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Background: 'Conditional trial design' is a framework for efficiently planning new clinical trials based on a network of relevant existing trials. The framework considers whether new trials are required and how the existing evidence can be used to answer the research question and plan future research. The potential of this approach has not been fully realized., Methods: We conducted an online survey among trial statisticians, methodologists, and users of evidence synthesis research using referral sampling to capture opinions about the conditional trial design framework and current practices among clinical researchers. The questions included in the survey were related to the decision of whether a meta-analysis answers the research question, the optimal way to synthesize available evidence, which relates to the acceptability of network meta-analysis, and the use of evidence synthesis in the planning of new studies., Results: In total, 76 researchers completed the survey. Two out of three survey participants (65%) were willing to possibly or definitely consider using evidence synthesis to design a future clinical trial and around half of the participants would give priority to such a trial design. The median rating of the frequency of using such a trial design was 0.41 on a scale from 0 (never) to 1 (always). Major barriers to adopting conditional trial design include the current regulatory paradigm and the policies of funding agencies and sponsors., Conclusions: Participants reported moderate interest in using evidence synthesis methods in the design of future trials. They indicated that a major paradigm shift is required before the use of network meta-analysis is regularly employed in the design of trials.

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985-2009). Our model accommodated modification of the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modification of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for persons who smoked more than 20-30 cigarettes per day. Patterns of effect modification were similar across individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smoking cessation. Application of our method in this example of cigarette smoking and lung cancer demonstrated that reducing a complex exposure history to a metric such as cumulative exposure is too restrictive.

Background: Heat waves and air pollution are both associated with increased mortality. Their joint effects are less well understood., Methods: We explored the role of air pollution in modifying the effects of heat waves on mortality, within the EuroHEAT project. Daily mortality, meteorologic, and air pollution data from nine European cities for the years 1990-2004 were assembled. We defined heat waves by taking both intensity and duration into account. The city-specific effects of heat wave episodes were estimated using generalized estimating equation models, adjusting for potential confounders with and without inclusion of air pollutants (particles, ozone, nitrogen dioxide, sulphur dioxide, carbon monoxide). To investigate effect modification, we introduced an interaction term between heat waves and each single pollutant in the models. Random effects meta-analysis was used to summarize the city-specific results., Results: The increase in the number of daily deaths during heat wave episodes was 54% higher on high ozone days compared with low, among people age 75-84 years. The heat wave effect on high PM10 days was increased by 36% and 106% in the 75-84 year and 85+ year age groups, respectively. A similar pattern was observed for effects on cardiovascular mortality. Effect modification was less evident for respiratory mortality, although the heat wave effect itself was greater for this cause of death. The heat wave effect was smaller (15-30%) after adjustment for ozone or PM10., Conclusions: The heat wave effect on mortality was larger during high ozone or high PM10 days. When assessing the effect of heat waves on mortality, lack of adjustment for ozone and especially PM10 overestimates effect parameters. This bias has implications for public health policy.

Introduction: Thyroid disorders are prevalent and their manifestations are determined by the dietary iodine availability., Sources of Data: Data from screening large population samples from USA and Europe., Areas of Agreement: The most common cause of thyroid disorders worldwide is iodine deficiency, leading to goitre formation and hypothyroidism. In iodine-replete areas, most persons with thyroid disorders have autoimmune disease., Areas of Controversy: Definition of thyroid disorders, selection criteria used, influence of age and sex, environmental factors and the different techniques used for assessment of thyroid function., Growing Points: Increasing incidence of well-differentiated thyroid cancer. Environmental iodine influences the epidemiology of non-malignant thyroid disease., Areas Timely for Developing Research: Iodine supplementation of populations with mild-to-moderate iodine deficiency. An evidence-based strategy for the risk stratification, treatment and follow-up of benign nodular thyroid disease. Is there any benefit in screening adults for thyroid dysfunction?

Background: There is widespread concern that the present economic crisis, particularly its effect on unemployment, will adversely affect population health. We investigated how economic changes have affected mortality rates over the past three decades and identified how governments might reduce adverse effects., Methods: We used multivariate regression, correcting for population ageing, past mortality and employment trends, and country-specific differences in health-care infrastructure, to examine associations between changes in employment and mortality, and how associations were modified by different types of government expenditure for 26 European Union (EU) countries between 1970 and 2007., Findings: We noted that every 1% increase in unemployment was associated with a 0.79% rise in suicides at ages younger than 65 years (95% CI 0.16-1.42; 60-550 potential excess deaths [mean 310] EU-wide), although the effect size was non-significant at all ages (0.49%, -0.04 to 1.02), and with a 0.79% rise in homicides (95% CI 0.06-1.52; 3-80 potential excess deaths [mean 40] EU-wide). By contrast, road-traffic deaths decreased by 1.39% (0.64-2.14; 290-980 potential fewer deaths [mean 630] EU-wide). A more than 3% increase in unemployment had a greater effect on suicides at ages younger than 65 years (4.45%, 95% CI 0.65-8.24; 250-3220 potential excess deaths [mean 1740] EU-wide) and deaths from alcohol abuse (28.0%, 12.30-43.70; 1550-5490 potential excess deaths [mean 3500] EU-wide). We noted no consistent evidence across the EU that all-cause mortality rates increased when unemployment rose, although populations varied substantially in how sensitive mortality was to economic crises, depending partly on differences in social protection. Every US$10 per person increased investment in active labour market programmes reduced the effect of unemployment on suicides by 0.038% (95% CI -0.004 to -0.071)., Interpretation: Rises in unemployment are associated with significant short-term increases in premature deaths from intentional violence, while reducing traffic fatalities. Active labour market programmes that keep and reintegrate workers in jobs could mitigate some adverse health effects of economic downturns., Funding: Centre for Crime and Justice Studies, King's College, London, UK; and Wates Foundation (UK).

