Aims The aim of the UK Biobank sample handling and storage protocol is to specify methods for the collection and storage of participant samples that give maximum scientific return within the available budget. Processing or storage methods that, as far as can be predicted, will preclude current or future assays have been avoided.
Methods The protocol was developed through a review of the literature on sample handling and processing, wide consultation within the academic community and peer review. Protocol development addressed which samples should be collected, how and when they should be processed and how the processed samples should be stored to ensure their long-term integrity. The recommended protocol was extensively tested in a series of validation studies. UK Biobank collects about 45 ml blood and 9 ml of urine with minimal local processing from each participant using the vacutainer system. A variety of preservatives, anti-coagulants and clot accelerators is used appropriate to the expected end use of the samples. Collection of other material (hair, nails, saliva and faeces) was also considered but rejected for the full cohort. Blood and urine samples from participants are transported overnight by commercial courier to a central laboratory where they are processed and aliquots of urine, plasma, serum, white cells and red cells stored in ultra-low temperature archives. Aliquots of whole blood are also stored for potential future production of immortalized cell lines. A standard panel of haematology assays is completed on whole blood from all participants, since such assays need to be conducted on fresh samples (whereas other assays can be done on stored samples). By the end of the recruitment phase, 15 million sample aliquots will be stored in two geographically separate archives: 9.5 million in a –80°C automated archive and 5.5 million in a manual liquid nitrogen archive at –180°C. Because of the size of the study and the numbers of samples obtained from participants, the protocol stipulates a highly automated approach for the processing and storage of samples. Implementation of the processes, technology, systems and facilities has followed best practices used in manufacturing industry to reduce project risk and to build in quality and robustness. The data produced from sample collection, processing and storage are highly complex and are managed by a commercially available LIMS system fully integrated with the entire process.
Conclusion The sample handling and storage protocol adopted by UK Biobank provides quality assured and validated methods that are feasible within the available funding and reflect the size and aims of the project. Experience from recruiting and processing the first 40 000 participants to the study demonstrates that the adopted methods and technologies are fit-for-purpose and robust.
]]>Small body size at birth and slow growth during the first 2 years after birth, leading to low body mass index (BMI) at 2 years, are associated with coronary heart disease and stroke in adult life. We tested the hypothesis that this path of growth is associated with an atherogenic lipid profile in later life.
We measured serum lipid concentrations at age 57–70 years in 1999 members of the Helsinki Birth Cohort. They were randomly selected from an original cohort of 8760 people and had on average 11 measurements of height and weight between birth and 2 years of age.
The 18% of subjects who used lipid-lowering medication had a lower BMI at birth and at 2 years. These subjects were excluded from the analyses of lipid profiles. A 1 kg/m2 lower BMI at birth was associated with 0.051 mmol/l (95% CI –0.001 to 0.103; P = 0.05) higher non-HDL cholesterol and 0.018 g/l higher (0.005–0.031; P = 0.006) apolipoprotein B concentrations. A slower increase in BMI during the first 6 months after birth was associated with lower HDL and higher non-HDL cholesterol concentrations. A 1 kg/m2 lower BMI at 2 years was associated with 0.020 mmol/l lower (0.004–0.036; P = 0.02) HDL cholesterol and 0.059 mmol/l (0.020–0.099; P = 0.003) higher non-HDL cholesterol and 0.018 mmol/l higher (0.008–0.028; P < 0.001) apolipoprotein B concentrations. The age at weaning off breast milk was not associated with lipid profile in later life.
Small body size at birth and slow weight gain during infancy are associated with an atherogenic lipid profile in adult life.
Methods Five variants of the CRP gene were used to investigate whether SEP differences in CRP levels are determined at conception. SEP and serum CRP were assessed in childhood (age 3–9), adolescence (age 12–18) and in adulthood (age 24–39). SEP was measured using parental education and occupational status in childhood and adolescence, and participants’ own education and occupational status in adulthood. Participants with CRP > 10 mg/l were excluded.
