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1.  Conditional Poisson models: a flexible alternative to conditional logistic case cross-over analysis 
Background
The time stratified case cross-over approach is a popular alternative to conventional time series regression for analysing associations between time series of environmental exposures (air pollution, weather) and counts of health outcomes. These are almost always analyzed using conditional logistic regression on data expanded to case–control (case crossover) format, but this has some limitations. In particular adjusting for overdispersion and auto-correlation in the counts is not possible. It has been established that a Poisson model for counts with stratum indicators gives identical estimates to those from conditional logistic regression and does not have these limitations, but it is little used, probably because of the overheads in estimating many stratum parameters.
Methods
The conditional Poisson model avoids estimating stratum parameters by conditioning on the total event count in each stratum, thus simplifying the computing and increasing the number of strata for which fitting is feasible compared with the standard unconditional Poisson model. Unlike the conditional logistic model, the conditional Poisson model does not require expanding the data, and can adjust for overdispersion and auto-correlation. It is available in Stata, R, and other packages.
Results
By applying to some real data and using simulations, we demonstrate that conditional Poisson models were simpler to code and shorter to run than are conditional logistic analyses and can be fitted to larger data sets than possible with standard Poisson models. Allowing for overdispersion or autocorrelation was possible with the conditional Poisson model but when not required this model gave identical estimates to those from conditional logistic regression.
Conclusions
Conditional Poisson regression models provide an alternative to case crossover analysis of stratified time series data with some advantages. The conditional Poisson model can also be used in other contexts in which primary control for confounding is by fine stratification.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2288-14-122) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2288-14-122
PMCID: PMC4280686  PMID: 25417555
Statistics; Conditional distributions; Poisson regression; Time series regression; Environment
2.  Effects of high summer temperatures on mortality in 50 Spanish cities 
Environmental Health  2014;13:48.
Background
Periods of high temperature have been widely found to be associated with excess mortality but with variable relationships in different cities. How these specifics depend on climatic and other characteristics of cities is not well understood. We assess summer temperature-mortality relationships using data from 50 provincial capitals in Spain, during the period 1990–2004.
Methods
Poisson time series regression analyses were applied to daily temperature and mortality data, adjusting for potential confounding seasonal factors. Associations of heat with mortality were summarised for each city as the risk increments at the 99th compared to the 90th percentiles of the whole-year temperature distributions, as predicted from spline curves.
Results
Risk increments averaged 14.6% between both centiles, or 3.3% per 1 Celsius degree. Although risk increments varied substantially between cities, the range of temperature from the 90th to 99th centile was the only characteristic independently significantly associated with them. The heat increment did not depend on other city climatic, socio-demographic and geographic determinants.
Conclusions
Cities in Spain are partially adapted to high mean summer temperatures but not to high variation in summer temperatures.
doi:10.1186/1476-069X-13-48
PMCID: PMC4078369  PMID: 24912929
Temperature; Heat; Mortality; Spain; Time-series; Heterogeneity; Adaptation
3.  Breastfeeding: A Potential Excretion Route for Mothers and Implications for Infant Exposure to Perfluoroalkyl Acids 
Environmental Health Perspectives  2013;122(2):187-192.
Background: The presence of perfluoroalkyl acids (PFAAs) in breast milk has been documented, but their lactational transfer has been rarely studied. Determination of the elimination rates of these chemicals during breastfeeding is important and critical for assessing exposure in mothers and infants.
Objectives: We aimed to investigate the association between breastfeeding and maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS). For a subset of the population, for whom we also have their infants’ measurements, we investigated associations of breastfeeding with infant serum PFAA concentrations.
Methods: The present analysis included 633 women from the C8 Science Panel Study who had a child < 3.5 years of age and who provided blood samples and reported detailed information on breastfeeding at the time of survey. PFAA serum concentrations were available for all mothers and 8% (n = 49) of the infants. Maternal and infant serum concentrations were regressed on duration of breastfeeding.
Results: Each month of breastfeeding was associated with lower maternal serum concentrations of PFOA (–3%; 95% CI: –5, –2%), PFOS (–3%; 95% CI: –3, –2%), PFNA (–2%; 95% CI: –2, –1%), and PFHxS (–1%; 95% CI: –2, 0%). The infant PFOA and PFOS serum concentrations were 6% (95% CI: 1, 10%) and 4% (95% CI: 1, 7%) higher per month of breastfeeding.
Conclusions: Breast milk is the optimal food for infants, but is also a PFAA excretion route for lactating mothers and exposure route for nursing infants.
Citation: Mondal D, Weldon RH, Armstrong BG, Gibson LJ, Lopez-Espinosa MJ, Shin HM, Fletcher T. 2014. Breastfeeding: a potential excretion route for mothers and implications for infant exposure to perfluoroalkyl acids. Environ Health Perspect 122:187–192; http://dx.doi.org/10.1289/ehp.1306613
doi:10.1289/ehp.1306613
PMCID: PMC3915259  PMID: 24280536
4.  Multivariate meta-analysis: a method to summarize non-linear associations 
Statistics in medicine  2011;30(20):10.1002/sim.4226.
