Michal Kicinski

An epidemiological appraisal of the association between heart rate variability and particulate air pollution: a meta-analysis

Objective Studies on the association between short-term exposure to ambient air pollution and heart rate variability (HRV) suggest that particulate matter (PM) exposure is associated with reductions in measures of HRV, but there is heterogeneity in the nature and magnitude of this association between studies. The authors performed a meta-analysis to determine how consistent this association is. Data source The authors searched the Pubmed citation database and Web of Knowledge to identify studies on HRV and PM. Study selection Of the epidemiologic studies reviewed, 29 provided sufficient details to be considered. The meta-analysis included 18667 subjects recruited from the population in surveys, studies from patient groups, and from occupationally exposed groups. Data extraction Two investigators read all papers and computerised all relevant information. Results The authors computed pooled estimates from a random-effects model. In the combined studies, an increase of 10 μg/m3 in PM2.5 was associated with significant reductions in the time-domain measurements, including low frequency (−1.66%, 95% CI −2.58% to −0.74%) and high frequency (−2.44%, 95% CI −3.76% to −1.12%) and in frequency-domain measurements, for SDNN (−0.12%, 95% CI −0.22% to −0.03%) and for rMSSD (−2.18%, 95% CI −3.33% to −1.03%). Funnel plots suggested that no publication bias was present and a sensitivity analysis confirmed the robustness of our combined estimates. Conclusion The meta-analysis supports an inverse relationship between HRV, a marker for a worse cardiovascular prognosis, and particulate air pollution.

An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis.

Studies on familial aggregation of cancer may suggest an overall contribution of inherited genes or a shared environment in the development of malignant disease. We performed a meta-analysis on familial clustering of prostate cancer. Out of 74 studies reporting data on familial aggregation of prostate cancer in unselected populations retrieved by a Pubmed search and browsing references, 33 independent studies meeting the inclusion criteria were used in the analysis performed with the random effects model. The pooled rate ratio (RR) for first-degree family history, i.e. affected father or brother, is 2.48 (95% confidence interval: 2.25–2.74). The incidence rate for men who have a brother who got prostate cancer increases 3.14 times (CI:2.37–4.15), and for those with affected father 2.35 times (CI:2.02–2.72). The pooled estimate of RR for two or more affected first-degree family members relative to no history in father and in brother is 4.39 (CI:2.61–7.39). First-degree family history appears to increase the incidence rate of prostate cancer more in men under 65 (RR:2.87, CI:2.21–3.74), than in men aged 65 and older (RR:1.92, CI:1.49–2.47), p for interaction = 0.002. The attributable fraction among those having an affected first-degree relative equals to 59.7% (CI:55.6–63.5%) for men at all ages, 65.2% (CI:57.7–71.4%) for men younger than 65 and 47.9% (CI:37.1–56.8%) for men aged 65 or older. For those with a family history in 2 or more first-degree family members 77.2% (CI:65.4–85.0%) of prostate cancer incidence can be attributed to the familial clustering. Our combined estimates show strong familial clustering and a significant effect-modification by age meaning that familial aggregation was associated with earlier disease onset (before age 65).

Publication bias in recent meta-analyses.

Introduction Positive results have a greater chance of being published and outcomes that are statistically significant have a greater chance of being fully reported. One consequence of research underreporting is that it may influence the sample of studies that is available for a meta-analysis. Smaller studies are often characterized by larger effects in published meta-analyses, which can be possibly explained by publication bias. We investigated the association between the statistical significance of the results and the probability of being included in recent meta-analyses. Methods For meta-analyses of clinical trials, we defined the relative risk as the ratio of the probability of including statistically significant results favoring the treatment to the probability of including other results. For meta-analyses of other studies, we defined the relative risk as the ratio of the probability of including biologically plausible statistically significant results to the probability of including other results. We applied a Bayesian selection model for meta-analyses that included at least 30 studies and were published in four major general medical journals (BMJ, JAMA, Lancet, and PLOS Medicine) between 2008 and 2012. Results We identified 49 meta-analyses. The estimate of the relative risk was greater than one in 42 meta-analyses, greater than two in 16 meta-analyses, greater than three in eight meta-analyses, and greater than five in four meta-analyses. In 10 out of 28 meta-analyses of clinical trials, there was strong evidence that statistically significant results favoring the treatment were more likely to be included. In 4 out of 19 meta-analyses of observational studies, there was strong evidence that plausible statistically significant outcomes had a higher probability of being included. Conclusions Publication bias was present in a substantial proportion of large meta-analyses that were recently published in four major medical journals.

