Showing papers by "Clinical Trial Service Unit published in 2008"

Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p

Abstract: Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studies. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8x10(-13); OR = 1.29; 95% CI: 1.20-1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'yin-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglyceride levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus.

Part I: Cancer in Indigenous Africans—burden, distribution, and trends

Abstract: Cancer is an under-emphasised issue in Africa, partly because of the overwhelming burden of communicable diseases. However cancer is a common disease in Africa with 650 000 people, of a population of 965 million, diagnosed annually. Furthermore, the lifetime risk in females (between 0 and 64 years) of cancer is about 10%, which is only about 30% lower than the risk in developed countries. In females, the lifetime risk of dying from cancer in Africa is almost double the risk in developed countries. This Review is the first of two papers and focuses on the current knowledge of the distribution and trends of the most common cancers in Africa. The cancers with the highest incidence are cervical, breast, and now HIV-associated Kaposi's sarcoma. The top five cancers in males--Kaposi's sarcoma (constituting 12.9% of all cancers in males) and cancer of the liver (14.8%), prostate (9.5%), bladder (6.1%), and non-Hodgkin lymphoma (5.7%)--and in females--cancer of the cervix (constituting 23.3% of all cancers in females) and breast (19.2%), Kaposi's sarcoma (5.1%), cancer of the liver (5.0%), and non-Hodgkin lymphoma (3.7%)--are discussed in detail. The second paper will focus on the causes and control of cancer in Africa. The cancer burden in Africa is likely to increase as a result of increases in HIV-associated cancers, changes in lifestyles associated with economic development, and the increasing age of the population (despite AIDS). Although the knowledge of cancer in this region is improving, better surveillance of cancer incidence, mortality, and prevalence of risk factors is urgently needed to monitor the development of the cancer epidemic, formulate appropriate cancer-control strategies, and assess the outcomes of these strategies.

The global burden of urinary bladder cancer.

Abstract: Statistics on the incidence of bladder cancer are particularly hard to interpret, because of changing classification, variations in counting of multiple cancers in the same individual and, most importantly, the variable inclusion of non-invasive cancers in different data sets. Mortality statistics are almost certainly more comparable, but as indirect estimators of disease risk, require some cautious interpretation, because of differing survival between populations, and over time. Cancer of the bladder is estimated to be the ninth most common cause of cancer worldwide (357000 cases in 2002) and the 13th most numerous cause of death from cancer (145000 deaths). Rates in males are three to four times those in females. Incidence rates are high in many southern and eastern European countries, in parts of Africa and the Middle East, and in North America. The highest estimated mortality is in Egypt, where rates are more than three times greater than the highest rates in Europe and eight times those in the USA. I...

Analyses of cancer data from three ezetimibe trials.

Abstract: Background Five years of statin therapy lowers low-density lipoprotein (LDL) cholesterol substantially and, over a 5-year period, results in reductions in the incidence of cardiovascular events. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677) has raised the hypothesis that adding ezetimibe to statin therapy for larger LDL cholesterol reductions might increase the incidence of cancer. Methods We compared the results of a hypothesis-generating analysis of the incidence of cancer in the SEAS trial of ezetimibe plus simvastatin in 1873 patients (mean followup after ezetimibe or matching placebo was begun, 4.1 years) with a hypothesistesting analysis of cancer data from the two large ongoing trials of this regimen: the Study of Heart and Renal Protection (SHARP) (NCT00125593) with 9264 patients (mean follow-up, 2.7 years) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), currently with 11,353 patients (mean follow-up, 1.0 year). Results In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P = 0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P = 0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P = 0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up. Conclusions The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.

