Response to : 'Domestic use of bleach and infections in children: a multicentre cross-sectional study' Response

Non peer reviewe

A systematic comparison of statistical methods to detect interactions in exposome-health associations

Background There is growing interest in examining the simultaneous effects of multiple exposures and, more generally, the effects of mixtures of exposures, as part of the exposome concept (being defined as the totality of human environmental exposures from conception onwards). Uncovering such combined effects is challenging owing to the large number of exposures, several of them being highly correlated. We performed a simulation study in an exposome context to compare the performance of several statistical methods that have been proposed to detect statistical interactions. Methods Simulations were based on an exposome including 237 exposures with a realistic correlation structure. We considered several statistical regression-based methods, including two-step Environment-Wide Association Study (EWAS2), the Deletion/Substitution/Addition (DSA) algorithm, the Least Absolute Shrinkage and Selection Operator (LASSO), Group-Lasso INTERaction-NET (GLINTERNET), a three-step method based on regression trees and finally Boosted Regression Trees (BRT). We assessed the performance of each method in terms of model size, predictive ability, sensitivity and false discovery rate. Results GLINTERNET and DSA had better overall performance than the other methods, with GLINTERNET having better properties in terms of selecting the true predictors (sensitivity) and of predictive ability, while DSA had a lower number of false positives. In terms of ability to capture interaction terms, GLINTERNET and DSA had again the best performances, with the same trade-off between sensitivity and false discovery proportion. When GLINTERNET and DSA failed to select an exposure truly associated with the outcome, they tended to select a highly correlated one. When interactions were not present in the data, using variable selection methods that allowed for interactions had only slight costs in performance compared to methods that only searched for main effects. Conclusions GLINTERNET and DSA provided better performance in detecting two-way interactions, compared to other existing methods

Land Use Regression Models for Ultrafine Particles in Six European Areas

Long-term ultrafine particle (UFP) exposure estimates at a fine spatial scale are needed for epidemiological studies. Land use regression (LUR) models were developed and evaluated for six European areas based on repeated 30 min monitoring following standardized protocols. In each area; Basel (Switzerland), Heraklion (Greece), Amsterdam, Maastricht, and Utrecht ("The Netherlands"), Norwich (United Kingdom), Sabadell (Spain), and Turin (Italy), 160-240 sites were monitored to develop LUR models by supervised stepwise selection of GIS predictors. For each area and all areas combined, 10 models were developed in stratified random selections of 90% of sites. UFP prediction robustness was evaluated with the intraclass correlation coefficient (ICC) at 31-50 external sites per area. Models from Basel and The Netherlands were validated against repeated 24 h outdoor measurements. Structure and model R2 of local models were similar within, but varied between areas (e.g., 38-43% Turin; 25-31% Sabadell). Robustness of predictions within areas was high (ICC 0.73-0.98). External validation R2 was 53% in Basel and 50% in The Netherlands. Combined area models were robust (ICC 0.93-1.00) and explained UFP variation almost equally well as local models. In conclusion, robust UFP LUR models could be developed on short-term monitoring, explaining around 50% of spatial variance in longer-term measurements

Biological marks of early-life socioeconomic experience is detected in the adult inflammatory transcriptome.

Consistent evidence is accumulating to link lower socioeconomic position (SEP) and poorer health, and the inflammatory system stands out as a potential pathway through which socioeconomic environment is biologically embedded. Using bloodderived genome-wide transcriptional profiles from 268 Italian participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we evaluated the association between early life, young and later adulthood SEP and the expression of 845 genes involved in human inflammatory responses. These were examined individually and jointly using several inflammatory scores. Our results consistently show that participants whose father had a manual (as compared to nonmanual) occupation exhibit, later in life, a higher inflammatory score, hence indicating an overall increased level of expression for the selected inflammatory-related genes. Adopting a life course approach, these associations remained statistically significant upon adjustment for later-in-life socioeconomic experiences. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated, and were replicated in an independent study. Our study provides additional evidence that childhood SEP is associated with a sustainable upregulation of the inflammatory transcriptome, independently of subsequent socioeconomic experiences. Our results support the hypothesis that early social inequalities impacts adult physiology

Nanomaterials at the workplace: measuring and modelling inhalation exposure

At the nanoscale (<100 nm), materials can exhibit properties that differ physically, chemically, and biologically from their larger counterparts. These new sizedependent properties offer huge possibilities to make materials effectively stronger, lighter, better electrical conductive, flexible, water resistant, dirt repellent, etc. The distinctive size-related properties of nanomaterials are applied by incorporating them in a wide range of products. However, increasing production and use of nanomaterial embedded products raises concerns and questions about the potential health risks of these nanomaterials. The extremely small dimensions of nano-objects increase their ability to cross cell membranes and reach the organs through the blood stream. Due to the greater surface to volume ratio of nanoobjects compared to their larger counterparts, a certain mass concentration of nano-objects will have a higher reactivity than the same mass concentration of larger particles of the same composition. Workers who are frequently handling nanomaterials or products they are incorporated in, run the risk of being exposed to nano-objects and their agglomerates and aggregates (NOAA). Information about the potential for occupational exposure to NOAA is therefore essential for determining whether there is any potential risk of adverse health effects and for the implementation of risk management measures to reduce exposure at the workplace. This thesis aimed to 1) get an overview of the occupational NOAA exposure scenarios and the levels of occupational exposure to NOAA across the various life cycle stages, 2) gain insight into the determinants affecting NOAA exposure, and 3) provide a scientific basis for future modelling of worker exposure to NOAA