Neurobehavioral function and low-level exposure to brominated flame retardants in adolescents: a cross-sectional study

BackgroundAnimal and in vitro studies demonstrated a neurotoxic potential of brominated flame retardants, a group of chemicals used in many household and commercial products to prevent fire. Although the first reports of detrimental neurobehavioral effects in rodents appeared more than ten years ago, human data are sparse.MethodsAs a part of a biomonitoring program for environmental health surveillance in Flanders, Belgium, we assessed the neurobehavioral function with the Neurobehavioral Evaluation System (NES-3), and collected blood samples in a group of high school students. Cross-sectional data on 515 adolescents (13.6-17 years of age) was available for the analysis. Multiple regression models accounting for potential confounders were used to investigate the associations between biomarkers of internal exposure to brominated flame retardants [serum levels of polybrominated diphenyl ether (PBDE) congeners 47, 99, 100, 153, 209, hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA)] and cognitive performance. In addition, we investigated the association between brominated flame retardants and serum levels of FT3, FT4, and TSH.ResultsA two-fold increase of the sum of serum PBDE’s was associated with a decrease of the number of taps with the preferred-hand in the Finger Tapping test by 5.31 (95% CI: 0.56 to 10.05, p = 0.029). The effects of the individual PBDE congeners on the motor speed were consistent. Serum levels above the level of quantification were associated with an average decrease of FT3 level by 0.18 pg/mL (95% CI: 0.03 to 0.34, p = 0.020) for PBDE-99 and by 0.15 pg/mL (95% CI: 0.004 to 0.29, p = 0.045) for PBDE-100, compared with concentrations below the level of quantification. PBDE-47 level above the level of quantification was associated with an average increase of TSH levels by 10.1% (95% CI: 0.8% to 20.2%, p = 0.033), compared with concentrations below the level of quantification. We did not observe effects of PBDE’s on neurobehavioral domains other than the motor function. HBCD and TBBPA did not show consistent associations with performance in the neurobehavioral tests.ConclusionsThis study is one of few studies and so far the largest one investigating the neurobehavioral effects of brominated flame retardants in humans. Consistently with experimental animal data, PBDE exposure was associated with changes in the motor function and the serum levels of the thyroid hormones.

Publication bias in meta-analyses from the Cochrane Database of Systematic Reviews.

UNLABELLED We used a Bayesian hierarchical selection model to study publication bias in 1106 meta-analyses from the Cochrane Database of Systematic Reviews comparing treatment with either placebo or no treatment. For meta-analyses of efficacy, we estimated the ratio of the probability of including statistically significant outcomes favoring treatment to the probability of including other outcomes. For meta-analyses of safety, we estimated the ratio of the probability of including results showing no evidence of adverse effects to the probability of including results demonstrating the presence of adverse effects. RESULTS In the meta-analyses of efficacy, outcomes favoring treatment had on average a 27% (95% Credible Interval (CI): 18% to 36%) higher probability to be included than other outcomes. In the meta-analyses of safety, results showing no evidence of adverse effects were on average 78% (95% CI: 51% to 113%) more likely to be included than results demonstrating that adverse effects existed. In general, the amount of over-representation of findings favorable to treatment was larger in meta-analyses including older studies. CONCLUSIONS In the largest study on publication bias in meta-analyses to date, we found evidence of publication bias in Cochrane systematic reviews. In general, publication bias is smaller in meta-analyses of more recent studies, indicating their better reliability and supporting the effectiveness of the measures used to reduce publication bias in clinical trials. Our results indicate the need to apply currently underutilized meta-analysis tools handling publication bias based on the statistical significance, especially when studies included in a meta-analysis are not recent.