Cardiac Dose From Tangential Breast Cancer Radiotherapy in the Year 2006

Abstract: Purpose To quantify the radiation doses received by the heart and coronary arteries from contemporary tangential breast or chest wall radiotherapy. Methods and Materials Fifty consecutive patients with left-sided breast cancer and 5 consecutive patients with right-sided breast cancer treated at a large United Kingdom radiotherapy center during the year 2006 were selected. All patients were irradiated with 6- or 8-MV tangential beams to the breast or chest wall. For each dose plan, dose–volume histograms for the heart and left anterior descending (LAD) coronary artery were calculated. For 5 of the left-sided and all 5 right-sided patients, dose–volume histograms for the right and circumflex coronary arteries were also calculated. Detailed spatial assessment of dose to the LAD coronary artery was performed for 3 left-sided patients. Results For the 50 patients given left-sided irradiation, the average mean (SD) dose was 2.3 (0.7) Gy to the heart and 7.6 (4.5) Gy to the LAD coronary artery, with the distal LAD receiving the highest doses. The right and circumflex coronary arteries received approximately 2 Gy mean dose. Part of the heart received >20 Gy in 22 left-sided patients (44%). For the 5 patients given right-sided irradiation, average mean doses to all cardiac structures were in the range 1.2 to 2 Gy. Conclusions Heart dose from left-tangential radiotherapy has decreased considerably over the past 40 years, but part of the heart still receives >20 Gy for approximately half of left-sided patients. Cardiac dose for right-sided patients was generally from scattered irradiation alone.

Sensible approaches for reducing clinical trial costs.

Abstract: Background Over the past decade, annual funding for biomedical research has more than doubled while new molecular entity approvals have declined by one third.Objective To assess the value of practices commonly employed in the conduct of large-scale clinical trials, and to identify areas where costs could be reduced without compromising scientific validity.Methods In the qualitative phase of the study, an expert panel recommended potential modifications of mega-trial designs and operations in order to maximize their value (cost versus scientific benefit tradeoff). In the quantitative phase, a mega-trial economic model was used to assess the financial implications of these recommendations. Our initial chronic disease trial design included 20,000 patients randomized at 1000 sites. Each site was assigned 24 monitoring visits and a $10,000 per patient site payment. The case report form (CRF) was 60 pages long, and trial duration was assumed to be 48 months.Results The total costs of the initial trial design we...

Ensuring trial validity by data quality assurance and diversification of monitoring methods.

Abstract: Errors in the design, the conduct, the data collection process, and the analysis of a randomized trial have the potential to affect not only the safety of the patients in the trial, but also, throu...

Part II: Cancer in Indigenous Africans—causes and control

Abstract: Summary Africa has contributed substantial knowledge to the understanding of certain risk factors for cancer, such as the role of several infectious agents (eg, viruses, bacteria, and parasites), aflatoxins, and certain lifestyle factors. Although the relative importance of many lifestyle factors is becoming better understood in developed countries, more work is needed to understand the importance of these factors in different African settings. In view of the substantial genetic diversity in Africa, it would be prudent not to generalise too widely from one place to the next. We argue that risks for several exposures related to certain cancers differ from the patterns seen in developed countries. In this paper, we review the current knowledge of causes of some of the leading cancers in Africa, namely cancers of the cervix, breast, liver, prostate, stomach, bladder, and oesophagus, Kaposi's sarcoma, non-Hodgkin lymphoma, and tobacco-related cancers. There are no comprehensive cancer-control programmes in Africa and provision of radiotherapy, chemotherapy, and palliation is inadequate. Certain cost-effective interventions, such as tobacco control, provision of antiretroviral therapy, and malarial and bilharzial control, can cause substantial decreases in the burden of some of these cancers. Vaccinations against hepatitis B and oncogenic human papilloma viruses can make the biggest difference, but very few countries in Africa can afford these vaccines without substantial subsidisation.

High incidence of avascular necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL XII analysis.

Abstract: Avascular necrosis (AVN) is a serious complication of acute lymphoblastic leukaemia (ALL) therapy. Little is known of the scope and magnitude of this problem among adults with ALL. We analysed the incidence and risk factors for AVN in 1053 patients on the UKALLXII/ECOG2993 study. AVN affected 99 joints in 42 patients at a median of 2.2 years post-diagnosis, giving a crude incidence rate of 4.0%. Statistically significant risk factors for the development of AVN were age and treatment with chemotherapy. Patients receiving prolonged chemotherapy without stem cell transplant were at significantly greater risk of developing AVN than stem cell transplant recipients (P 20 years old; P=0.0004; odds ratio 0.28 (95% CI=0.14-0.56).