Multivariate meta-analysis represents a promising statistical tool in several research areas. Here we provide a brief overview of the application of this methodology to combining complex multi-parameterized relationships, such as non-linear or delayed associations, in multi-site studies. The discussion focuses on the advantages over simpler univariate methods, estimation and computational issues and directions for further research.
doi:10.1002/sim.4226
PMCID: PMC3841810  PMID: 24293793
5.  Measurement error in time-series analysis: a simulation study comparing modelled and monitored data 
Background
Assessing health effects from background exposure to air pollution is often hampered by the sparseness of pollution monitoring networks. However, regional atmospheric chemistry-transport models (CTMs) can provide pollution data with national coverage at fine geographical and temporal resolution. We used statistical simulation to compare the impact on epidemiological time-series analysis of additive measurement error in sparse monitor data as opposed to geographically and temporally complete model data.
Methods
Statistical simulations were based on a theoretical area of 4 regions each consisting of twenty-five 5 km × 5 km grid-squares. In the context of a 3-year Poisson regression time-series analysis of the association between mortality and a single pollutant, we compared the error impact of using daily grid-specific model data as opposed to daily regional average monitor data. We investigated how this comparison was affected if we changed the number of grids per region containing a monitor. To inform simulations, estimates (e.g. of pollutant means) were obtained from observed monitor data for 2003–2006 for national network sites across the UK and corresponding model data that were generated by the EMEP-WRF CTM. Average within-site correlations between observed monitor and model data were 0.73 and 0.76 for rural and urban daily maximum 8-hour ozone respectively, and 0.67 and 0.61 for rural and urban loge(daily 1-hour maximum NO2).
Results
When regional averages were based on 5 or 10 monitors per region, health effect estimates exhibited little bias. However, with only 1 monitor per region, the regression coefficient in our time-series analysis was attenuated by an estimated 6% for urban background ozone, 13% for rural ozone, 29% for urban background loge(NO2) and 38% for rural loge(NO2). For grid-specific model data the corresponding figures were 19%, 22%, 54% and 44% respectively, i.e. similar for rural loge(NO2) but more marked for urban loge(NO2).
Conclusion
Even if correlations between model and monitor data appear reasonably strong, additive classical measurement error in model data may lead to appreciable bias in health effect estimates. As process-based air pollution models become more widely used in epidemiological time-series analysis, assessments of error impact that include statistical simulation may be useful.
doi:10.1186/1471-2288-13-136
PMCID: PMC3871053  PMID: 24219031
Measurement error; Epidemiology; Time-series; Mortality; Nitrogen dioxide; Ozone
6.  Effectiveness of Inactivated Influenza Vaccines in Preventing Influenza-Associated Deaths and Hospitalizations among Ontario Residents Aged ≥65 Years: Estimates with Generalized Linear Models Accounting for Healthy Vaccinee Effects 
PLoS ONE  2013;8(10):e76318.
Background
Estimates of the effectiveness of influenza vaccines in older adults may be biased because of difficulties identifying and adjusting for confounders of the vaccine-outcome association. We estimated vaccine effectiveness for prevention of serious influenza complications among older persons by using methods to account for underlying differences in risk for these complications.
Methods
We conducted a retrospective cohort study among Ontario residents aged ≥65 years from September 1993 through September 2008. We linked weekly vaccination, hospitalization, and death records for 1.4 million community-dwelling persons aged ≥65 years. Vaccine effectiveness was estimated by comparing ratios of outcome rates during weeks of high versus low influenza activity (defined by viral surveillance data) among vaccinated and unvaccinated subjects by using log-linear regression models that accounted for temperature and time trends with natural spline functions. Effectiveness was estimated for three influenza-associated outcomes: all-cause deaths, deaths occurring within 30 days of pneumonia/influenza hospitalizations, and pneumonia/influenza hospitalizations.
Results
During weeks when 5% of respiratory specimens tested positive for influenza A, vaccine effectiveness among persons aged ≥65 years was 22% (95% confidence interval [CI], −6%–42%) for all influenza-associated deaths, 25% (95% CI, 13%–37%) for deaths occurring within 30 days after an influenza-associated pneumonia/influenza hospitalization, and 19% (95% CI, 4%–31%) for influenza-associated pneumonia/influenza hospitalizations. Because small proportions of deaths, deaths after pneumonia/influenza hospitalizations, and pneumonia/influenza hospitalizations were associated with influenza virus circulation, we estimated that vaccination prevented 1.6%, 4.8%, and 4.1% of these outcomes, respectively.