The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case-control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people

Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition

Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested case-control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF-I concentration was not associated with overall lymphoma risk (multivariable-adjusted OR for highest versus lowest third = 0.77 [95% CI = 0.57-1.03], ptrend  = 0.06). There was no statistical evidence of heterogeneity in this association with IGF-I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (pheterogeneity for all  ≥ 0.05). There were no associations between IGF-I concentration and risk for specific BCL subtypes, T-cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF-I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF-I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF-I concentrations with lymphoma subtypes.The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A11692, C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom)

Is the New EN689 a Better Standard to Test Compliance With Occupational Exposure Limits in the Workplace?

OBJECTIVE: To evaluate the performance of three measurement strategies to test compliance with occupational exposure limits of similarly exposed groups (SEGs): the old and new versions of EN689, and the BOHS-NVvA guidance on measuring compliance. METHODS: Respirable dust exposures concentrations (n = 1383) measured within the member companies of IMA-Europe were used to compare compliance decisions between the three measurement strategies. A total of 210 SEGs of which 158 with repeated measurements were analysed. An R studio OHcomplianceStrategies package was created for the purpose. RESULTS: The old EN689 strategy resulted in the highest number of compliant SEGs in the preliminary tests and statistical test (49-52% and 83%) with lower percentages of compliance with the new EN689 standard (32-44% and 71%). The percentage of non-compliant SEGs was relatively similar between the old and new EN689 for the preliminary tests (1-12% versus 6-11%). However, the new EN689 declared almost twofold more SEGs non-compliant when applying the statistical test (29% versus 17%). The BOHS-NVvA individual test showed results in between the 26% non-compliant SEGs. CONCLUSION: This study showed differences in compliance decisions between the old and new EN689, with the new EN689 being considerably more stringent and resulting in more non-compliant SEGs

Is the New EN689 a Better Standard to Test Compliance With Occupational Exposure Limits in the Workplace?

OBJECTIVE: To evaluate the performance of three measurement strategies to test compliance with occupational exposure limits of similarly exposed groups (SEGs): the old and new versions of EN689, and the BOHS-NVvA guidance on measuring compliance. METHODS: Respirable dust exposures concentrations (n = 1383) measured within the member companies of IMA-Europe were used to compare compliance decisions between the three measurement strategies. A total of 210 SEGs of which 158 with repeated measurements were analysed. An R studio OHcomplianceStrategies package was created for the purpose. RESULTS: The old EN689 strategy resulted in the highest number of compliant SEGs in the preliminary tests and statistical test (49-52% and 83%) with lower percentages of compliance with the new EN689 standard (32-44% and 71%). The percentage of non-compliant SEGs was relatively similar between the old and new EN689 for the preliminary tests (1-12% versus 6-11%). However, the new EN689 declared almost twofold more SEGs non-compliant when applying the statistical test (29% versus 17%). The BOHS-NVvA individual test showed results in between the 26% non-compliant SEGs. CONCLUSION: This study showed differences in compliance decisions between the old and new EN689, with the new EN689 being considerably more stringent and resulting in more non-compliant SEGs

Lung function, bronchial hyperresponsiveness, and atopy among firefighters

Objectives The aim of this study was to determine associations between lung function, bronchial hyperresponsiveness (BHR), and atopy with exposure to fire smoke among firefighters. Methods The study was comprised of 402 firefighters, a randomly chosen subset of a previous survey among firefighters in the Netherlands. Subjects underwent spirometry and methacholine provocation, and blood samples were taken to assess atopy. Exposure to fire smoke was registered by a questionnaire. Results Hyperresponsiveness expressed as dose-response slope (DRS) was positively and significantly associated with the number of fires fought in the last 12 months with and without adjustments for smoking, gender, atopy, age, and exposure in the main job held. Limiting the analysis to firefighters without exposure within 7 days of testing did not change any of the associations. The association between the number of fires and the DRS was stronger among atopics, and hyperresponsiveness expressed as PD(20) was also significantly associated, indicating that atopics are at higher risk of developing BHR as a result of smoke exposure. Respiratory protection devices were not optimally used. Conclusions It is recommended that awareness be heightened among firefighters to avoid exposure to all fire smoke and that management be sensitive to the adequate use of sell-contained breathing apparatuses by their personnel