Tobacco Smoking, Smoking Cessation, and Cumulative Risk of Upper Aerodigestive Tract Cancers

Abstract: Upper aerodigestive tract cancers are strongly related to smoking, and their incidence is substantially lower in former smokers than in continuing smokers. To estimate the effect of smoking cessation on the cumulative incidence of these cancers by age 75 years (in the absence of competing causes of death), the authors combined odds ratios for males from a network of Italian hospital-based case-control studies (1984-2000) with 1993-1997 incidence data for Italian men. The studies included 961 cases with oral/pharyngeal cancer, 618 cases with esophageal cancer, and 613 cases with laryngeal cancer, plus 3,781 controls. For all upper aerodigestive tract cancers, the cumulative risks by 75 years of age were 6.3% for men who continued to smoke any type of tobacco, 3.1% and 1.2% for men who stopped smoking at around 50 and 30 years of age, respectively, and 0.8% among lifelong nonsmokers. Corresponding figures were 3.3%, 1.4%, 0.5%, and 0.2% for oral/pharyngeal cancer; 1.0%, 0.5%, 0.4%, and 0.2% for esophageal cancer; and 2.1%, 1.1%, 0.2%, and 0.2% for laryngeal cancer. In this Italian population, men who stopped smoking before age 50 years avoided more than half of the excess risk of upper aerodigestive tract cancer as men who did not, and men who stopped smoking before age 30 years avoided more than 90% of the risk.

Body Mass Index, Blood Pressure, and Mortality From Stroke A Nationally Representative Prospective Study of 212 000 Chinese Men

Abstract: Background and Purpose— Despite previous investigations, substantial uncertainty remains about the relation between body mass index (BMI) and stroke, especially in populations with a relatively low BMI but a high stroke rate. Methods— A nationally representative prospective study of mortality included 212 000 Chinese men 40 to 79 years old without known cardiovascular disease in 1990 to 1991 who were followed up for 10 years. Standardized hazard ratios were calculated for stroke mortality by baseline systolic blood pressure (SBP) and BMI. Results— Mean SBP and BMI were 124 mm Hg and 21.7 kg/m2, respectively. During 10 years of follow-up, 5766 stroke deaths were recorded. There were strong, positive relations between BMI and SBP and between SBP and stroke mortality, with a 3-mm Hg higher baseline SBP associated with a 5.6% (95% CI, 5.3% to 6.0%; P<0.00001) higher stroke mortality. The association between BMI and stroke mortality was, however, not linear, with the hazard increasing substantially only for BM...

Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK.

Abstract: Concerns about risks for older people with vitamin B12 deficiency have delayed the introduction of mandatory folic acid fortification in the UK. We examined the risks of anaemia and cognitive impairment in older people with low B12 and high folate status in the setting of voluntary fortification in the UK. Data were obtained from two cross-sectional studies (n 2403) conducted in Oxford city and Banbury in 1995 and 2003, respectively. Associations (OR and 95 % CI) of cognitive impairment and of anaemia with low B12 status (holotranscobalamin 30 nmol/l or >60 nmol/l) were estimated after adjustment for age, sex, smoking and study. Mean serum folate levels increased from 15.8 (sd 14.7) nmol/l in 1995 to 31.1 (sd 26.2) nmol/l in 2003. Serum folate levels were greater than 30 nmol/l in 9 % and greater than 60 nmol/l in 5 %. The association of cognitive impairment with low B12 status was unaffected by high v. low folate status (>30 nmol/l) (OR 1.50 (95 % CI 0.91, 2.46) v. 1.45 (95 % CI 1.19, 1.76)), respectively. The associations of cognitive impairment with low B12 status were also similar using the higher cut-off point of 60 nmol/l for folate status ((OR 2.46; 95 % CI 0.90, 6.71) v. (1.56; 95 % CI 1.30, 1.88)). There was no evidence of modification by high folate status of the associations of low B12 with anaemia or cognitive impairment in the setting of voluntary fortification, but periodic surveys are needed to monitor fortification.

B-vitamins and prevention of dementia.

