[Digital Transformation of Healthcare: A Delphi Study of the Working Groups Digital Health and Validation and Linkage of Secondary Data of the German Network for Health Services Research (DNVF)]. / Digitale Transformation des Gesundheitswesens ­ eine Delphi-Studie der Arbeitsgruppen Digital Health und Validierung und Linkage von Sekundärdaten des Deutschen Netzwerk Versorgungsforschung (DNVF).

AIM OF THE STUDY: The digital transformation in healthcare is also of fundamental importance for healthcare research. For this reason, experts should agree on, prioritize and identify key topics for a medium-term strategy of the German Network for Health Services Research and classify the general development of digital health in the context of health services research. METHODS: Between April and September 2018, the working groups "Digital Health" and "Validation and Linkage of Secondary Data" of the German Network for Health Services Research were asked to submit their expertise online using the methodological approach of a Delphi study. For this purpose, a multi-stage modified Delphi method with quantitative and qualitative approaches was chosen. Initially, a list of theses was drawn from the network's published position papers on digital health applications and medical apps. A total of 131 statements were formulated. The final survey instrument included questions on the biographical background of the participants, 42 developed items (33 statements and 8 open-ended questions), and one free-text field to add further aspects. Items were evaluated with a five-point Likert scale. A statement was accepted if the agreement rate was 75% or higher. RESULTS: Of the 110 potential participants, 50 (46%) took part in the first round and 39 (36%) in the second round of the Delphi survey. In the first round, there was a clear result for 24 of 33 statements. There were 20 statements "agreed with" and four "disagreed with." Nine statements were between 60 and 75% and were presented to the participants again for evaluation in the second round. In round two, of these nine statements, four statements were "agreed with" and five statements were "disagreed with." Digital Health Literacy" emerged as a particular focus in this Delphi study. CONCLUSION: In this Delphi study, experts were involved in selecting and prioritizing possible topics for the Digital Health working group and assessing future developments in digital health in the context of health services research. The results reflect both the expectations and interests of the members and are largely consistent with the recommendations of the report "Digitalization for Health" made by the expert council for assessing developments in the health sector.

Nonatopic eczema in elderly women: Effect of air pollution and genes.

BACKGROUND: Although many risk factors have been described for atopic eczema in children, little is known about the eczema phenotype in middle-aged or elderly adults. OBJECTIVE: We sought to examine the association between air pollution, atopy, and eczema in adulthood. METHODS: This analysis was based on 834 women from the Study on the influence of Air pollution on Lung Function, Inflammation and Ageing cohort in Germany. Incident symptoms of eczema after age 55 years and prevalent symptoms of eczema 12 months or less before investigation were assessed by means of questionnaire at the second follow-up (2007-2010). Total serum IgE levels were measured at baseline (1985-1994) and in 2007-2010. Exposure to air pollution was assessed by using land-use regression. Adjusted logistic regression models were applied to estimate the association between air pollution and incident and prevalent symptoms of eczema. Weighted genetic risk scores were used to investigate the effect of atopic eczema-related risk alleles on this association. RESULTS: Exposures to oxides of nitrogen (nitrogen dioxide and nitrogen oxides) and particulate matter (fine particulate matter with an aerodynamic diameter of ≤2.5 µm [PM2.5] and particulate matter with an aerodynamic diameter of <10 µm) were significantly associated with increased odds of incident eczema (eg, with PM2.5 per 4.7 µg/m3; odds ratio, 1.45; 95% CI, 1.06-1.99). These associations were slightly more pronounced with nonatopic eczema (eg, with PM2.5; odds ratio of 1.65 and 95% CI of 1.15-2.34 for participants without hay fever or increased IgE levels). Associations with air pollution were stronger in carriers of fewer risk alleles for atopic eczema. CONCLUSION: Nonatopic eczema in the elderly is associated with traffic-related air pollutants, and this phenotype differs from genetically driven atopic eczema.

