Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function

Background: Errors in address geocodes may affect estimates of the effects of air pollution on health.Objective: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults.Methods: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant's address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects.Results: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 μg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: -0.56, -6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: -0.14, -3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted -2.81 (95% CI: -0.26, -5.35) using NavTEQ or 2.08 (95% CI -4.63, 0.47, p = 0.11) using Google Maps].Conclusions: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model.Citation: Jacquemin B, Lepeule J, Boudier A, Arnould C, Benmerad M, Chappaz C, Ferran J, Kauffmann F, Morelli X, Pin I, Pison C, Rios I, Temam S, Künzli N, Slama R, Siroux V. 2013. Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function. Environ Health Perspect 121:1054-1060; http://dx.doi.org/10.1289/ehp.1206016

Cent scientifiques répliquent à SEA (Suppression des Expériences sur l’Animal vivant) et dénoncent sa désinformation

La lutte contre la maltraitance animale est sans conteste une cause moralement juste. Mais elle ne justifie en rien la désinformation à laquelle certaines associations qui s’en réclament ont recours pour remettre en question l’usage de l’expérimentation animale en recherche

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Genetic architecture of primary congenital hydrocephalus

Primary congenital hydrocephalus (PCH) is characterized by ventriculomegaly, defined as a dilation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. PCH, highly heterogenous in etiology, affects 1 in 1,000 live births, where its poor prognosis and lack of satisfactory treatments, underscores our incomplete understanding of PCH pathogenesis. While epidemiological data suggest an underlying genetic cause in up to 40% of congenital hydrocephalus cases, few genes have been discovered as causal of PCH where ventriculomegaly is the sole or primary clinical feature.The work presented within this thesis represents the study through whole-exome sequencing (WES) of a cohort of 28 inbred/outbred families with PCH. Analysis for rare transmitted or de novo mutations (MAF <0.005) uncovered novel mutations in known genes associated with PCH (POMT2, POMGNT1, CRADD, ARID1A and KIDINS220), thus broadening the spectrum of known mutations in PCH. In a consanguineous family we identified a mutation in KIDINS220 shared among the three fetuses presenting brain ventriculomegaly and limb contractures, a gene previously reported in one family with an identical phenotype. Through immunoprecipitation experiments, we showed that the mutation diminished the interaction of KIDINS220 with TrkA, a receptor important in cell survival signaling.In three PCH probands, we identified variants in three potential candidate genes, which reflect the heterogenous genetic landscape of PCH as they are involved in minor spliceosome (RNPC3), angiogenesis (TIE1) and ciliary structure (DNAH2). Though literature poses these genes as strong candidates, further investigation will be required to ascertain them as such.With the increasing number of reports demonstrating that disorders traditionally considered as monogenic are in fact caused by a combination of mutant genes, possible oligogenic inheritance of human PCH was investigated. As ciliary defects of motile and more recently of primary cilia have been associated to the development of hydrocephalus in animal models, we conducted a mutation burden analysis in ciliary genes. This analysis revealed a statistically significant mutation burden in primary cilia genes in PCH patients compared to controls. Then, using a bio-informatic prediction tool for digenic inheritance, individual patient variants in ciliary genes were analyzed, revealing for one proband strong evidence of a true digenic pair. Altogether, these findings suggest, for the first time, that a subset of PCH patients may be associated to oligogenic inheritance involving primary cilia.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)info:eu-repo/semantics/nonPublishe

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