Conclusions
By using confounding-reducing techniques with 15 years of provincial-level data including vaccination and health outcomes, we estimated that influenza vaccination prevented ∼4% of influenza-associated hospitalizations and deaths occurring after hospitalizations among older adults in Ontario.
doi:10.1371/journal.pone.0076318
PMCID: PMC3797825  PMID: 24146855
7.  Time series regression studies in environmental epidemiology 
Time series regression studies have been widely used in environmental epidemiology, notably in investigating the short-term associations between exposures such as air pollution, weather variables or pollen, and health outcomes such as mortality, myocardial infarction or disease-specific hospital admissions. Typically, for both exposure and outcome, data are available at regular time intervals (e.g. daily pollution levels and daily mortality counts) and the aim is to explore short-term associations between them. In this article, we describe the general features of time series data, and we outline the analysis process, beginning with descriptive analysis, then focusing on issues in time series regression that differ from other regression methods: modelling short-term fluctuations in the presence of seasonal and long-term patterns, dealing with time varying confounding factors and modelling delayed (‘lagged’) associations between exposure and outcome. We finish with advice on model checking and sensitivity analysis, and some common extensions to the basic model.
doi:10.1093/ije/dyt092
PMCID: PMC3780998  PMID: 23760528
Time series; environmental epidemiology; air pollution
8.  Serum perfluoroalkyl acids concentrations and memory impairment in a large cross-sectional study 
BMJ Open  2013;3(6):e002414.
Objectives
To examine the cross-sectional association between serum perfluorooctanate (PFOA), perfuorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonate (PFHxS) concentrations with self-reported memory impairment in adults and the interaction of these associations with diabetes status.
Design
Cross-sectional study.
Setting
Population-based in Mid-Ohio Valley, West Virginia following contamination by a chemical plant.
Participants
The C8 Health Project collected data and measured the serum level of perfluoroalkyl acids (PFAAs) of 21 024 adults aged 50+ years.
Primary outcome measure
Self-reported memory impairment as defined by the question ‘have experienced short-term memory loss?’
Results
A total of 4057 participants self-reported short-term memory impairment. Inverse associations between PFOS and PFOA and memory impairment were highly statistically significant with fully adjusted OR=0.93 (95% CI 0.90 to 0.96) for doubling PFOS and OR=0.96 (95% CI 0.94 to 0.98) for doubling PFOA concentrations. Comparable inverse associations with PFNA and PFHxS were of borderline statistical significance. Inverse associations of PFAAs with memory impairment were weaker or non-existent in patients with diabetes than overall in patients without diabetes.
Conclusions
An inverse association between PFAA serum levels and self-reported memory impairment has been observed in this large population-based, cross-sectional study that is stronger and more statistically significant for PFOA and PFOS. The associations can be potentially explained by a preventive anti-inflammatory effect exerted by a peroxisome proliferator-activated receptor agonist effect of these PFAAs, but confounding or even reverse causation cannot be excluded as an alternative explanation.
doi:10.1136/bmjopen-2012-002414
PMCID: PMC3686223  PMID: 23794579
9.  Reducing and meta-analysing estimates from distributed lag non-linear models 
Background
The two-stage time series design represents a powerful analytical tool in environmental epidemiology. Recently, models for both stages have been extended with the development of distributed lag non-linear models (DLNMs), a methodology for investigating simultaneously non-linear and lagged relationships, and multivariate meta-analysis, a methodology to pool estimates of multi-parameter associations. However, the application of both methods in two-stage analyses is prevented by the high-dimensional definition of DLNMs.
Methods
In this contribution we propose a method to synthesize DLNMs to simpler summaries, expressed by a reduced set of parameters of one-dimensional functions, which are compatible with current multivariate meta-analytical techniques. The methodology and modelling framework are implemented in R through the packages dlnm and mvmeta.
Results
As an illustrative application, the method is adopted for the two-stage time series analysis of temperature-mortality associations using data from 10 regions in England and Wales. R code and data are available as supplementary online material.
Discussion and Conclusions
The methodology proposed here extends the use of DLNMs in two-stage analyses, obtaining meta-analytical estimates of easily interpretable summaries from complex non-linear and delayed associations. The approach relaxes the assumptions and avoids simplifications required by simpler modelling approaches.
doi:10.1186/1471-2288-13-1
PMCID: PMC3599933  PMID: 23297754
Distributed lag models; Multivariate meta-analysis; Two-stage analysis; Time series
10.  Concentration–Response Function for Ozone and Daily Mortality: Results from Five Urban and Five Rural U.K. Populations 
Environmental Health Perspectives  2012;120(10):1411-1417.
Background: Short-term exposure to ozone has been associated with increased daily mortality. The shape of the concentration–response relationship—and, in particular, if there is a threshold—is critical for estimating public health impacts.
Objective: We investigated the concentration–response relationship between daily ozone and mortality in five urban and five rural areas in the United Kingdom from 1993 to 2006.
Methods: We used Poisson regression, controlling for seasonality, temperature, and influenza, to investigate associations between daily maximum 8-hr ozone and daily all-cause mortality, assuming linear, linear-threshold, and spline models for all-year and season-specific periods. We examined sensitivity to adjustment for particles (urban areas only) and alternative temperature metrics.
Results: In all-year analyses, we found clear evidence for a threshold in the concentration–response relationship between ozone and all-cause mortality in London at 65 µg/m3 [95% confidence interval (CI): 58, 83] but little evidence of a threshold in other urban or rural areas. Combined linear effect estimates for all-cause mortality were comparable for urban and rural areas: 0.48% (95% CI: 0.35, 0.60) and 0.58% (95% CI: 0.36, 0.81) per 10-µg/m3 increase in ozone concentrations, respectively. Seasonal analyses suggested thresholds in both urban and rural areas for effects of ozone during summer months.