[DNVF Memorandum Health Literacy (Part 1) - Background, Relevance, Research Topics and Questions in Health Services Research]. / DNVF Memorandum Gesundheitskompetenz (Teil 1) ­ Hintergrund, Relevanz, Gegenstand und Fragestellungen in der Versorgungsforschung.

More than half of the German population has difficulties in dealing with health information. It is an important task of health services research to examine how healthcare professionals and health care organizations can meet this challenge. The DNVF Memorandum Health Literacy (Part 1) defines the terms of individual and organizational health literacy, presents the national and international state of research and ethical aspects of health literacy research in health care settings. The relevance of health literacy research is worked out in different phases of life, for different target groups and in different healthcare contexts. Central research topics and future research desiderata are derived.

[DNVF Memorandum Health Literacy (Part 1) - Background, Relevance, Research Topics and Questions in Health Services Research: Short Version]. / DNVF Memorandum Gesundheitskompetenz (Teil 1) ­ Hintergrund, Relevanz, Gegenstand und Fragestellungen in der Versorgungsforschung: Kurzfassung.

More than half of the German population has difficulties in dealing with health information. It is an important task of health services research to examine how healthcare professionals and health care organizations can meet this challenge. This short version of the DNVF Memorandum Health Literacy (Part 1) defines the terms of individual and organizational health literacy, presents the national and international state of research and ethical aspects of health literacy research in health care settings. Central research topics and future research desiderata are derived.

Benefits of improved air quality on ageing lungs: impacts of genetics and obesity.

INTRODUCTION: The beneficial effect of improving air quality on lung function in the elderly remains unclear. We examined associations between decline in air pollutants and lung function, and effect modifications by genetics and body mass index (BMI), in elderly German women. METHODS: Data were analysed from the prospective SALIA (Study on the influence of Air pollution on Lung function, Inflammation and Aging) study (n=601). Spirometry was conducted at baseline (1985-1994; age 55 years), in 2007-2010 and in 2012-2013. Air pollution concentrations at home addresses were determined for each time-point using land-use regression models. Global Lung Initiative 2012 z-scores were calculated. Weighted genetic risk scores (GRSs) were determined from lung function-related risk alleles and used to investigate interactions with improved air quality. Multiple linear mixed models were fitted. RESULTS: Air pollution levels decreased substantially during the study period. Reduction of air pollution was associated with an increase in z-scores for forced expiratory volume in 1 s (FEV1) and the FEV1/forced vital capacity ratio. For a decrease of 10 µg·m-3 in nitrogen dioxide (NO2), the z-score for FEV1 increased by 0.14 (95% CI 0.01-0.26). However, with an increasing number of lung function-related risk alleles, the benefit from improved air quality decreased (GRS×NO2 interaction: p=0.029). Interactions with BMI were not significant. CONCLUSIONS: Reduction of air pollution is associated with a relative improvement of lung function in elderly women, but also depends on their genetic make-up.

[DNVF-Memorandum - Health and Medical Apps]. / DNVF-Memorandum ­ Gesundheits- und Medizin-Apps (GuMAs).

There are huge expectations to improve quality and efficiency of prevention and healthcare by using digital health applications. In contrast to the dynamically growing supply and a high affinity of large parts of the population to use health and medical apps, there is a lack of data and methods to assess quality, benefit, and patient safety with health apps, most of them are not yet regulated .This memorandum outlines core questions that should be addressed by future health services research in order to evaluate the impact of health and medical apps on quality of processes and patient outcomes and to take advantage of their potential as new data sources for scientific research.

[DNVF-Memorandum - Health and Medical Apps]. / DNVF-Memorandum ­ Gesundheits- und Medizin-Apps (GuMAs).

The memorandum outlines core questions that should be addressed by future health services research in order to evaluate the impact of health and medical apps on quality of processes and patient outcomes and to take advantage of their potential as new data sources for scientific research.

[Air pollution and atopic eczema : Systematic review of findings from environmental epidemiological studies]. / Luftverschmutzung und atopisches Ekzem : Systematisches Review der Erkenntnisse aus umweltepidemiologischen Studien.

