.

Aged↗

PubMed2003

Television viewing and low participation in vigorous recreation are independently associated with obesity and markers of cardiovascular disease risk: EPIC-Norfolk population-based study.

OBJECTIVE: This study describes the associations between sedentary behaviour (television viewing) and participation in vigorous recreational activity with obesity and with biomarkers of cardiovascular disease (CVD) risk profile. DESIGN: Cross-sectional analysis of the EPIC-Norfolk cohort study. SETTING: The study is a population-based study of participants living in Norfolk, UK. SUBJECTS: A total of 15 515 men and women aged between 45 and 74 y, recruited through General Practice lists, who completed the detailed physical activity questionnaire. RESULTS: Following exclusion of those with self-reported myocardial infarction, stroke and diabetes, 14 189 participants remained for the analysis. Self-reported television viewing was positively and participation in vigorous activity negatively associated with markers of obesity, blood pressure and plasma lipids. In multiple regression analysis, adjusting for age, alcohol, smoking, treatment for hypertension, vigorous and total physical activity, these associations remained significant. For women who participated in more than 1 h/week of vigorous activity and who watched fewer than 2 h of television each day, the adjusted mean body mass index was 1.92 kg/m(2) less than for women who reported participating in no vigorous activity and who watched more than 4 h of television each day (P<0.001). The equivalent figure for men was 1.44 kg/m(2) (P<0.001). In a similar analysis, with blood pressure as the outcome, mean diastolic blood pressure difference between the extreme groups of vigorous activity and television viewing was 3.6 mmHg in men (P<0.001) and 2.7 mmHg (P=0.001) in women. CONCLUSIONS: These data suggest that time spent participating in vigorous recreational physical activity and television viewing, an indicator of a sedentary lifestyle, are associated with obesity and markers of CVD disease risk independent of total reported physical activity. Whether these observations represent the true underlying aetiological relations or are a manifestation of the different precision with which the subdimensions of activity are measured remains uncertain.

Aged↗

PubMed2003

The detection of gene-environment interaction for continuous traits: should we deal with measurement error by bigger studies or better measurement?

BACKGROUND: The search for biologically relevant gene-environment interactions has been facilitated by technological advances in genotyping. The design of studies to detect interactions on continuous traits such as blood pressure and insulin sensitivity is attracting increasing attention. We have previously described power calculations for such studies, and this paper describes the extension of those calculations to take account of measurement error. METHODS: The model considered in this paper is a simple linear regression relating a continuous outcome to a continuously distributed exposure variable in which the ratio of slopes for each genotype is considered as the interaction parameter. The classical measurement error model is used to describe the uncertainty in measurement in the outcome and the exposure. The sample size to detect differing magnitudes of interaction with varying frequencies of the minor allele are calculated for a given main effect observed with error both in the exposure and the outcome. The sample size to detect a given interaction for a given minor allele frequency is calculated for differing degrees of measurement error in the assessment of the exposure and the outcome. RESULTS: The required sample size is dependent upon the magnitude of the interaction, the allele frequency and the strength of the association in those with the common allele. As an example, we take the situation in which the effect size in those with the common allele was a quarter of a standard deviation change in the outcome for a standard deviation change in the exposure. If a minor allele with a frequency of 20% leads to a doubling of that effect size, then the sample size is highly dependent upon the precision with which the exposure and outcome are measured. rho(Tx) and rho(Ty) are the correlation between the measured exposure and outcome, respectively and the true value. If poor measures of the exposure and outcome are used, (e.g. rho(Tx) = 0.3, rho(Ty) = 0.4), then a study size of 150 989 people would be required to detect the interaction with 95% power at a significance level of 10(-4). Such an interaction could be detected in study samples of under 10 000 people if more precise measurements of exposure and outcome were made (e.g. rho(Tx) = 0.7, rho(Ty) = 0.7), and possibly in samples of under 5000 if the precision of estimation were enhanced by taking repeated measurements. CONCLUSIONS: The formulae for calculating the sample size required to study the interaction between a continuous exposure and a genetic factor on a continuous outcome variable in the face of measurement error will be of considerable utility in designing studies with appropriate power. These calculations suggest that smaller studies with repeated and more precise measurement of the exposure and outcome will be as powerful as studies even 20 times bigger, which necessarily employ less precise measures because of their size. Even though the cost of genotyping is falling, the magnitude of the effect of measurement error on the power to detect interaction on continuous traits suggests that investment in studies with better measurement may be a more appropriate strategy than attempting to deal with error by increasing sample sizes.

