Showing papers by "Clinical Trial Service Unit published in 2012"

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

Abstract: Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

Cancer burden in Africa and opportunities for prevention.

Abstract: Cancer is an emerging public health problem in Africa. About 715,000 new cancer cases and 542,000 cancer deaths occurred in 2008 on the continent, with these numbers expected to double in the next 20 years simply because of the aging and growth of the population. Furthermore, cancers such as lung, female breast, and prostate cancers are diagnosed at much higher frequencies than in the past because of changes in lifestyle factors and detection practices associated with urbanization and economic development. Breast cancer in women and prostate cancer in men have now become the most commonly diagnosed cancers in many Sub-Saharan African countries, replacing cervical and liver cancers. In most African countries, cancer control programs and the provision of early detection and treatment services are limited despite this increasing burden. This paper reviews the current patterns of cancer in Africa and the opportunities for reducing the burden through the application of resource level interventions, including implementation of vaccinations for liver and cervical cancers, tobacco control policies for smoking-related cancers, and low-tech early detection methods for cervical cancer, as well as pain relief at the palliative stage of cancer.

UK Biobank: Current status and what it means for epidemiology

Abstract: UK Biobank is a very large prospective study which aims to provide a resource for the investigation of the genetic, environmental and lifestyle determinants of a wide range of diseases of middle age and later life. Between 2006 and 2010, over 500,000 men and women aged 40 to 69 years were recruited and extensive data on participants' lifestyles, environment, medical history and physical measures, along with biological samples, were collected. The health of the participants is now being followed long-term, principally through linkage to a wide range of health-related records, with validation and characterisation of health-related outcomes. Further enhancements are also underway to improve phenotype characterisation, including internet-based dietary assessment, biomarker measurements on the baseline blood samples and, in sub-samples of the cohort, physical activity monitoring and proposals for extensive brain and body imaging. UK Biobank is now available for use by all researchers, without exclusive or preferential access, for any health-related research that is in the public interest. The open-access nature of the resource will allow researchers from around the world to conduct research that leads to better strategies for the prevention, diagnosis and treatment of a wide range of life-threatening and disabling conditions.

Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study

Abstract: Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...

Seasonal variation in blood pressure and its relationship with outdoor temperature in 10 diverse regions of China: the China Kadoorie Biobank.

Abstract: OBJECTIVES Mean blood pressure varies moderately with outdoor air temperature in many western populations. Substantial uncertainty exists, however, about the strength of the relationship in other populations and its relevance to age, adiposity, medical treatment, climate and housing conditions. METHODS To investigate the relationship of blood pressure with season and outdoor temperature, we analysed cross-sectional data from the China Kadoorie Biobank study of 506,673 adults aged 30-79 years recruited from 10 diverse urban and rural regions in China. Analyses related mean blood pressure - overall and in various subgroups - to mean local outdoor temperature. RESULTS The mean difference in SBP between summer (June-August) and winter (December-February) was 10 mmHg overall, and was more extreme, on average, in rural than in urban areas (12 vs. 8 mmHg; P for interaction <0.0001). Above 5°C, SBP was strongly inversely associated with outdoor temperature in all 10 areas studied, with 5.7 (SE 0.04) mmHg higher SBP per 10°C lower outdoor temperature. The association was stronger in older people and in those with lower BMI. At lower temperatures, there was no evidence of an association among participants who reported having central heating in their homes. CONCLUSION Blood pressure was strongly inversely associated with outdoor temperature in Chinese adults across a range of climatic conditions, although access to home central heating appeared to remove much of the association during the winter months. Seasonal variation in blood pressure should be considered in the clinical management of hypertension.

Homocysteine and Coronary Heart Disease: Meta- analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

Abstract: Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so ‘‘Mendelian randomization’’ studies using this variant as an instrumental variable could help test causality Methods and Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 102 (098–107; p=028) overall, and 101 (095–107) in unsupplemented low-folate populations By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 115 (109–121), significantly discrepant (p=0001) with the OR in the unpublished datasets Within the meta-analysis of published studies, the OR was 112 (104–121) in the 14 larger studies (those with variance of log OR,005; total 13,119 cases) and 118 (109–128) in the 72 smaller ones (total 15,498 cases) Conclusions: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD The discrepant overall result from previously published studies reflects publication bias or methodological problems Please see later in the article for the Editors’ Summary

Body mass index and mortality in China: a 15-year prospective study of 220 000 men