BACKGROUND: Among the many risk factors for the development of atopic eczema (AE), the influence of air pollution has recently been discussed more often. A systematic review about this topic however is lacking. AIMS: Which effects of outdoor air pollution (particles, nitric oxides, sulfur dioxide, ozone or general traffic exhaust emissions) on AE can be demonstrated in a systematic analysis of available environmental epidemiologic studies? METHODS: All environmental epidemiologic studies on AE and air pollution found in the literature database PubMed were identified. The most important key figures of these studies were tabulated, the quality of evidence was graded and the studies described. RESULTS: A total of 57 studies were identified. Only one of the 15 cross-sectional studies with a large-scale exposure assessment found a significant association between AE and air pollution. In contrast 23 of 30 studies with small-scale exposure assessment found a significant association between AE and traffic related emissions-especially from trucks. Of the 30 studies, 14 were cohort studies (1 adult, 13 birth cohorts). The sole adult cohort found an association with intrinsic AE. In the East Asian cohorts (all published since 2015), an association between maternal exposure to traffic-related pollution and incidence of AE in the offspring was found. This was less clear in cohorts from Europe/US or simply not investigated. In 5/5 panel studies (all from South Korea), symptom severity of AE was found to be significantly and positively related to outdoor air pollution. CONCLUSIONS: In a systematic analysis of environmental epidemiologic studies about air pollution and AE rather good evidence was found that, based on small-scale exposure measurements, especially truck traffic emissions increased AE prevalence, while large-scale exposure to larger particles (PM10) or SO2 was without effect. Considering pathophysiologic aspects traffic exhaust emissions seem to affect both skin barrier function and activation of immune responses.

The role of air pollution and lung function in cognitive impairment.

Air pollution has been associated with impaired lung and cognitive function, especially impairment in visuo-construction performance (VCP). In this article, we evaluate whether the effect of air pollution on VCP is mediated by lung function.We used data from the SALIA cohort (baseline 1985-1994 and follow-up 2007-2010) including 587 women aged 55 years at baseline. Particulate matter (PM) and nitrogen dioxide (NO2) exposures at baseline were estimated via land-use regression models. Lung function was characterised by averages between baseline and follow-up. We used age- and height-controlled Global Lung Initiative (GLI) z-scores of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC. VCP was assessed at follow-up with the CERAD-Plus neuropsychological test battery and causal mediation analysis was conducted.An increase of one interquartile range in FEV1 and FVC was positively associated with VCP (ß=0.18 (95% CI 0.02-0.34) and ß=0.23 (95% CI 0.07-0.39), respectively). The proportion of the association between NO2 on VCP mediated by FEV1 was 6.2% and this was higher in never smokers (7.2%) and non-carriers of the APOE-ε4 allele (11.2%). However, none of the mediations were statistically significant.In conclusion, air pollution associated VCP was partially mediated by lung function. Further studies on the mechanisms underlying this pathway are required to develop new strategies to prevent air pollution induced cognitive impairment.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

Atopic dermatitis: Interaction between genetic variants of GSTP1, TNF, TLR2, and TLR4 and air pollution in early life.

BACKGROUND: Associations between traffic-related air pollution (TRAP) and childhood atopic dermatitis (AD) remain inconsistent, possibly due to unexplored gene-environment interactions. The aim of this study was to examine whether a potential effect of TRAP on AD prevalence in children is modified by selected single nucleotide polymorphisms (SNPs) related to oxidative stress and inflammation. METHODS: Doctor-diagnosed AD up to age 2 years and at 7-8 years, as well as AD symptoms up to age 2 years, was assessed using parental-reported questionnaires in six birth cohorts (N = 5685). Associations of nitrogen dioxide (NO2 ) estimated at the home address of each child at birth and nine SNPs within the GSTP1, TNF, TLR2, or TLR4 genes with AD were examined. Weighted genetic risk scores (GRS) were calculated from the above SNPs and used to estimate combined marginal genetic effects of oxidative stress and inflammation on AD and its interaction with TRAP. RESULTS: GRS was associated with childhood AD and modified the association between NO2 and doctor-diagnosed AD up to the age of 2 years (P(interaction) = .029). This interaction was mainly driven by a higher susceptibility to air pollution in TNF rs1800629 minor allele (A) carriers. TRAP was not associated with the prevalence of AD in the general population. CONCLUSIONS: The marginal genetic association of a weighted GRS from GSTP1, TNF, TLR2, and TLR4SNPs and its interaction with air pollution supports the role of oxidative stress and inflammation in AD.