Environmental Exposure↗

PubMed2003

Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk.

A substantial proportion of the familial risk of breast cancer may be attributable to genetic variants each contributing a small effect. Polymorphisms in DNA repair genes are good candidates for such low penetrance breast cancer susceptibility alleles. Checkpoint kinase 2 (CHEK2) is a kinase in which the yeast counterpart regulates a cell cycle checkpoint and causes cells to arrest proliferation after DNA damage. A rare, protein truncating mutation in the CHEK2 gene has recently been shown to confer a modest risk of breast cancer. The aim of this study was to determine whether common polymorphic variants in CHEK2 are associated with an increase in breast cancer risk. We assessed two variants in CHEK2 using a case control study design (n = 1786 cases and 1828 controls). No differences in genotype frequencies were found between cases and control for either the IVS1 + 38insa or the a1013g polymorphisms (P = 0.3 and 0.2 respectively), and no genotype-specific risk was significantly different from unity. The haplotype frequency distribution in cases and controls were also similar (P = 0.3). We conclude that the CHEK2 polymorphisms IVS + 1a and a1013g do not confer an increased risk of breast cancer. It is also unlikely that other, as yet unidentified, common polymorphisms that affect risk are present in the gene in the British population.

Breast Neoplasms↗

PubMed2002

Exposure to power frequency electric fields and the risk of childhood cancer in the UK.

The United Kingdom Childhood Cancer Study, a population-based case-control study covering the whole of Great Britain, incorporated a pilot study measuring electric fields. Measurements were made in the homes of 473 children who were diagnosed with a malignant neoplasm between 1992 and 1996 and who were aged 0-14 at diagnosis, together with 453 controls matched on age, sex and geographical location. Exposure assessments comprised resultant spot measurements in the child's bedroom and the family living-room. Temporal stability of bedroom fields was investigated through continuous logging of the 48-h vertical component at the child's bedside supported by repeat spot measurements. The principal exposure metric used was the mean of the pillow and bed centre measurements. For the 273 cases and 276 controls with fully validated measures, comparing those with a measured electric field exposure >/=20 V m(-1) to those in a reference category of exposure <10 V m(-1), odds ratios of 1.31 (95% confidence interval 0.68-2.54) for acute lymphoblastic leukaemia, 1.32 (95% confidence interval 0.73-2.39) for total leukaemia, 2.12 (95% confidence interval 0.78-5.78) for central nervous system cancers and 1.26 (95% confidence interval 0.77-2.07) for all malignancies were obtained. When considering the 426 cases and 419 controls with no invalid measures, the corresponding odds ratios were 0.86 (95% confidence interval 0.49-1.51) for acute lymphoblastic leukaemia, 0.93 (95% confidence interval 0.56-1.54) for total leukaemia, 1.43 (95% confidence interval 0.68-3.02) for central nervous system cancers and 0.90 (95% confidence interval 0.59-1.35) for all malignancies. With exposure modelled as a continuous variable, odds ratios for an increase in the principal metric of 10 V m(-1) were close to unity for all disease categories, never differing significantly from one.

Adolescent↗

PubMed2002

The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial.