Background: International multicentre studies on diet and cancer are relatively new in epidemiological research. They offer a series of challenging methodological issues for the evaluation of the association between dietary exposure and disease outcomes, which can both be quite heterogeneous across different geographical regions. This requires considerable work to standardize dietary measurements at the food and the nutrient levels., 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.

Background: A recent analysis indicates that the excess odds ratio for lung cancer by smoking is described by a function that is linear in pack-years and exponential in the logarithm of smoking intensity and its square (Cancer Epidemiol Biomarkers Prev. 2006;15:517-523). The model suggests that below 15-20 cigarettes per day there is a "direct exposure rate" effect, ie, the excess odds ratio per pack-year for higher intensity (and shorter duration) smokers is greater than for lower-intensity (and longer duration) smokers. Above 20 cigarettes per day, there is an "inverse-exposure-rate" effect, ie, the excess odds ratio per pack-year for higher intensity smokers is smaller than for lower-intensity smokers., Methods: Using pooled data from 2 large case-control studies of lung cancer (the European Smoking and Health Study and the German Radon Study), we evaluated effect modification of the association between smoking and lung cancer., Results: Interaction effects are very specific. Variations in risk of lung cancer with years since cessation of smoking, age, method of inhalation, and type of cigarette result from interactions with smoking intensity, and not total pack-years. In contrast, risk variations by sex result from the interaction with total pack-years, while intensity effects are homogeneous. Risk variations by age at which smoking started result from interactions with both total pack-years and intensity. All intensity interactions are homogeneous across studies., Conclusions: The specificity of the interactions may provide clues for the molecular basis of the smoking and lung cancer relationship.

Nowadays the burden of cancer in elderly people has reached an alarming extent. The purpose of this study is comparing cumulative and conditional relative survival in elderly patients between 65 and 84 years and younger adults aged from 55 to 64. Fifty-three cancer registries of 22 European countries, participating in the EUROCARE-3 programme, collected information on the cases diagnosed over the period 1990-1994. We computed cumulative and conditional relative survival for 16 cancer sites. Middle aged patients experienced a better prognosis than the elderly for all cancer sites, in both sexes and the differences were more marked at 1 than 5 years since diagnosis. The very large differences noted in the first period after cancer detection declined in the subsequent years and, when 5-years conditional survival was considered, for several cancers the elderly and younger adults had the same probabilities of surviving. The death relative excess risks (RERs) in the elderly with respect younger individuals were really very high and markedly larger at 1 than 5 years, and in women than men. Genitourinary and gynaecological cancers showed the highest RERs, around 2.0 and between 1.5 and 2.5 respectively. This very high early mortality could be due not only to clinical aspects: the barriers to health care access and a consequent late diagnosis might represent for elderly patients the main determinant of this very large prognostic disadvantage. In conclusion, clinical management of cancer in the elderly remains a major issue to be faced with complex social and health care policies., ((c) 2007 Wiley-Liss, Inc.)

Objectives: NO2)is a major urban air pollutant. Previously reported associations between ambient NO2)and children's respiratory health have been inconsistent, and independent effects of correlated pollutants hard to assess. The authors examined effects of NO2 on a spectrum of 11 respiratory symptoms, controlling for PM10 and SO2, using a large pooled dataset., Methods: Cross sectional studies were conducted in Russia, Austria, Italy, Switzerland, and the Netherlands, during 1993-99, contributing in total 23 955 children. Study-specific odds ratios for associations with ambient NO2 are estimated using logistic regressions with area-level random effects. Heterogeneity between study-specific results, and mean estimates (allowing for heterogeneity) are calculated., Results: Long term average NO2 concentrations were unrelated to prevalences of bronchitis or asthma. Associations were found for sensitivity to inhaled allergens and allergy to pets, with mean odds ratios around 1.14 per 10 microg/m3 NO2. SO2 had little confounding effect, but an initial association between NO2 and morning cough was reduced after controlling for PM10. Associations with reported allergy were not reduced by adjustment for the other pollutants. Odds ratios for allergic symptoms tended to be higher for the 9-12 year old children compared with the 6-8 year old children., Conclusions: Evidence for associations between NO2 and respiratory symptoms was robust only for inhalation allergies. NO2 most likely is acting as an indicator of traffic related air pollutants, though its direct effect cannot be ruled out. This remains important, as policies to reduce traffic related air pollution will not result in rapid reductions.