Detection of gene-environment interactions in the presence of linkage disequilibrium and noise by using genetic risk scores with internal weights from elastic net regression.

BACKGROUND: For the analysis of gene-environment (GxE) interactions commonly single nucleotide polymorphisms (SNPs) are used to characterize genetic susceptibility, an approach that mostly lacks power and has poor reproducibility. One promising approach to overcome this problem might be the use of weighted genetic risk scores (GRS), which are defined as weighted sums of risk alleles of gene variants. The gold-standard is to use external weights from published meta-analyses. METHODS: In this study, we used internal weights from the marginal genetic effects of the SNPs estimated by a multivariate elastic net regression and thereby provided a method that can be used if there are no external weights available. We conducted a simulation study for the detection of GxE interactions and compared power and type I error of single SNPs analyses with Bonferroni correction and corresponding analysis with unweighted and our weighted GRS approach in scenarios with six risk SNPs and an increasing number of highly correlated (up to 210) and noise SNPs (up to 840). RESULTS: Applying weighted GRS increased the power enormously in comparison to the common single SNPs approach (e.g. 94.2% vs. 35.4%, respectively, to detect a weak interaction with an OR ≈ 1.04 for six uncorrelated risk SNPs and n = 700 with a well-controlled type I error). Furthermore, weighted GRS outperformed the unweighted GRS, in particular in the presence of SNPs without any effect on the phenotype (e.g. 90.1% vs. 43.9%, respectively, when 20 noise SNPs were added to the six risk SNPs). This outperforming of the weighted GRS was confirmed in a real data application on lung inflammation in the SALIA cohort (n = 402). However, in scenarios with a high number of noise SNPs (>200 vs. 6 risk SNPs), larger sample sizes are needed to avoid an increased type I error, whereas a high number of correlated SNPs can be handled even in small samples (e.g. n = 400). CONCLUSION: In conclusion, weighted GRS with weights from the marginal genetic effects of the SNPs estimated by a multivariate elastic net regression were shown to be a powerful tool to detect gene-environment interactions in scenarios of high Linkage disequilibrium and noise.

Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies.

BACKGROUND: Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects ("GRS-marginal-internal") are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect. METHODS: In this paper, we present a weighting approach for such predominant interactions ("GRS-interaction-training") in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS-marginal-internal approach and to GRS with external weights. RESULTS: Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS-interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations). CONCLUSION: When appropriate external weights are unavailable, we recommend to use internal weights from the study population itself to construct weighted GRS for GxE interaction studies. If the SNPs were chosen because a strong marginal genetic effect was hypothesized, GRS-marginal-internal should be used. If the SNPs were chosen because of their collective impact on the biological mechanisms mediating the environmental effect (hypothesis of predominant interactions) GRS-interaction-training should be applied.

Genetic susceptibility for air pollution-induced airway inflammation in the SALIA study.