BACKGROUND: Opposing views have been published on the importance of ultrasound screening for abdominal aortic aneurysms. The Multicentre Aneurysm Screening Study was designed to assess whether or not such screening is beneficial. METHODS: A population-based sample of men (n=67800) aged 65-74 years was enrolled, and each individual randomly allocated to either receive an invitation for an abdominal ultrasound scan (invited group, n=33839) or not (control group, n=33961). Men in whom abdominal aortic aneurysms (> or =3 cm in diameter) were detected were followed-up with repeat ultrasound scans for a mean of 4.1 years. Surgery was considered on specific criteria (diameter > or =5.5 cm, expansion > or =1 cm per year, symptoms). Mortality data were obtained from the Office of National Statistics, and an intention-to-treat analysis was based on cause of death. Quality of life was assessed with four standardised scales. The primary outcome measure was mortality related to abdominal aortic aneurysm. FINDINGS: 27147 of 33839 (80%) men in the invited group accepted the invitation to screening, and 1333 aneurysms were detected. There were 65 aneurysm-related deaths (absolute risk 0.19%) in the invited group, and 113 (0.33%) in the control group (risk reduction 42%, 95% CI 22-58; p=0.0002), with a 53% reduction (95% CI 30-64) in those who attended screening. 30-day mortality was 6% (24 of 414) after elective surgery for an aneurysm, and 37% (30 of 81) after emergency surgery. INTERPRETATION: Our results provide reliable evidence of benefit from screening for abdominal aortic aneurysms.

Aged↗

PubMed2002

A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes.

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene 'BRCA3', and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021-0.125%) and of BRCA2 0.068% (95% CI: 0.033-0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families.

Adult↗

PubMed2002

Deterministic models for breast cancer progression: application to the association between mammographic parenchymal pattern and histologic grade of breast cancers.

Dense mammographic patterns are a risk factor for breast cancer. In a recent case-control study, dense patterns were observed to be associated with a higher relative risk estimate for the more aggressive grade 3 tumors than for grade 1 or 2 tumors. The present study was designed to ascertain, by reference to odds ratio estimates of relative risk by tumor size and histologic grade, whether this was more likely to be due to increased innate predisposition of dense parenchymal patterns to grade 3 tumors, or to dedifferentiation of cases missed at screening due to dense patterns. If the observation were due entirely to dedifferentiation, then for a given size the relative risk of grade 3 tumors would be the same as for grades 1-2. Size-specific relative risks of grade 3 tumors were higher than those of grade 1-2 tumors. It is concluded that the majority of the enhanced risk of grade 3 tumors is due to enhanced innate predisposition to grade 3 tumors in dense breasts.

Adult↗

PubMed2002

Cross-sectional association between total level and type of alcohol consumption and glycosylated haemoglobin level: the EPIC-Norfolk Study.

OBJECTIVE: To investigate the association between total level and type of alcohol consumed and glycaemia. DESIGN: Cross-sectional study. SETTING: The EPIC-Norfolk Study, a population-based cohort study of diet and chronic disease. SUBJECTS AND METHODS: Non-diabetic men (n=2842) and women (n=3572), aged 40-78 y. Alcohol intake was assessed by self-reported questionnaire, and glycaemia measured by glycosylated haemoglobin (HbA(1c)). RESULTS: Ten percent of men and 18% of women reported drinking no alcohol. Among drinkers, median alcohol intake was 8 units/week for men and 3 units/week for women. In analyses stratified by sex and adjusted for age, total energy intake, education, fruit and vegetable intake, smoking, family history of diabetes, physical activity, body mass index and waist:hip ratio, alcohol intake was inversely associated with HbA(1c) in men and women, although the association was stronger in women. A 1 unit/week increase in alcohol intake was associated with 0.0049% (s.e.=0.00223; P-value=0.028) and 0.017% (s.e.=0.00343; P-value <0.001) reduction in HbA(1c) in men and women respectively. In similar multivariate analyses, wine intake was inversely associated with HbA(1c) in men, and wine, spirits and beer intake were inversely associated with HbA(1c) in women. When also adjusted for total alcohol intake, only the association between wine intake and HbA(1c) in men remained significant. CONCLUSION: Alcohol intake was associated with lower HbA(1c) level, an association not explained by confounding. The distinction between type of alcohol consumed was particularly important in men.

Adult↗

PubMed2002

Diet and basal cell skin cancer: results from the EPIC-Norfolk cohort.