Abstract: (HRs) and 95% confidence intervals (95% CIs) per 5 kg/m 2 calculated within either a lower (15 to <23.5 kg/m 2 ) or higher (23.5 to <35 kg/m 2 ) range. Results The association between BMI and all-cause mortality was U-shaped with the lowest mortality at � 22.5–25 kg/m 2 . In the lower range, 5 kg/m 2 higher BMI was associated with 14% lower mortality (HR 0.86, 95% CI 0.82–0.91); in the upper range, it was associated with 27% higher mortality (HR 1.27, 95% CI 1.15–1.40). The absolute excess mortality in the lower range was largely accounted for by excess mortality from specific smoking-related diseases: 54% by that for COPD, 12% other respiratory disease, 13% lung cancer, 11% stomach cancer. The excess mortality in the upper BMI range was largely accounted for by excess mortality from specific vascular diseases: 55% by that for stroke, 16% CHD. In this range, 5 kg/m 2 higher BMI was associated with � 50% higher mortality from stroke (HR 1.61, 95% CI 1.36–1.92) and CHD (HR 1.48, 95% CI 1.12–1.95). Conclusions For China, previous evidence may have overestimated the excess mortality at low BMI but underestimated that at high BMI. The main way obesity kills in China appears to be stroke.

Impact of smoking on mortality and life expectancy in Japanese smokers: a prospective cohort study.

Abstract: Objective To investigate the impact of smoking on overall mortality and life expectancy in a large Japanese population, including some who smoked throughout adult life. Design The Life Span Study, a population-based prospective study, initiated in 1950. Setting Hiroshima and Nagasaki, Japan. Participants Smoking status for 27 311 men and 40 662 women was obtained during 1963-92. Mortality from one year after first ascertainment of smoking status until 1 January 2008 has been analysed. Main outcome measures Mortality from all causes in current, former, and never smokers. Results Smokers born in later decades tended to smoke more cigarettes per day than those born earlier, and to have started smoking at a younger age. Among those born during 1920-45 (median 1933) and who started smoking before age 20 years, men smoked on average 23 cigarettes/day, while women smoked 17 cigarettes/day, and, for those who continued smoking, overall mortality was more than doubled in both sexes (rate ratios versus never smokers: men 2.21 (95% confidence interval 1.97 to 2.48), women 2.61 (1.98 to 3.44)) and life expectancy was reduced by almost a decade (8 years for men, 10 years for women). Those who stopped smoking before age 35 avoided almost all of the excess risk among continuing smokers, while those who stopped smoking before age 45 avoided most of it. Conclusions The lower smoking related hazards reported previously in Japan may have been due to earlier birth cohorts starting to smoke when older and smoking fewer cigarettes per day. In Japan, as elsewhere, those who start smoking in early adult life and continue smoking lose on average about a decade of life. Much of the risk can, however, be avoided by giving up smoking before age 35, and preferably well before age 35.

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.

Abstract: Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had ≥1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.

Effect of statins on venous thromboembolic events: A meta-analysis of published and unpublished evidence from randomised controlled trials

Abstract: Background: It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins. Methods and Findings: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months’ follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR]=0.89, 95% CI 0.78–1.01, p=0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR=0.93 [95% CI 0.82–1.07], p=0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR=0.98, 95% CI 0.80– 1.20, p=0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Conclusions: The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out. Please see later in the article for the Editors’ Summary.

Estimating and validating disability-adjusted life years at the global level: a methodological framework for cancer

Abstract: Disability-adjusted life years (DALYs) link data on disease occurrence to health outcomes, and they are a useful aid in establishing country-specific agendas regarding cancer control. The variables required to compute DALYs are however multiple and not readily available in many countries. We propose a methodology that derives global DALYs and validate variables and DALYs based on data from various cancer registries. We estimated DALYs for four countries (Norway, Bulgaria, India and Uganda) within each category of the human development index (HDI). The following sources (indicators) were used: Globocan2008 (incidence and mortality), various cancer registries (proportion cured, proportion treated and duration of disease), treatment guidelines (duration of treatment), specific burden of disease studies (sequelae and disability weights), alongside expert opinion. We obtained country-specific population estimates and identified resource levels using the HDI, DALYs are computed as the sum of years of life lost and years lived with disabilities. Using mortality:incidence ratios to estimate country-specific survival, and by applying the human development index we derived country-specific estimates of the proportion cured and the proportion treated. The fit between the estimates and observed data from the cancer registries was relatively good. The final DALY estimates were similar to those computed using observed values in Norway, and in WHO’s earlier global burden of disease study. Marked cross-country differences in the patterns of DALYs by cancer sites were observed. In Norway and Bulgaria, breast, colorectal, prostate and lung cancer were the main contributors to DALYs, representing 54% and 45%, respectively, of the totals. These cancers contributed only 27% and 18%, respectively, of total DALYs in India and Uganda. Our approach resulted in a series of variables that can be used to estimate country-specific DALYs, enabling global estimates of DALYs and international comparisons that support priorities in cancer control.