BACKGROUND: Long-term air pollution exposure has been associated with chronic inflammation providing a link to the development of chronic health effects. Furthermore, there is evidence that pathways activated by endoplasmatic reticulum (ER) stress induce airway inflammation and thereby play an important role in the pathogenesis of inflammatory diseases. OBJECTIVE: We investigated the role of genetic variation of the ER stress pathway on air pollution-induced inflammation. METHODS: We used the follow-up examination of the German SALIA study (N=402, age 68-79 years). Biomarkers of inflammation were determined in induced sputum. We calculated biomarker-specific weighted genetic risk scores (GRS) out of eight ER stress related single nucleotide polymorphisms and tested their interaction with PM2.5, PM2.5 absorbance, PM10 and NO2 exposure on inflammation by adjusted linear regression. RESULTS: Genetic variation of the ER stress pathway was associated with higher concentration of inflammation-related biomarkers (levels of leukotriene (LT)B4, tumor necrosis factor-α (TNF-α), the total number of cells and nitric oxide (NO) derivatives). Furthermore, we observed a significant interaction between air pollution exposure and the ER stress risk score on the concentration of inflammation-related biomarkers. The strongest gene-environment interaction was found for LTB4 (PM2.5: p-value=0.002, PM2.5 absorbance: p-value=0.002, PM10: p-value=0.001 and NO2: p-value=0.004). Women with a high GRS had a 38% (95%-CI: 16-64%) higher LTB4 level for an increase of 2.06µg/m³(IQR) in PM2.5 (no associations in women with a low GRS). CONCLUSION: These results indicate that genetic variation in the ER stress pathway might play a role in air pollution induced inflammation in the lung.

3D Ultrasound Evaluation of the Fetal Ear - Comparison of an xMatrix Probe with a Conventional Mechanical Probe.

Purpose New 3 D technologies like xMatrix probes promise superiority over conventional mechanical probes and may allow a more detailed and time-saving prenatal diagnosis. In a comparison study we evaluate fetal ears. The aim of our study was to compare the following aspects of both techniques: (1) ultrasound detail resolution, (2) raw data acquisition time (AT) and (3) influence of covariates. Materials and Methods 3 D raw data volumes of the fetal ear were collected with the V6 - 2 (V6) and with the xMatrix (X6) probe and were stored after offline customization to a single picture. Two observers scored these images independently. Furthermore, the 3 D raw data acquisition time (AT) was recorded. Concordance between observers, maternal age, body mass index (BMI), weeks of gestation and location of the placenta were evaluated. Results Data volumes of 103 patients were analyzed. The X6 detected anatomic structures like the scapha (p = 0.0146), fossa triangularis (p = 0.0075) and cymba conchae (p = 0.0025) more often. The mean AT of the X6 was shorter compared to the V6 (p < 0.0001). A placenta location in the scanning field increased the AT only for the V6 (p < 0.01). Concordance between observers was higher for the X6 in most cases. Detailed structures were less visible at the end of pregnancy for both devices. Conclusion The comparison study demonstrated clear advantages of the new xMatrix technology concerning an advanced and fast examination of detailed structures like the fetal ear. The importance of 3 D assessment in cases of fetal ear anomaly should be proven in further studies.

[Position Paper of The AG Digital Health DNVF on Digital Health Applications: Framework Conditions For Use in Health Care, Structural Development and Science]. / Digitale Gesundheitsanwendungen ­ Rahmenbedingungen zur Nutzung in Versorgung, Strukturentwicklung und Wissenschaft ­ Positionspapier der AG Digital Health des DNVF.

The term "digital health" is currently the most comprehensive term that includes all information and communication technologies in healthcare, including e-health, mobile health, telemedicine, big data, health apps and others. Digital health can be seen as a good example of the use of the concept and methodology of health services research in the interaction between complex interventions and complex contexts. The position paper deals with 1) digital health as the subject of health services research; 2) digital health as a methodological and ethical challenge for health services research. The often-postulated benefits of digital health interventions should be demonstrated with good studies. First systematic evaluations of apps for "treatment support" show that risks are higher than benefits. The need for a rigorous proof applies even more to big data-assisted interventions that support decision-making in the treatment process with the support of artificial intelligence. Of course, from the point of view of health services research, it is worth participating as much as possible in data access available through digital health and "big data". However, there is the risk that a noncritical application of digital health and big data will lead to a return to a linear understanding of biomedical research, which, at best, accepts complex conditions assuming multivariate models but does not take complex facts into account. It is not just a matter of scientific ethical requirements in health services care research, for instance, better research instead of unnecessary research ("reducing waste"), but it is primarily a matter of anticipating the social consequences (system level) of scientific analysis and evaluation. This is both a challenge and an attractive option for health services research to present itself as a mature and responsible scientific discipline.