Conclusions: Our results suggest that health impacts should be estimated across the whole ambient range of ozone using both threshold and nonthreshold models, and models stratified by season. Evidence of a threshold effect in London but not in other study areas requires further investigation. The public health impacts of exposure to ozone in rural areas should not be overlooked.
doi:10.1289/ehp.1104108
PMCID: PMC3491921  PMID: 22814173
concentration–response function; daily mortality; ozone; U.K. population
11.  The Association of Season and Temperature with Adverse Pregnancy Outcome in Two German States, a Time-Series Analysis 
PLoS ONE  2012;7(7):e40228.
Background
A seasonality of low birth weight (LBW) and preterm birth (PTB) has been described for most regions and there is evidence that this pattern is caused by ambient outdoor temperature. However, the association as such, the direction of effect and the critical time of exposure remain controversial.
Methods
Logistic, time-series regression was performed on nearly 300,000 births from two German states to study the association between season and daily mean temperature and changes in daily proportions of term LBW (tLBW) or PTB. Analyses were adjusted for time-varying factors. Temperature exposures were examined during different periods of pregnancy.
Results
Weak evidence for an association between season of conception, season of birth or ambient outdoor temperature and tLBW or PTB was found. Results of analyses of temperature were not consistent between the two states. Different sources of bias which would have artificially led to stronger findings were detected and are described.
Conclusions
No clear evidence for an association between season of conception, season of birth or temperature and tLBW or PTB was found. In the study of pregnancy outcome different sources of bias can be identified which can potentially explain heterogeneous findings of the past.
doi:10.1371/journal.pone.0040228
PMCID: PMC3391296  PMID: 22792247
12.  Thyroid Function and Perfluoroalkyl Acids in Children Living Near a Chemical Plant 
Environmental Health Perspectives  2012;120(7):1036-1041.
Background: Animal studies suggest that some perfluoroalkyl acids (PFAAs), including perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA) may impair thyroid function. Epidemiological findings, mostly related to adults, are inconsistent.
Objectives: We investigated whether concentrations of PFAAs were associated with thyroid function among 10,725 children (1–17 years of age) living near a Teflon manufacturing facility in the Mid-Ohio Valley (USA).
Methods: Serum levels of thyroid-stimulating hormone (TSH), total thyroxine (TT4), and PFAAs were measured during 2005–2006, and information on diagnosed thyroid disease was collected by questionnaire. Modeled in utero PFOA concentrations were based on historical information on PFOA releases, environmental distribution, pharmacokinetic modeling, and residential histories. We performed multivariate regression analyses.
Results: Median concentrations of modeled in utero PFOA and measured serum PFOA, PFOS, and PFNA were 12, 29, 20, and 1.5 ng/mL, respectively. The odds ratio for hypothyroidism (n = 39) was 1.54 [95% confidence interval (CI): 1.00, 2.37] for an interquartile range (IQR) contrast of 13 to 68 ng/mL in serum PFOA measured in 2005–2006. However, an IQR shift in serum PFOA was not associated with TSH or TT4 levels in all children combined. IQR shifts in serum PFOS (15 to 28 ng/mL) and serum PFNA (1.2 to 2.0 ng/mL) were both associated with a 1.1% increase in TT4 in children 1–17 years old (95% CIs: 0.6, 1.5 and 0.7, 1.5 respectively).
Conclusions: This is the first large-scale report in children suggesting associations of serum PFOS and PFNA with thyroid hormone levels and of serum PFOA and hypothyroidism.
doi:10.1289/ehp.1104370
PMCID: PMC3404658  PMID: 22453676
children; PFAA; PFNA; PFOA; PFOS; T4; thyroid disease; thyroid hormones; TSH
13.  Relationships of Perfluorooctanoate and Perfluorooctane Sulfonate Serum Concentrations between Mother–Child Pairs in a Population with Perfluorooctanoate Exposure from Drinking Water 
Environmental Health Perspectives  2012;120(5):752-757.
Background: There are limited data on the associations between maternal or newborn and child exposure to perfluoroalkyl acids (PFAAs), including perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS). This study provides an opportunity to assess the association between PFAA concentrations in mother–child pairs in a population exposed to PFOA via drinking water.
Objectives: We aimed to determine the relationship between mother–child PFAA serum concentrations and to examine how the child:mother ratio varies with child’s age, child’s sex, drinking-water PFOA concentration, reported bottled water use, and mother’s breast-feeding intention.
Methods: We studied 4,943 mother–child pairs (children, 1–19 years of age). The child:mother PFAA ratio was stratified by possible determinants. Results are summarized as geometric mean ratios and correlation coefficients between mother–child pairs, overall and within strata.
Results: Child and mother PFOA and PFOS concentrations were correlated (r = 0.82 and 0.26, respectively). Up to about 12 years of age, children had higher serum PFOA concentrations than did their mothers. The highest child:mother PFOA ratio was found among children ≤ 5 years (44% higher than their mothers), which we attribute to in utero exposure and to exposure via breast milk and drinking water. Higher PFOS concentrations in children persisted until at least 19 years of age (42% higher than their mothers). Boys > 5 years of age had significantly higher PFOA and PFOS child:mother ratios than did girls.