Results All CRP gene variants were associated with circulating CRP concentrations in childhood, but there were no differences in the distribution of these variants by SEP. No strong evidence was found of associations between parental SEP and CRP. A graded association between higher SEP and lower CRP was observed in adulthood for education (P = 0.0005) but not for occupational status. Trajectories that led to high educational achievement both in the participants and their parents were associated with lower (P ≤ 0.047) CRP levels in adulthood. Excluding participants with infectious diseases, pregnant or lactating women and women using oral contraceptives did not change the findings.
Conclusion In this cohort, SEP differences in CRP concentrations seen in adulthood appear not to be determined at conception or evident in childhood or adolescence.
]]>Methods We studied 1167 participants in Project Viva, a longitudinal cohort study of pregnant women and their children. We estimated first and second trimester maternal iron intake from food frequency questionnaires. We used an electronic laboratory database to identify haemoglobin and MCV levels in pregnancy. We measured child BP up to five times with a Dinamap and used mixed-effects regression models in our analysis.
Results Mean (SD) child SBP at 3 years was 92.0 (9.9) mmHg. Adjusting for confounders, for each 10 mg increase in first trimester iron intake, child SBP was not lower, but was in fact 0.4 mmHg higher (95% CI 0.1, 0.7). For second trimester iron intake, and for first or second trimester haemoglobin and MCV levels, we did not find any appreciable association with 3 year SBP.
Conclusions In contrast to animal studies, we did not find that lower maternal iron status during pregnancy was associated with higher offspring BP.
]]>Methods A Poisson regression model relating the daily fluctuations in summer temperature and mortality in France from 1975 to 2003 was used to estimate the daily expected number of deaths over the period 2004–2006 as a function of the observed temperatures.
Results During the 2006 heat wave (from 11 to 28 July), about 2065 excess deaths occurred in France. Considering the observed temperatures and with the hypothesis that heat-related mortality had not changed since 2003, 6452 excess deaths were predicted for the period. The observed mortality during the 2006 heat wave was thus markedly less than the expected mortality (~4400 less deaths).
Conclusions The excess mortality during the 2006 heat wave, which was markedly lower than that predicted by the model, may be interpreted as a decrease in the population's vulnerability to heat, together with, since 2003, increased awareness of the risk related to extreme temperatures, preventive measures and the set-up of the warning system.
]]>A recent monograph by the International Agency for Research on Cancer (IARC) has identified indoor air pollution from coal usage as a known human carcinogen, while that from biomass as a probable human carcinogen. Although as much as 74% of the Indian population relies on solid fuels for cooking, very little information is available on cancer risk associated with these fuels in India.
Using data from a multicentric case–control study of 799 lung and 1062 hypopharyngeal/laryngeal cancer cases, and 718 controls, we investigated indoor air pollution from various solid fuels as risk factors for these cancers in India.
Compared with never users, individuals who always used coal had an increased risk of lung cancer [odds ratio (OR) 3.76, 95% confidence interval (CI) 1.64–8.63]. Long duration of coal usage (>50 years) was a risk factor for hypopharyngeal (OR 3.47, CI 0.95–12.69) and laryngeal (OR 3.65, CI 1.11–11.93) cancers. An increased risk of hypopharyngeal cancer was observed among lifelong users of wood (OR 1.62, CI 1.14–2.32), however this was less apparent among never-smokers. Increasing level of smokiness inside the home was associated with an increasing risk of hypopharyngeal and lung cancer (Ptrend < 0.05).
This study showed differential risks associated with indoor air pollution from wood and coal burning, and provides novel evidence on cancer risks associated with solid fuel usage in India. Our findings suggest that reducing indoor air pollution from solid fuels may contribute to prevention of these cancers in India, in addition to tobacco and alcohol control programs.