Abstract: Elevated plasma homocysteine (Hcy) concentrations have been implicated with risk of cognitive impairment and dementia, but it is unclear whether low vitamin B12 or folate status is responsible for cognitive decline. Most studies reporting associations between cognitive function and Hcy or B-vitamins have used a cross-sectional or case-control design and have been unable to exclude the possibility that such associations are a result of the disease rather than being causal. The Hcy hypothesis of dementia has attracted considerable interest, as Hcy can be easily lowered by folic acid and vitamin B12, raising the prospect that B-vitamin supplementation could lower the risk of dementia. While some trials assessing effects on cognitive function have used folic acid alone, vitamin B12 alone or a combination, few trials have included a sufficient number of participants to provide reliable evidence. An individual-patient-data meta-analysis of all randomised trials of the effects on cognitive function and vascular risk of lowering Hcy with B-vitamins will maximise the power to assess the epidemiologically-predicted differences in risk. Among the twelve large randomised Hcy-lowering trials for prevention of vascular disease, data should be available on about 30 000 participants with cognitive function. The principal investigators of such trials have agreed to combine individual-participant data from their trials after their separate publication.

Passive smoking and breast cancer in never smokers: prospective study and meta-analysis

Abstract: Background Active smoking has little or no effect on women's risk of developing breast cancer, but it has been suggested that passive exposure to tobacco smoke may increase this risk among women who have never smoked. Objective To evaluate the possible relationship between passive smoking and breast cancer risk within the Million Women Study, a large UK prospective study, and to report a meta-analysis of published results. Methods In the large prospective study, 224 917 never smokers who completed a questionnaire that asked women whether their parents had smoked and if their current partner smoked were followed up for an average of 3.5 years for incident breast cancer. In the meta-analysis, studies that had recorded exposure information prospectively and retrospectively were considered separately. Main outcome measures Adjusted relative risk of breast cancer in never smokers who were passively exposed to tobacco smoke at various ages compared with never smokers with no such exposure. Results In the prospective study, 2518 incident invasive breast cancers occurred during follow-up and the adjusted relative risk of breast cancer for passive exposure either as a child or as an adult vs neither exposure was 0.98 (95% CI 0.88-1.09); results were similarly null for childhood exposure (0.98, 0.88-1.08) and adult exposure (1.02, 0.89-1.16) separately. We identified seven other studies with prospectively recorded exposure data; when results of all eight studies were combined (including 5743 never smokers with breast cancer), the aggregate relative risk was 0.99 (0.93-1.05) for any passive exposure. The aggregate findings differed substantially (P = 0.0002) between these 8 studies and 17 other studies with retrospectively recorded information (including 5696 never smokers with breast cancer). Conclusions Aggregate results from studies with prospectively reported information show that the incidence of breast cancer is similar in women who did and did not report passive exposure to tobacco smoke either as a child or as an adult. The aggregate findings from the retrospective studies may have been distorted by some women becoming more likely to report past exposures because they knew that they had breast cancer.

Patients’ experience of chronic lymphocytic leukaemia: baseline health‐related quality of life results from the LRF CLL4 trial

Abstract: We examined the effects of active untreated chronic lymphocytic leukaemia (CLL) on health-related quality of life (HRQoL), measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) at randomisation into the Leukaemia Research Fund CLL4 trial. Patients were scored 0-100 within each of 15 domains. A difference between groups of > or = 10 points was deemed clinically significant (asterisked * below). 431 valid baseline questionnaires were returned. Compared with population norms, patients had impaired HRQoL in 13/15 domains. The greatest differences were in fatigue*, sleep disturbance*, role functioning and global HRQoL. Fatigue was reported by 81% of patients, compared with the next most common symptoms: sleep disturbance (56%) and dyspnoea (49%). There was no association between spleen, liver or lymph node enlargement, or lymphocytosis and any HRQoL domain. Older age (> or =70 years) was associated with poorer physical functioning (P < 0.001) but fewer financial difficulties (P < 0.001*). Impairment of HRQoL at baseline was most apparent in stage A-progressive patients with B-symptoms and stage C patients with haemoglobin <120 g/l: compared with all others, these patients had poorer physical, role and social functioning, more fatigue and dyspnoea and poorer global HRQoL (all P < or = 0.001*). These findings support the recommendation to begin treatment when patients experience symptomatic disease, to improve HRQoL.

Plasma phospholipid fatty acids and CHD in older men: Whitehall study of London civil servants.