Conclusion: Concentrations of both PFOA and PFOS tended to be higher in children than in their mothers. This difference persisted until they were about 12 years of age for PFOA and at least 19 years of age for PFOS.
doi:10.1289/ehp.1104538
PMCID: PMC3346790  PMID: 22271837
mother–child pairs; drinking water; in utero exposure; lactation; Mid-Ohio Valley; PFOA; PFOS; serum concentration
14.  The impact of heat waves on mortality 
Background
Heat waves have been linked with an increase in mortality, but the associated risk has been only partly characterized.
Methods
We examined this association by decomposing the risk for temperature into a “main effect” due to independent effects of daily high temperatures, and an “added” effect due to sustained duration of heat during waves, using data from 108 communities in USA during 1987-2000. We adopted different definitions of heat-wave days based on combinations of temperature thresholds and days of duration. The main effect was estimated through distributed lag non-linear functions of temperature, which account for non-linear delayed effects and short-time harvesting. We defined the main effect as the relative risk between the median city-specific temperature during heat-wave days and the 75th percentile of the year-round distribution. The added effect was defined first using a simple indicator, and then a function of consecutive heat-wave days. City-specific main and added effects were pooled through univariate and multivariate meta-analytic techniques.
Results
The added wave effect was small (0.2%-2.8% excess relative risk, depending on wave definition) compared with the main effect (4.9%-8.0%), and was apparent only after 4 consecutive heat wave days.
Conclusions
Most of the excess risk with heat waves in the USA can be simply summarized as the independent effects of individual days’ temperatures. A smaller added effect arises in heat waves lasting more than 4 days.
doi:10.1097/EDE.0b013e3181fdcd99
PMCID: PMC3324776  PMID: 21150355
15.  Mortality on extreme heat days using official thresholds in Spain: a multi-city time series analysis 
BMC Public Health  2012;12:133.
Background
The 2003 heat wave had a high impact on mortality in Europe, which made necessary to develop heat health watch warning systems. In Spain this was carried-out by the Ministry of Health in 2004, being based on exceeding of city-specific simultaneous thresholds of minimum and maximum daily temperatures. The aim of this study is to assess effectiveness of the official thresholds established by the Ministry of Health for each provincial capital city, by quantifying and comparing the short-term effects of above-threshold days on total daily mortality.
Methods
Total daily mortality and minimum and maximum temperatures for the 52 capitals of province in Spain were collected during summer months (June to September) for the study period 1995-2004. Data was analysed using GEE for Poisson regression. Relative Risk (RR) of total daily mortality was quantified for the current day of official thresholds exceeded.
Results
The number of days in which the thresholds were exceeded show great inconsistency, with provinces with great number of exceeded days adjacent to provinces that did not exceed or rarely exceeded. The average overall excess risk of dying during an extreme heat day was about 25% (RR = 1.24; 95% confidence interval (CI) = [1.19-1.30]). Relative risks showed a significant heterogeneity between cities (I2 = 54.9%). Western situation and low mean summer temperatures were associated with higher relative risks, suggesting thresholds may have been set too high in these areas.
Conclusions
This study confirmed that extreme heat days have a considerable impact on total daily mortality in Spain. Official thresholds gave consistent relative risk in the large capital cities. However, in some other cities thresholds
doi:10.1186/1471-2458-12-133
PMCID: PMC3314548  PMID: 22340020
16.  Long-term effects of flooding on mortality in England and Wales, 1994-2005: controlled interrupted time-series analysis 
Environmental Health  2011;10:11.
Background
Limited evidence suggests that being flooded may increase mortality and morbidity among affected householders not just at the time of the flood but for months afterwards. The objective of this study is to explore the methods for quantifying such long-term health effects of flooding by analysis of routine mortality registrations in England and Wales.
Methods
Mortality data, geo-referenced by postcode of residence, were linked to a national database of flood events for 1994 to 2005. The ratio of mortality in the post-flood year to that in the pre-flood year within flooded postcodes was compared with that in non-flooded boundary areas (within 5 km of a flood). Further analyses compared the observed number of flood-area deaths in the year after flooding with the number expected from analysis of mortality trends stratified by region, age-group, sex, deprivation group and urban-rural status.
Results
Among the 319 recorded floods, there were 771 deaths in the year before flooding and 693 deaths in the year after (post-/pre-flood ratio of 0.90, 95% CI 0.82, 1.00). This ratio did not vary substantially by age, sex, population density or deprivation. A similar post-flood 'deficit' of deaths was suggested by the analyses based on observed/expected deaths.
Conclusions
The observed post-flood 'deficit' of deaths is counter-intuitive and difficult to interpret because of the possible influence of population displacement caused by flooding. The bias that might arise from such displacement remains unquantified but has important implications for future studies that use place of residence as a marker of exposure.
doi:10.1186/1476-069X-10-11
PMCID: PMC3042000  PMID: 21288358
17.  Outdoor air pollution and infant mortality: analysis of daily time‐series data in 10 English cities 
Background
There is growing concern that moderate levels of outdoor air pollution may be associated with infant mortality, representing substantial loss of life‐years. To date, there has been no investigation of the effects of outdoor pollution on infant mortality in the UK.