Methods The search was concluded in April 2006. Bibliographic databases consulted included PubMed, EMBASE, Cochrane Library and NIOSHTIC2. Pooled estimates were obtained using random-effects meta-analysis. Sources of heterogeneity between studies were explored, as was publication bias.
Results Fourteen different studies (nine case-control and five cohort studies) accomplished inclusion criteria. All these studies followed standardized criteria for AD diagnosis and most of them obtained quantitative estimates of exposure. Pooled estimates suggest an increased risk of AD from case-control studies (ORpooled 2.03; 95% CI 1.38–3.00) and from cohort studies (RRpooled 1.62; 95% CI 1.16–2.27), with moderate to high statistical heterogeneity in both cases (respectively, I2 = 58% and I2 = 54%). Cohort studies showed consistently increased risks for exposed men (RRpooled 2.05; 95% CI 1.51–2.80, I2 = 0%). Evidence of dose–response relationship was not present. Test for publication bias suggests small study effects, mostly for case-control studies.
Conclusions Available epidemiological evidence suggests an association between occupational exposure to ELF-EMF and AD. However, some limitations affecting the results from this meta-analysis should be considered. More information on relevant duration and time windows of exposure, on biological mechanisms for this potential association and on interactions between electromagnetic fields exposure and established risk factors for AD is needed.
]]>Methods A case-control study was carried out from June to December 2006. Cases were recruited at Amudat hospital, Nakapiripirit district, Uganda, after clinical and parasitological confirmation of symptomatic VL infection. Controls were individuals that tested negative using a rK39 antigen-based dipstick, which were recruited at random from the same communities as the cases. Data were analysed using conditional logistic regression.
Results Ninty-three cases and 226 controls were recruited into the study. Multivariate analysis identified low socio-economic status and treating livestock with insecticide as risk factors for VL. Sleeping near animals, owning a mosquito net and knowing about VL symptoms were associated with a reduced risk of VL.
Conclusions VL affects the poorest of the poor of the Pokot tribe. Distribution of insecticide-treated mosquito nets combined with dissemination of culturally appropriate behaviour-change education is likely to be an effective prevention strategy.
]]>Although measles incidence has been reduced to low levels in many countries, the potential exists for HIV-1 infection to enhance measles virus (MV) transmission and hinder measles control and elimination efforts.
HIV-1 infection was incorporated into an age-structured, deterministic compartmental model of MV transmission. Parameter estimates were obtained from published studies. The model was then adapted to simulate the introduction of antiretroviral therapy (ART).
The model suggests that prior to the introduction of ART, HIV-1 infection has little impact on the transmission dynamics of MV. High mortality rates in HIV-1-infected children without access to ART counteract the higher rates of vaccine failure, shorter duration of maternal antibody protection and longer duration of infectiousness in HIV-1-infected children, as many of these children die before they are able to contribute to MV transmission. The introduction of ART into the model resulted in an increase in measles prevalence.
High overall mortality among HIV-1-infected children without access to ART limits the impact of the HIV-1 epidemic on MV transmission and may help to explain the initial success of measles control strategies in Africa. The scaling-up of ART should improve children's survival but could lead to an increase in measles prevalence in the absence of sustained measles control efforts. Further study of the duration of immunity in HIV-1-infected children receiving ART and their response to revaccination is needed to determine whether a second dose of measles vaccine will protect these children and further reduce MV transmission.
Methods Within the European Prospective Investigation into Cancer and Nutrition (EPIC), a calibration study was set up to express individual dietary intakes according to the same reference scale. A linear regression calibration model was used to correct the association between diet and disease for measurement errors in dietary exposures. In the present work, we describe an approach for analysing the EPIC data, using as an example the evaluation of the association between fish intake and colorectal cancer incidence.
Results Sex- and country-specific attenuation factors ranged from 0.083 to 0.784, with values overall higher for men compared with women. Hazard ratio estimates of colorectal cancer for a 10 g/day increase in fish intake were 0.97 [95% confidence interval (CI): 0.95–0.99] and 0.93 (0.88–0.98), before and after calibration, respectively.