Abstract: Dietary fatty acids (FA) are the major determinants of blood lipids, and measurements of plasma phospholipid FA (PL-FA) composition that reflect the dietary intake of FA may provide insights into the relationships between diet and CHD. We assessed CHD mortality associations with PL-FA (SFA, PUFA and MUFA) levels measured in a nested case-control study of 116 cases of CHD death and 239 controls that were frequency-matched for age and employment grade. The participants had plasma levels of total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol, apo B and apo A1, C-reactive protein (CRP) and fibrinogen recorded. SFA levels were significantly positively correlated with total cholesterol, LDL-C, apo B, CRP protein and fibrinogen. By contrast, phospholipid-PUFA were inversely associated with CRP, but not with any of the lipids. A higher SFA content (top v. bottom quarter) was associated with a 2-fold higher risk of CHD (OR and 95 % CI: OR 2.12; 95 % CI: 1.13, 3.99), and an equivalent difference in PUFA was associated with a halving in CHD risk (OR 0.49; 95 % CI: 0.26, 0.94), but MUFA was unrelated to CHD risk. These associations were substantially attenuated, after additional adjustment for lipids and inflammatory markers. Higher levels of saturated fat and lower levels of polyunsaturated fats were each associated with a higher risk of CHD in elderly men, and these associations were partly explained by their effects on blood lipids and biomarkers of inflammation.

Biomarkers of inflammation predict both vascular and non-vascular mortality in older men

Abstract: AIMS: To compare the predictive value of inflammatory biomarkers and lipids for vascular and non-vascular mortality in older men. METHODS AND RESULTS: The relevance of inflammatory biomarkers and lipids for vascular and non-vascular mortality was assessed in a prospective study of 5360 men (mean age 77 years) followed for 7 years. Vascular mortality was positively associated with log C-reactive protein (lnCRP), fibrinogen and total/HDL-C (high-density lipoprotein cholesterol), and inversely associated with albumin [age adjusted hazard ratio (HR) per 2-SD higher usual level (approximately the difference between the top and the bottom thirds of the distribution): 2.09 for lnCRP; 1.70 for fibrinogen; 0.50 for albumin and 1.45 for total/HDL-C]. The associations with the inflammatory markers were attenuated after adjustment for established risk factors, including lipids [adjusted HRs: 1.86 (lnCRP); 1.44 (fibrinogen); 0.51 (albumin)], and further attenuated (and, for fibrinogen, no longer predictive) after adjustment for each other [fully adjusted HRs: 1.60 (lnCRP); 1.01 (fibrinogen); 0.61 (albumin)]. Higher CRP and lower albumin levels were also associated with significantly raised non-vascular mortality independently of other characteristics [fully adjusted HRs: 1.62 (lnCRP); 0.65 (albumin)]. CONCLUSION: In this cohort of older men, higher CRP and lower albumin levels strongly predicted both vascular and non-vascular mortality, independently of other characteristics.

Plasma homocysteine, but not folate or vitamin B-12, predicts mortality in older people in the United Kingdom.

Abstract: There is uncertainty about the importance of plasma levels of homocysteine, vitamin B-12, and folate for all-cause and cardiovascular disease (CVD) mortality in older people. We examined the associations between plasma levels of folate, vitamin B-12, and homocysteine, and all-cause and CVD mortality among community-dwelling adults aged > or = 75 y living in the United Kingdom. In a population-based prospective cohort study, 853 men and women aged > or = 75 y were examined in 1995-98 as part of the Medical Research Council Trial of Assessment and Management of Older People in the Community. During a median follow-up of 7.6 y (5528 person-years of follow-up), 429 individuals (50.3%) died, including 185 from CVD. Individuals with plasma homocysteine levels in the top one-third compared with the bottom one-third had a 2-fold higher risk of all-cause mortality (hazard ratio, 2.20; 95% CI, 1.76, 2.75; P < 0.001) and CVD mortality (hazard ratio, 1.96; 95% CI, 1.39, 2.78; P < 0.001) after adjustment for age, sex, and other covariates. There was no association of plasma folate or vitamin B-12 levels with mortality. Our results extend previously reported associations of homocysteine with mortality, and the absence of associations of folate and vitamin B-12 with mortality, to the older population.