Methods
Daily time‐series data of air pollution and all infant deaths between 1990 and 2000 in 10 major cities of England: Birmingham, Bristol, Leeds, Liverpool, London, Manchester, Middlesbrough, Newcastle, Nottingham and Sheffield, were analysed. City‐specific estimates were pooled across cities in a fixed‐effects meta‐regression to provide a mean estimate.
Results
Few associations were observed between infant deaths and most pollutants studied. The exception was sulphur dioxide (SO2), of which a 10 μg/m3 increase was associated with a RR of 1.02 (95% CI 1.01 to 1.04) in all infant deaths. The effect was present in both neonatal and postneonatal deaths.
Conclusions
Continuing reductions in SO2 levels in the UK may yield additional health benefits for infants.
doi:10.1136/jech.2006.053942
PMCID: PMC2653013  PMID: 17630372
18.  An approach for estimating the health effects of changes over time in air pollution: an illustration using cardio-respiratory hospital admissions in London 
Objectives
First, we present a general analytical approach to estimating the association between medium-term changes in air pollution and health across small areas. As a specific illustration, we then applied the approach to data on London residents from a 4-year period to test whether reductions in traffic-related air pollution were associated with reductions in cardio-respiratory hospital admissions.
Methods
A binomial distribution was used to model change in admissions over time in each small area, which was measured as the proportion of admissions in 2003–2004 out of admissions over all study years (2001–2004). Annual average concentrations of nitrogen oxides (NOx) were modelled using an emissions-dispersion model. The association between change in NOx and change in hospital admissions was estimated using logistic regression and an instrumental variable approach.
Results
For some diagnostic groups, suggestive associations between reductions in NOx and reductions in admissions were observed, for example, OR=0.97 (95% CI 0.96 to 0.99) for an IQR decrease in NOx (3 μg/m3) and all respiratory admissions. Accounting for spatial dependence attenuated several of the associations; for respiratory admissions, the OR was 1.00 (95% CI 0.98 to 1.02), leaving only that for bronchiolitis significant (OR=0.91; 95% CI 0.84 to 0.99). In this particular illustration, the instrumental variable approach did not appear to add information.
Conclusions
In this illustration, there was relatively limited power to detect an association between changes in air pollution and hospital admissions over time. However, the analytical approach could deliver more robust estimates of the health effects of changes in air pollution in settings with greater spatial contrast in changes in air pollution over time.
doi:10.1136/oem.2009.048702
PMCID: PMC2989168  PMID: 19914909
Air pollution; hospitalisation; methods; epidemiology; mathematical models
19.  Current and future climate- and air pollution-mediated impacts on human health 
Environmental Health  2009;8(Suppl 1):S8.
Background
We describe a project to quantify the burden of heat and ozone on mortality in the UK, both for the present-day and under future emission scenarios.
Methods
Mortality burdens attributable to heat and ozone exposure are estimated by combination of climate-chemistry modelling and epidemiological risk assessment. Weather forecasting models (WRF) are used to simulate the driving meteorology for the EMEP4UK chemistry transport model at 5 km by 5 km horizontal resolution across the UK; the coupled WRF-EMEP4UK model is used to simulate daily surface temperature and ozone concentrations for the years 2003, 2005 and 2006, and for future emission scenarios. The outputs of these models are combined with evidence on the ozone-mortality and heat-mortality relationships derived from epidemiological analyses (time series regressions) of daily mortality in 15 UK conurbations, 1993-2003, to quantify present-day health burdens.
Results
During the August 2003 heatwave period, elevated ozone concentrations > 200 μg m-3 were measured at sites in London and elsewhere. This and other ozone photochemical episodes cause breaches of the UK air quality objective for ozone. Simulations performed with WRF-EMEP4UK reproduce the August 2003 heatwave temperatures and ozone concentrations. There remains day-to-day variability in the high ozone concentrations during the heatwave period, which on some days may be explained by ozone import from the European continent.
Preliminary calculations using extended time series of spatially-resolved WRF-EMEP4UK model output suggest that in the summers (May to September) of 2003, 2005 & 2006 over 6000 deaths were attributable to ozone and around 5000 to heat in England and Wales. The regional variation in these deaths appears greater for heat-related than for ozone-related burdens.
Changes in UK health burdens due to a range of future emission scenarios will be quantified. These future emissions scenarios span a range of possible futures from assuming current air quality legislation is fully implemented, to a more optimistic case with maximum feasible reductions, through to a more pessimistic case with continued strong economic growth and minimal implementation of air quality legislation.
Conclusion
Elevated surface ozone concentrations during the 2003 heatwave period led to exceedences of the current UK air quality objective standards. A coupled climate-chemistry model is able to reproduce these temperature and ozone extremes. By combining model simulations of surface temperature and ozone with ozone-heat-mortality relationships derived from an epidemiological regression model, we estimate present-day and future health burdens across the UK. Future air quality legislation may need to consider the risk of increases in future heatwaves.
doi:10.1186/1476-069X-8-S1-S8
PMCID: PMC2796504  PMID: 20102593
20.  Effect of 20 mph traffic speed zones on road injuries in London, 1986-2006: controlled interrupted time series analysis 
Objective To quantify the effect of the introduction of 20 mph (32 km an hour) traffic speed zones on road collisions, injuries, and fatalities in London.