Conclusions In a multicentre study, the diet/disease association can be evaluated by exploiting the whole variability of intake over the entire study. Calibration may reduce between-centre heterogeneity in the diet–disease relationship caused by differential impact of measurement errors across cohorts.
]]>Methods A total of 14 445 participants, aged 39–54 in 1993, completed the personality questionnaires composed of the Bortner Type-A scale, the Buss–Durkee Hostility Inventory (for total, neurotic and reactive hostility) and the Grossarth-Maticek–Eysenck Personality Stress Inventory that assesses six personality types [cancer-prone, coronary heart disease (CHD)-prone, ambivalent, healthy, rational, anti-social]. The association between personality traits and mortality, during a mean follow-up of 12.7 years, was assessed using the Relative Index of Inequality (RII) in Cox regression.
Results In models adjusted for age, sex, marital status and education, all-cause and cause-specific mortality were predicted by ‘total hostility’, its ‘neurotic hostility’ component as well as by ‘CHD-prone’, ‘ambivalent’ ‘antisocial’, and ‘healthy’ personality types. After mutually adjusting personality traits for each other, only high ‘neurotic hostility’ remained a robust predictor of excess mortality from all causes [RII = 2.62; 95% confidence interval (CI) = 1.68–4.09] and external causes (RII = 3.24; 95% CI = 1.03–10.18). ‘CHD-prone’ (RII = 2.23; 95% CI = 0.72–6.95) and ‘anti-social’ (RII = 2.13; 95% CI 0.61–6.58) personality types were associated with cardiovascular mortality and with mortality from external causes, respectively, but CIs were wider. Adjustment for potential behavioural mediators had only a modest effect on these associations.
Conclusions Neurotic hostility, CHD-prone personality and anti-social personality were all predictive of mortality outcomes. Further research is required to determine the precise mechanisms that contribute to these associations.
]]>Methods We included all person-time in women aged 15–50 between 1983 and 2001 and compared mortality rates by time since pregnancy outcome (live birth, stillbirth, induced and spontaneous abortion) using Poisson regression, adjusting for socio-demographic factors.
Results Mortality was highest on the first day after pregnancy (adjusted RR compared with third to fourth year post-partum 105.74, 95% CI: 76.08, 146.95) and remained elevated until 180 days (adjusted RR 1.55, 95% CI: 1.13, 2.11). Pregnancies ending in abortions and stillbirths accounted for 50% of deaths in women within 6 weeks of the end of pregnancy, and mortality after these outcomes was between two and four times as high as mortality after a livebirth.
Conclusion The high mortality rates immediately after birth provide strong support for a skilled attendance strategy. After abortions or stillbirths, women should be under surveillance for up to 1 week. Further work on the cause of deaths in the late post-partum period is required to understand the mechanisms behind increased mortality risks at these times.
]]>Methods The study population included patients aged 40+ years who received a prescription for Cox-2 inhibitors and were included in the General Practice Research Database. The incidence of upper GI events, myocardial infarction (MI) and stroke was estimated in this cohort. It was assumed that patients had experienced the upper GI and cardiovascular effects, as observed in clinical trials [relative rate (RR) of 0.49 for upper GI and 1.86 for MI]. Simulation methodology was used to estimate attributable risks, i.e. the difference between exposed and unexposed event probabilities.
Results The study population included 155 439 Cox-2 users. The number of upper GI events prevented by Cox-2 inhibitors was 179, while the number of excess MI cases was 83 per 10 000 patients treated for 4 years. A strong association was found between extent of GI benefit and cardiovascular harm. There was a large difference in the frequency of benefit over harm in only 6% of the patients (difference of 1% or more); 23% of the patients had more harm than benefit, including those with a history of ischaemic heart disease.
Conclusions The benefit of Cox-2 inhibitors in reducing the frequency of upper GI events may be offset by their cardiovascular harm, particularly in patients with risk factors for cardiovascular disease.
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