Effects of deworming on malnourished preschool children in India: an open-labelled, cluster-randomized trial.

Abstract: More than a third of the worlds children are infected with intestinal nematodes. Current control approaches emphasise treatment of school age children and there is a lack of information on the effects of deworming preschool children. We studied the effects on the heights and weights of 3935 children initially 1 to 5 years of age of five rounds of anthelmintic treatment (400 mg albendazole) administered every 6 months over 2 years. The children lived in 50 areas each defined by precise government boundaries as urban slums in Lucknow North India. All children were offered vitamin A every 6 months and children in 25 randomly assigned slum areas also received 6-monthly albendazole. Treatments were delivered by the State Integrated Child Development Scheme (ICDS) and height and weight were monitored at baseline and every 6 months for 24 months (trial registration number NCT00396500). p Value calculations are based only on the 50 area-specific mean values as randomization was by area. The ICDS infrastructure proved able to deliver the interventions. 95% (3712/3912) of those alive at the end of the study had received all five interventions and had been measured during all four follow-up surveys and 99% (3855/3912) were measured at the last of these surveys. At this final follow up the albendazole-treated arm exhibited a similar height gain but a 35 (SE 5) % greater weight gain equivalent to an extra 1 (SE 0.15) kg over 2 years (99% CI 0.6-1.4 kg p = 10211). In such urban slums in the 1990s five 6-monthly rounds of single dose anthelmintic treatment of malnourished poor children initially aged 1-5 years results in substantial weight gain. The ICDS system could provide a sustainable inexpensive approach to the delivery of anthelmintics or micronutrient supplements to such populations. As however we do not know the control parasite burden these results are difficult to generalize. (authors)

Anthropometric characteristics as predictors of coronary heart disease in women.

Abstract: Objectives. Obesity and other anthropometric measures are clearly related to risk of coronary heart disease (CHD), although debate remains as to which measures are most important and how the impact of obesity varies over the life course. Aim. We aimed to investigate these issues in a large cohort of Swedish women. The Women's Lifestyle and Health Cohort Study includes 49 259 women, aged 30-50 years at baseline (1991-1992) when an extensive questionnaire was completed. Methods. Women were given standard instructions for self-measurement of anthropometric characteristics. Women were followed through linkages to national registries until December 2003, during which time 256 cases of incident fatal CHD or nonfatal myocardial infarction occurred. Results. Waist circumference was associated with increased CHD risk after multivariate adjustment for confounders (HR = 1.9; 95% CI:1.1-3.3; highest versus lowest quartile), whereas height, weight and hip circumference were not. Measures of obesity were strongly related to CHD, and after mutual adjustment, waist-hip ratio (HR = 1.9, 95% CI: 1.2-3.2) was more closely related to CHD risk than BMI (HR = 1.5, 95% CI: 1.0-2.4). Risk of CHD was increased in women who remained heavy, those who were heavy at age 18, and those with low birth weight. Conclusions. In conclusion, there is strong evidence for supporting control of obesity, in particular avoidance of abdominal obesity, as a strategy to prevent CHD.

Measurement error in the explanatory variable of a binary regression: regression calibration and integrated conditional likelihood in studies of residential radon and lung cancer.

Abstract: In epidemiology, one approach to investigating the dependence of disease risk on an explanatory variable in the presence of several confounding variables is by fitting a binary regression using a conditional likelihood, thus eliminating the nuisance parameters When the explanatory variable is measured with error, the estimated regression coefficient is biased usually towards zero Motivated by the need to correct for this bias in analyses that combine data from a number of case-control studies of lung cancer risk associated with exposure to residential radon, two approaches are investigated Both employ the conditional distribution of the true explanatory variable given the measured one The method of regression calibration uses the expected value of the true given measured variable as the covariate The second approach integrates the conditional likelihood numerically by sampling from the distribution of the true given measured explanatory variable The two approaches give very similar point estimates and confidence intervals not only for the motivating example but also for an artificial data set with known properties These results and some further simulations that demonstrate correct coverage for the confidence intervals suggest that for studies of residential radon and lung cancer the regression calibration approach will perform very well, so that nothing more sophisticated is needed to correct for measurement error