BACKGROUND: The incidence of non-melanoma skin cancer (NMSC) in Britain has been increasing over the past 50 years. This has been attributed to increased sunlight exposure, but the increased exposure has not been quantified, and in any case, much of the increase in incidence has occurred in those parts of the body, mainly the head and neck, that have always been exposed to sunlight. There is evidence that increased dietary fat intake has increased the sensitivity of the skin to the carcinogenic potential of sunlight, particularly in causing squamous cell tumours. OBJECTIVES: To test the hypothesis that increased dietary fat is a risk factor for NMSC. METHODS: The hypothesis was tested in a nested case-control study. The cohort was that recruited for the EPIC-Norfolk study, the cases (n = 123) were subjects with NMSC diagnosed since recruitment, and the controls (n = 247) were randomly selected from the same cohort. The effect of diet on the incidence of NMSC was assessed using conditional logistic regression. RESULTS: As there were so few cases (14) with squamous cell tumours they were excluded from the statistical analyses. Fat intake was not found to be a risk factor: the unadjusted odds ratio (OR) of basal cell cases vs. controls was estimated as 0.860/(25.5 g total fat daily) with 95% confidence interval (CI) (0.663, 1.116), P = 0.25. Exploratory analyses of diet components and food groups found a protective effect of increased vitamin E consumption: unadjusted OR of basal cell cases vs. controls was 0.731/(3.06 mg vitamin E daily), 95% CI (0.564, 0.948), P = 0.015. Adjusted analyses gave broadly similar results. CONCLUSIONS: The potentiating factor remains unknown: if dietary fat has any effect on NMSC, it is not apparent when basal cell tumours are considered. There was no evidence of a generalized healthy eating effect. A substantial protective effect was found in exploratory analyses for the fat soluble antioxidant vitamin E.

Aged↗

PubMed2002

Late results concerning feasibility and compliance from a randomized trial of ultrasonographic screening for abdominal aortic aneurysm.

BACKGROUND: The study was an update at 10 years of a randomized trial of the efficacy of screening for abdominal aortic aneurysm (AAA). The extent of benefit, feasibility and compliance were examined, and reasons why this intervention may fail a proportion of those screened were identified. METHODS: A total of 6058 men aged 65 years and over were randomized to a group invited to attend ultrasonographic screening or to a control group. The mortality rate from AAA in the two arms of the trial was compared using a Poisson model. Analyses were by intention to treat. RESULTS: There was a 21 per cent reduction in mortality rate from AAA over the 10-year follow-up (relative risk 0.79 (95 per cent confidence interval 0.53 to 1.40)). The observed relative mortality reduction peaked at 4 years with a 52 per cent reduction in the study group. Eighteen of 24 AAA deaths in the study group were among those who did not attend the first screen, or failed to comply with the follow-up protocol. CONCLUSION: A greater awareness of the benefits of full participation in a screening programme could provide a larger and sustained mortality reduction.

Aged↗

PubMed2002

European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection.

The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35-70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrollment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case-control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.

Adult↗

PubMed2002

Accuracy of serial screening for abdominal aortic aneurysms by ultrasound.

OBJECTIVES: To assess the accuracy of screening for abdominal aortic aneurysms (AAAs) by ultrasound (US). SETTING: An aneurysm screening programme in Huntingdon. METHODS: False negative tests were identified by tracing all patients with a ruptured aneurysm who were screened and then finding the number classified as normal on US. False positive tests were identified by calculating the number of aneurysmal aortas on US that were classified as normal on CT. Measurement variability of the infrarenal aortic diameter between US and CT was estimated. RESULTS: 14 out of 93 patients with a ruptured AAA since 1991 had been screened. No ruptured aneurysm had been classified as normal on US. All 64 patients with an AAA larger than 4.5 cm on US had their aneurysm confirmed on CT. The mean difference between CT and US measurements was 4 mm. The limit of variability between CT and US was 12 mm. CONCLUSION: No false negative scans were found using a cut off point of 3 cm as abnormal. No false positives were found if subjects with an AAA exceeding 4.5 cm were referred for further procedures. A serial US screening policy has excellent screening performance, justifying its use as a screening tool.

Aneurysm, Ruptured↗

PubMed2002