Design Observational study based on analysis of geographically coded police data on road casualties, 1986-2006. Analyses were made of longitudinal changes in counts of road injuries within each of 119 029 road segments with at least one casualty with conditional fixed effects Poisson models. Estimates of the effect of introducing 20 mph zones on casualties within those zones and in adjacent areas were adjusted for the underlying downward trend in traffic casualties.
Setting London.
Main outcome measures All casualties from road collisions; those killed and seriously injured (KSI).
Results The introduction of 20 mph zones was associated with a 41.9% (95% confidence interval 36.0% to 47.8%) reduction in road casualties, after adjustment for underlying time trends. The percentage reduction was greatest in younger children and greater for the category of killed or seriously injured casualties than for minor injuries. There was no evidence of casualty migration to areas adjacent to 20 mph zones, where casualties also fell slightly by an average of 8.0% (4.4% to 11.5%).
Conclusions 20 mph zones are effective measures for reducing road injuries and deaths.
doi:10.1136/bmj.b4469
PMCID: PMC2791801  PMID: 20007666
21.  Phosphorylation of ATXN1 at Ser776 in the cerebellum 
Journal of neurochemistry  2009;110(2):675-686.
Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative disorders caused by a mutant protein with an expanded polyglutamine tract. Phosphorylation of ataxin-1 (ATXN1) at serine 776 is implicated in SCA1 pathogenesis. Previous studies, utilizing transfected cell lines and a Drosophila photoreceptor model of SCA1, suggest that phosphorylating ATXN1 at S776 renders it less susceptible to degradation. This work also indicated that oncogene from AKR mouse thymoma (Akt) promotes the phosphorylation of ATXN1 at S776 and severity of neurodegeneration. Here, we examined the phosphorylation of ATXN1 at S776 in cerebellar Purkinje cells, a prominent site of pathology in SCA1. We found that while phosphorylation of S776 is associated with a stabilization of ATXN1 in Purkinje cells, inhibition of Akt either in vivo or in a cerebellar extract-based phosphorylation assay did not decrease the phosphorylation of ATXN1-S776. In contrast, immunodepletion and inhibition of cyclic AMP-dependent protein kinase decreased phosphorylation of ATXN1-S776. These results argue against Akt as the in vivo kinase that phosphorylates S776 of ATXN1 and suggest that cyclic AMP-dependent protein kinase is the active ATXN1-S776 kinase in the cerebellum.
doi:10.1111/j.1471-4159.2009.06164.x
PMCID: PMC2754139  PMID: 19500214
ataxin-1; cyclic AMP-dependent protein kinase; oncogene from AKR mouse thymoma; phosphorylation; spinocerebellar ataxia type 1
22.  Host, Weather and Virological Factors Drive Norovirus Epidemiology: Time-Series Analysis of Laboratory Surveillance Data in England and Wales 
PLoS ONE  2009;4(8):e6671.
Norovirus, the most commonly identified cause of both sporadic cases and outbreaks of infectious diarrhoea in developed countries, exhibits a complex epidemiology and has a strong wintertime seasonality. Viral populations are dynamic and evolve under positive selection pressure.
Methods
Time series-adapted Poisson regression models were fitted to daily counts of laboratory reports of norovirus in England and Wales from 1993 to 2006.
Findings
Inverse linear associations with daily temperature over the previous seven weeks (rate ratio (RR) = 0.85; 95% CI: 0.83 to 0.86 for every 1°C increase) and relative humidity over the previous five weeks (RR = 0.980; 95% CI: 0.973 to 0.987 for every 1% increase) were found, with temperature having a greater overall effect. The emergence of new norovirus variants (RR = 1.16; 95% CI: 1.10 to 1.22) and low population immunity were also associated with heightened norovirus activity. Temperature and humidity, which may be localised, had highly consistent effects in each region of England and Wales.
Conclusions
These results point to a complex interplay between host, viral and climatic factors driving norovirus epidemic patterns. Increases in norovirus are associated with cold, dry temperature, low population immunity and the emergence of novel genogroup 2 type 4 antigenic variants.
doi:10.1371/journal.pone.0006671
PMCID: PMC2726937  PMID: 19701458
23.  Risk of Asthmatic Episodes in Children Exposed to Sulfur Dioxide Stack Emissions from a Refinery Point Source in Montreal, Canada 
Environmental Health Perspectives  2008;117(4):653-659.
Background
Little is known about the respiratory effects of short-term exposures to petroleum refinery emissions in young children. This study is an extension of an ecologic study that found an increased rate of hospitalizations for respiratory conditions among children living near petroleum refineries in Montreal (Canada).