Retinal Microvascular Responses to Short-Term Changes in Particulate Air Pollution in Healthy Adults

Background: Microcirculation plays an important role in the physiology of cardiovascular health. Air pollution is an independent risk factor for the development and progression of cardiovascular diseases, but the number of studies on the relation between air pollution and the microcirculation is limited. Objectives: We examined the relationship between short-term changes in air pollution and microvascular changes. Methods: We measured retinal microvasculature using fundus image analysis in a panel of 84 healthy adults (52% female), 22–63 years of age, during January–May 2012. Blood vessels were measured as central retinal arteriolar/venular equivalent (CRAE/CRVE), with a median of 2 measurements (range, 1–3). We used monitoring data on particulate air pollution (PM10) and black carbon (BC). Mixed-effect models were used to estimate associations between CRAE/CRVE and exposure to PM10 and BC using various exposure windows. Results: CRAE and CRVE were associated with PM10 and BC concentrations, averaged over the 24 hr before the retinal examinations. Each 10-µg/m3 increase in PM10 was associated with a 0.93-µm decrease (95% CI: –1.42, –0.45; p = 0.0003) in CRAE and a 0.86-µm decrease (95% CI: –1.42, –0.30; p = 0.004) in CRVE after adjusting for individual characteristics and time varying conditions such as ambient temperature. Each 1-µg/m3 increase in BC was associated with a 1.84-µm decrease (95% CI: –3.18, –0.51; p < 0.001) in CRAE. Conclusions: Our findings suggest that the retinal microvasculature responds to short-term changes in air pollution levels. These results support a mechanistic pathway through which air pollution can act as a trigger of cardiovascular events at least in part through effects on the microvasculature. Citation: Louwies T, Int Panis L, Kicinski M, De Boever P, Nawrot TS. 2013. Retinal microvascular responses to short-term changes in particulate air pollution in healthy adults. Environ Health Perspect 121:1011–1016; http://dx.doi.org/10.1289/ehp.1205721

Neurobehavioral performance in adolescents is inversely associated with traffic exposure

On the basis of animal research and epidemiological studies in children and elderly there is a growing concern that traffic exposure may affect the brain. The aim of our study was to investigate the association between traffic exposure and neurobehavioral performance in adolescents. We examined 606 adolescents. To model the exposure, we constructed a traffic exposure factor based on a biomarker of benzene (urinary trans,trans-muconic acid) and the amount of contact with traffic preceding the neurobehavioral examination (using distance-weighted traffic density and time spent in traffic). We used a Bayesian structural equation model to investigate the association between traffic exposure and three neurobehavioral domains: sustained attention, short-term memory, and manual motor speed. A one standard deviation increase in traffic exposure was associated with a 0.26 standard deviation decrease in sustained attention (95% credible interval: -0.02 to -0.51), adjusting for gender, age, smoking, passive smoking, level of education of the mother, socioeconomic status, time of the day, and day of the week. The associations between traffic exposure and the other neurobehavioral domains studied had the same direction but did not reach the level of statistical significance. The results remained consistent in the sensitivity analysis excluding smokers and passive smokers. The inverse association between sustained attention and traffic exposure was independent of the blood lead level. Our study in adolescents supports the recent findings in children and elderly suggesting that traffic exposure adversely affects the neurobehavioral function.

How does under-reporting of negative and inconclusive results affect the false-positive rate in meta-analysis? A simulation study