Pediatric, elderly, and emerging adult‐onset peaks in Burkitt's lymphoma incidence diagnosed in four continents, excluding Africa

Abstract: Burkitt's lymphoma (BL) in the general population and immunosuppressed persons with AIDS in the United States was characterized by three age-specific incidence peaks near 10, 40, and 70 years. We hypothesized that BL from different geographical areas may exhibit pediatric, adult, and elderly age incidence peaks. We investigated this hypothesis using data on 3,403 cases obtained from the International Agency for Research on Cancer (1963-2002). Data from Africa were sparse or incomplete, and thus were excluded. Age-standardized rates (ASRs) and age-specific incidence rates were calculated, supplemented with the calculations performed using age-period-cohort (APC) models. The ASR rose 5.3% (95% confidence interval [CI], 5.0-5.6) per year in males and 4.6% (95% CI, 4.5-4.8) in females. The ASR increased gradually in children, steeply in adults and most rapidly in the elderly both in males and in females. Overall, BL male/female ASR ratio was 2.5, but it declined from 3.1 (95% CI, 3.0-3.3) for pediatric BL to 2.3 (95% CI, 2.2-2.4) for adult BL and 1.5 (95% CI, 1.4-1.6) for elderly BL. Age-specific incidence peaks occurred near 10 and 70 years in all regions and periods. A peak near 40 years of age emerged in the mid-1990s, particularly in men. Findings using APC models confirmed those based on the standard analyses. Our findings, based on the international BL cases, support our hypothesis that BL is multimodal and that BL peaks at different ages may be clues to differences in the etiology and/or biology of BL at those ages.

[The China Kadoorie Biobank: related methodology and baseline characteristics of the participants].

Abstract: Objective To study the separate and combined effects of environment, lifestyle, physical characteristics, blood biomarkers and genetic factors on aetiology of major chronic diseases in adult Chinese. Methods China Kadoorie Biobank （CKB） is a large blood-based prospective cohort study. The baseline survey took place in 5 urban and 5 rural areas across China during 2004-2008, with collection of data through questionnaire, physical examination and blood samples. Following the baseline survey, 5% of the randomly selected participants were surveyed in 2008, and repeated every 4-5 years. All participants would be followed for cause-specific mortality and morbidity through registries and for any hospital admission through linkages with health insurance databases. Results Overall, 512 891 adults aged 30-79 years （mean 51.5） were recruited, including 41.0% men and 55.9% from rural areas. Blood collection was successfully done in 99.98% of the participants. The prevalence of current regular smoking was 61.3% in men and 2.4% in women. The prevalence of regular alcohol consumption （i.e., weekly） was 33.4% in men and 2.1% in women. At the baseline,41.8% of men and 45.3% of women were overweight or obese （i.e., BMI≥24.0 kg/m2） and 32.2% of men and 30.2% of women were hypertensive （i.e., SBP ≥ 140 mm Hg or DBP ≥90 mm Hg）. For each of the main baseline variables, there were large variations on age, sex and areas of study. Conclusion CKB seemed to be a powerful and rich resource in studying the environmental and genetic determinants of major chronic diseases in the Chinese population. Key words: Chronic disease; Cohort study; Biobank

Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized LRF CLL4 trial.

Abstract: Health-related quality of life (HRQoL) is a key issue for patients with chronic lymphocytic leukemia. The multicenter LRF CLL4 trial, in which 777 patients were randomized to receive chlorambucil or fludarabine, alone or with cyclophosphamide (FC), assessed HRQoL at baseline, months 3, 6 and 12, then annually until 5 years, using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30). While on treatment, some HRQoL impairment was seen in patients receiving fludarabine, particularly FC, compared with chlorambucil. Thus at 3 months, role/social functioning and fatigue were ≥ 10 points worse than baseline in 41%/46%/56%, respectively, of patients receiving fludarabine alone and 48%/54%/60% receiving FC, compared with only 29%/31%/40% of those receiving chlorambucil. Thereafter HRQoL appeared similar between treatment groups. Sustained remissions were associated with long-term HRQoL benefit. In the primary HRQoL domains patients still in complete or partial remission at each time-point had scores close to those reported in general population studies, while patients whose disease had progressed had mean scores up to 22 points worse, in spite of subsequent treatments. These data offer support for the use of primary treatment regimens likely to achieve and sustain remission in otherwise medically fit patients of all ages, including those aged > 70 years.

Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression.

Abstract: Background Studies conducted in Europe and the USA have shown that co-morbidity between major depressive disorder (MDD) and anxiety disorders is associated with various MDD-related features, including clinical symptoms, degree of familial aggregation and socio-economic status. However, few studies have investigated whether these patterns of association vary across different co-morbid anxiety disorders. Here, using a large cohort of Chinese women with recurrent MDD, we examine the prevalence and associated clinical features of co-morbid anxiety disorders.

Evidence for under-diagnosis of childhood acute lymphoblastic leukaemia in poorer communities within Great Britain

Abstract: Evidence for under-diagnosis of childhood acute lymphoblastic leukaemia in poorer communities within Great Britain

Social inequalities, tobacco chewing, and cancer mortality in south India: a case-control analysis of 2,580 cancer deaths among non-smoking non-drinkers.

Abstract: Objective The objective of this work was to describe the relationships between educational level, tobacco chewing, and cancer mortality in south India, among middle-aged adults who never smoked tobacco or drank alcohol, to eliminate confounding by those habits.

Clinical Trials: Rethinking How We Ensure Quality

Abstract: This article is the version submitted to the publisher which was accepted without revision.

A comparison of the clinical characteristics of women with recurrent major depression with and without suicidal symptomatology

Abstract: BackgroundThe relationship between recurrent major depression (MD) in women and suicidality is complex. We investigated the extent to which patients who suffered with various forms of suicidal symptomatology can be distinguished from those subjects without such symptoms.MethodWe examined the clinical features of the worst episode in 1970 Han Chinese women with recurrent DSM-IV MD between the ages of 30 and 60 years from across China. Student's t tests, and logistic and multiple logistic regression models were used to determine the association between suicidality and other clinical features of MD.ResultsSuicidal symptomatology is significantly associated with a more severe form of MD, as indexed by both the number of episodes and number of MD symptoms. Patients reporting suicidal thoughts, plans or attempts experienced a significantly greater number of stressful life events. The depressive symptom most strongly associated with lifetime suicide attempt was feelings of worthlessness (odds ratio 4.25, 95% confidence interval 2.9–6.3). Excessive guilt, diminished concentration and impaired decision-making were also significantly associated with a suicide attempt.ConclusionsThis study contributes to the existing literature on risk factors for suicidal symptomatology in depressed women. Identifying specific depressive symptoms and co-morbid psychiatric disorders may help improve the clinical assessment of suicide risk in depressed patients. These findings could be helpful in identifying those who need more intense treatment strategies in order to prevent suicide.

A Review on Metaanalysis of Biomarkers:Promises and Pitfalls

Abstract: BACKGROUND: The last 30 years have seen an exponential increase in metaanalyses. By combining multiple studies, metaanalysis can provide an overview of the totality of evidence on a particular question and the statistical power needed to reduce random error and produce precise estimates of even modest effect sizes. This capability is of particular value when many small studies address similar questions [such as in the investigation of novel cardiovascular disease (CVD) biomarkers]. To provide reliable evidence, however, metaanalyses must be undertaken robustly. CONTENT: In this review, we describe the major issues to consider when designing and conducting metaanalyses, including the design of constituent studies, selection criteria, assessment of exposures and disease outcomes, and control of bias and confounding. Some of the potential challenges and pitfalls associated with metaanalysis are examined, and their consequences are considered. We use 2 examples of novel biomarkers for CVD—homocysteine and triglycerides—to illustrate how metaanalyses of observational studies have contributed to, and on occasion hindered, our understanding; and how subsequent work has built upon these findings. SUMMARY: Metaanalyses of observational studies, particularly metaanalyses of individual-participant data, have the power to provide robust evidence to support our understanding of the role of novel biomarkers for disease. The characteristic limitations and challenges of these studies, including their inability to detect causal associations, must be considered, however, and additional evidence from randomized controlled trials and genetic studies is frequently required to elucidate fully the role of novel biomarkers in predicting cardiovascular risk.