Estrogen receptor beta polymorphisms and cognitive performance in women: associations and modifications by genetic and environmental influences.

Genetic and environmental risk factors contribute to the pathogenesis of Alzheimer's dementia. Besides known genetic risk factors like the apolipoprotein (APO) Eε4 allele, single nuclear polymorphisms (SNPs) of the estrogen receptors (ESRs) are candidate genetic risk factors, while air pollution represents an environmental risk factor for dementia. Effects of these risk factors and their interaction were investigated in the SALIA cohort of 834 non-demented elderly women. Cognitive function was assessed by the CERAD-plus test battery. Air pollution was estimated by land use regression (LUR) models. Genotyping was carried out for nine ESR1 and ESR2 SNPs and two ApoE SNPs. Carriers of minor ESR2 alleles showed significantly reduced cognitive performance in the CERAD total score with most pronounced deficits in semantic memory (rs1256062, rs10144225, and rs2274705) and executive function (rs1256062). The minor allele effects of ESR2 were stronger in carriers of APOEε4 for the cognitive domain 'executive function' (p value of interaction 0.023 for rs1256062). The investigated ESR1 SNPs were not associated with cognition. Furthermore, we found a significant gene-environment interaction between the ESR2 SNP rs1256062 and air pollution on cognition. Carriers of two major alleles of rs1256062 were more susceptible for an air pollution-induced decrease in performance of 'figure copying' than carriers of minor alleles (p value of interaction, e.g., 0.031 for PM2.5). In conclusion, ESR2 but not ESR1 minor alleles were associated with lower cognitive performance in elderly women with an indication of a gene-gene interaction with APOEε4. We also found indications for gene-environment interactions of ESR2 with traffic-related air pollution exposure on cognitive performance.

Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project.

BACKGROUND: Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants. METHODS: We used data from 22 European cohort studies, which created a total study population of 367,251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 µm (PM2.5), less than 10 µm (PM10), and between 10 µm and 2.5 µm (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buffer. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis. FINDINGS: The total study population consisted of 367,251 participants who contributed 5,118,039 person-years at risk (average follow-up 13.9 years), of whom 29,076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 µg/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I(2) p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 µg/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 µg/m(3) (1.07, 1.01-1.13). INTERPRETATION: Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value. FUNDING: European Community's Seventh Framework Program (FP7/2007-2011).

Adult lung function and long-term air pollution exposure. ESCAPE: a multicentre cohort study and meta-analysis.

The chronic impact of ambient air pollutants on lung function in adults is not fully understood. The objective of this study was to investigate the association of long-term exposure to ambient air pollution with lung function in adult participants from five cohorts in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Residential exposure to nitrogen oxides (NO2, NOx) and particulate matter (PM) was modelled and traffic indicators were assessed in a standardised manner. The spirometric parameters forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from 7613 subjects were considered as outcomes. Cohort-specific results were combined using meta-analysis. We did not observe an association of air pollution with longitudinal change in lung function, but we observed that a 10 µg·m(-3) increase in NO2 exposure was associated with lower levels of FEV1 (-14.0 mL, 95% CI -25.8 to -2.1) and FVC (-14.9 mL, 95% CI -28.7 to -1.1). An increase of 10 µg·m(-3) in PM10, but not other PM metrics (PM2.5, coarse fraction of PM, PM absorbance), was associated with a lower level of FEV1 (-44.6 mL, 95% CI -85.4 to -3.8) and FVC (-59.0 mL, 95% CI -112.3 to -5.6). The associations were particularly strong in obese persons. This study adds to the evidence for an adverse association of ambient air pollution with lung function in adults at very low levels in Europe.