Methods
We used a time-stratified case–crossover design to assess the risk of asthma episodes in relation to short-term variations in sulfur dioxide levels among children 2–4 years of age living within 0.5–7.5 km of the refinery stacks. Health data used to measure asthma episodes included emergency department (ED) visits and hospital admissions from 1996 to 2004. We estimated daily levels of SO2 at the residence of children using a) two fixed-site SO2 monitors located near the refineries and b) the AERMOD (American Meteorological Society/Environmental Protection Agency Regulatory Model) atmospheric dispersion model. We used conditional logistic regression to estimate odds ratios associated with an increase in the interquartile range of daily SO2 mean and peak exposures (31.2 ppb for AERMOD peaks). We adjusted for temperature, relative humidity, and regional/urban background air pollutant levels.
Results
The risks of asthma ED visits and hospitalizations were more pronounced for same-day (lag 0) SO2 peak levels than for mean levels on the same day, or for other lags: the adjusted odds ratios estimated for same-day SO2 peak levels from AERMOD were 1.10 [95% confidence interval (CI), 1.00–1.22] and 1.42 (95% CI, 1.10–1.82), over the interquartile range, for ED visits and hospital admissions, respectively.
Conclusions
Short-term episodes of increased SO2 exposures from refinery stack emissions were associated with a higher number of asthma episodes in nearby children.
doi:10.1289/ehp.0800010
PMCID: PMC2679612  PMID: 19440507
asthma; case crossover; children; dispersion modeling; emergency department visits; hospital admissions; point source; refinery; short-term exposure; sulfur dioxide
24.  Long-Term Effects of Traffic-Related Air Pollution on Mortality in a Dutch Cohort (NLCS-AIR Study) 
Environmental Health Perspectives  2007;116(2):196-202.
Background
Several studies have found an effect on mortality of between-city contrasts in long-term exposure to air pollution. The effect of within-city contrasts is still poorly understood.
Objectives
We studied the association between long-term exposure to traffic-related air pollution and mortality in a Dutch cohort.
Methods
We used data from an ongoing cohort study on diet and cancer with 120,852 subjects who were followed from 1987 to 1996. Exposure to black smoke (BS), nitrogen dioxide, sulfur dioxide, and particulate matter ≤mu;M2.5), as well as various exposure variables related to traffic, were estimated at the home address. We conducted Cox analyses in the full cohort adjusting for age, sex, smoking, and area-level socioeconomic status.
Results
Traffic intensity on the nearest road was independently associated with mortality. Relative risks (95% confidence intervals) for a 10-μg/m3 increase in BS concentrations (difference between 5th and 95th percentile) were 1.05 (1.00–1.11) for natural cause, 1.04 (0.95–1.13) for cardiovascular, 1.22 (0.99–1.50) for respiratory, 1.03 (0.88–1.20) for lung cancer, and 1.04 (0.97–1.12) for mortality other than cardiovascular, respiratory, or lung cancer. Results were similar for NO2 and PM2.5, but no associations were found for SO2.
Conclusions
Traffic-related air pollution and several traffic exposure variables were associated with mortality in the full cohort. Relative risks were generally small. Associations between natural-cause and respiratory mortality were statistically significant for NO2 and BS. These results add to the evidence that long-term exposure to ambient air pollution is associated with increased mortality.
doi:10.1289/ehp.10767
PMCID: PMC2235230  PMID: 18288318
air pollution; cohort; mortality; traffic
25.  Geographic variation and localised clustering of congenital anomalies in Great Britain 
Background
Environmental pollution as a cause of congenital anomalies is sometimes suspected because of clustering of anomalies in areas of higher exposure. This highlights questions around spatial heterogeneity (clustering) in congenital anomaly rates. If spatial variation is endemic, then any one specific cluster is less remarkable, though the presence of uncontrolled geographically clustered risk factors is suggested. If rates are relatively homogeneous across space other than around specific hazards, then evidence for these hazards causing the clusters is strengthened. We sought to estimate the extent of spatial heterogeneity in congenital anomaly rates in the United Kingdom.
Methods
The study population covered about one million births from five registers in Britain from 1991–1999. We estimated heterogeneity across four geographical levels: register area, hospital catchment, electoral ward, and enumeration district, using a negative binomial regression model. We also sought clusters using a circular scan statistic.
Results
Congenital anomaly rates clearly varied across register areas and hospital catchments (p < 0.001), but not below this level (p > 0.2). Adjusting for socioeconomic deprivation and maternal age made little difference to the extent of geographical variation for most congenital anomaly subtypes. The two most significant circular clusters (of four ano-rectal atresias and six congenital heart diseases) contained two or more siblings.
Conclusion
The variation in rates between registers and hospital catchment area may have resulted in part from differences in case ascertainment, and this should be taken into account in geographical epidemiological studies of environmental exposures. The absence of evidence for variation below this level should be interpreted cautiously in view of the low power of general heterogeneity tests. Nevertheless, the data suggest that strong localised clusters in congenital anomalies are uncommon, so clusters around specific putative environmental hazards are remarkable when observed. Negative binomial models applied at successive hierarchical levels provide an approach of intermediate complexity to characterising geographical heterogeneity.
doi:10.1186/1742-7622-4-14
PMCID: PMC1939702  PMID: 17617898

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