Objective To investigate the impact of a higher publishing probability for statistically significant positive outcomes on the false-positive rate in meta-analysis. Design Meta-analyses of different sizes (N=10, N=20, N=50 and N=100), levels of heterogeneity and levels of publication bias were simulated. Primary and secondary outcome measures The type I error rate for the test of the mean effect size (ie, the rate at which the meta-analyses showed that the mean effect differed from 0 when it in fact equalled 0) was estimated. Additionally, the power and type I error rate of publication bias detection methods based on the funnel plot were estimated. Results In the presence of a publication bias characterised by a higher probability of including statistically significant positive results, the meta-analyses frequently concluded that the mean effect size differed from zero when it actually equalled zero. The magnitude of the effect of publication bias increased with an increasing number of studies and between-study variability. A higher probability of including statistically significant positive outcomes introduced little asymmetry to the funnel plot. A publication bias of a sufficient magnitude to frequently overturn the meta-analytic conclusions was difficult to detect by publication bias tests based on the funnel plot. When statistically significant positive results were four times more likely to be included than other outcomes and a large between-study variability was present, more than 90% of the meta-analyses of 50 and 100 studies wrongly showed that the mean effect size differed from zero. In the same scenario, publication bias tests based on the funnel plot detected the bias at rates not exceeding 15%. Conclusions This study adds to the evidence that publication bias is a major threat to the validity of medical research and supports the usefulness of efforts to limit publication bias.

Lower placental telomere length may be attributed to maternal residential traffic exposure; a twin study

BACKGROUND High variation in telomere length between individuals is already present before birth and is as wide among newborns as in adults. Environmental exposures likely have an impact on this observation, but remain largely unidentified. We hypothesize that placental telomere length in twins is associated with residential traffic exposure, an important environmental source of free radicals that might accelerate aging. Next, we intend to unravel the nature-nurture contribution to placental telomere length by estimating the heritability of placental telomere length. METHODS We measured the telomere length in placental tissues of 211 twins in the East Flanders Prospective Twin Survey. Maternal traffic exposure was determined using a geographic information system. Additionally, we estimated the relative importance of genetic and environmental sources of variance. RESULTS In this twin study, a variation in telomere length in the placental tissue was mainly determined by the common environment. Maternal residential proximity to a major road was associated with placental telomere length: a doubling in the distance to the nearest major road was associated with a 5.32% (95% CI: 1.90 to 8.86%; p=0.003) longer placental telomere length at birth. In addition, an interquartile increase (22%) in maternal residential surrounding greenness (5 km buffer) was associated with an increase of 3.62% (95% CI: 0.20 to 7.15%; p=0.04) in placental telomere length. CONCLUSIONS In conclusion, we showed that maternal residential proximity to traffic and lower residential surrounding greenness is associated with shorter placental telomere length at birth. This may explain a significant proportion of air pollution-related adverse health outcomes starting from early life, since shortened telomeres accelerate the progression of many diseases.

Serum levels of club cell secretory protein (Clara) and short- and long-term exposure to particulate air pollution in adolescents.

BACKGROUND Studies in populations have shown that particulate air pollution is associated with changes in lung function in adolescents. OBJECTIVE We investigated the effect of short- and long-term exposure to particulate matter (PM10) on the pulmonary health of adolescents, using serum lung club cell secretory protein (Clara) (CC16) as a biomarker for respiratory epithelium integrity. METHODS We measured serum CC16 in 825 adolescents (57% girls, mean age: 15 years). Short-term and long-term exposure to ambient PM10 was estimated for each participants home address using a kriging interpolation method. To explore the association between PM10 and serum CC16 we applied restricted cubic splines with 5 knots located at the 5th, 25th, 50th, 75th and 95th percentiles of the PM10 distribution. The explorative analyses showed a change in the slope of this association, after which a change-point analysis was performed. RESULTS After adjustment for potential covariates, the analysis showed strong associations between PM10 concentrations, averaged over the week preceding the clinical examination, and serum CC16 levels. Each 5 μg/m(3) increase in mean PM10 concentration in the week before the clinical examination was associated with a substantial increase of 0.52 μg/l (95% confidence interval: 0.31 to 0.73; p<0.0001) in serum CC16 levels. The association appears nonlinear with a flattening out of the slope at mean week PM10 levels above 37 μg/m(3). There was no evidence of an association between long-term exposure to PM10 and serum CC16 concentrations. CONCLUSIONS Our findings suggest that short-term exposure to particulate air pollution may compromise the integrity of the lung epithelium and lead to increased epithelial barrier permeability in the lungs of adolescents, even at low concentrations.