Earlier retrospective noise exposure assessments for use in epidemiological research were not adequately characterized because they did not properly account for use of hearing protection devices (HPD) which would result in potential misclassification. Exposure misclassification has been shown to attenuate exposure-outcomes relations. In the case of already subtle relationships such as noise and cardiovascular diseases, this would potentially annihilate any association. We investigated two approaches using Workers’ Compensation Board (WorkSafe BC) audiometric surveillance data to (i) re-assess the noise exposure in a cohort of lumber mill workers in British Columbia using data on the use of HPD and the determinants of their use available through WorkSafe BC, and (ii) test the validity of the new exposure measures by testing their predictions of noise-induced hearing loss, a well-established association. Work history, noise exposure measurements, and audiometric surveillance data were merged together, forming job-exposure-audiometric information for each of 13,147 lumber mill workers. Correction factors specific to each type and class of HPD were determined based on research and standards. HPD-relevant correction factors were created using 1) deterministic methods and self-reported HPD use after filling gaps in the exposure history, or 2) a model of the determinants of use of HPD, then adjusting noise estimates according to the methods’ predictions and attenuation factors. For both methods, the HPD-adjusted and unadjusted noise exposure estimates were cumulated across all jobs each worker held in a cohort-participating lumber mill. Finally, these noise metrics were compared by examining how well each predicted hearing loss. Analyses controlled for gender, age, race as well as medical and non-occupational risk factors. Both methods led to a strengthening of the noise-hearing loss relationships compared to methods using HPD-unadjusted noise estimates. The method based on the modeling of HPD use had the best performance with a four-fold increase in the slope compared to the unadjusted noise-hearing loss slope. Accounting for HPD use in noise exposure assessment is necessary since we have shown that misclassification attenuated the exposure-response relationships. Exposure-response analyses subsequent to exposure reassessment provide predictive validity and gives confidence in the exposure adjustment methods. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate

During the twentieth century, trends in childlessness varied strongly across European countries while educational attainment grew continuously across them. Using census and large-scale survey data from 13 European countries, we investigated the relationship between these two factors among women born between 1916 and 1965. Up to the 1940 birth cohort, the share of women childless at age 40+ decreased universally. Afterwards, the trends diverged across countries. The results suggest that the overall trends were related mainly to changing rates of childlessness within educational groups and only marginally to changes in the educational composition of the population. Over time, childlessness levels of the medium-educated and high-educated became closer to those of the low-educated, but the difference in level between the two better educated groups remained stable in Western and Southern Europe and increased slightly in the East.

This thesis examined associations between ecological indicators of residential radon and fine particulate matter air pollution (PM2.5) and lung cancer mortality using data from the American Cancer Society Cancer Prevention Study-II (CPS-II) prospective cohort. Nearly 1.2 million CPS-II participants were recruited in 1982. Mean county-level residential radon concentrations were linked to study participants according to ZIP code information at enrollment (mean (SD) = 53.5 (38.0) Bq/m3). Cox proportional hazards regression models were used to obtain adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer mortality associated with radon. After necessary exclusions, a total of 811,961 participants in 2,754 counties were retained for analysis. A significant positive linear trend was observed between categories of radon concentrations and lung cancer mortality (p = 0.02). A 15% (95% CI 1 - 31%) increase in the risk of lung cancer mortality was observed per each 100 Bq/m3 radon. Radon was also positively associated with chronic obstructive pulmonary disease mortality (HR per each 100 Bq/m3 = 1.13, 95% CI 1.05 - 1.21). No clear associations were observed between radon and non-respiratory mortality. In lifelong never smokers (n = 188,699), each 10 µg/m3 increase in mean metropolitan statistical area PM2.5 concentrations was associated with a 15-27% increase in the risk of lung cancer death which strengthened among individuals with a history of asthma or any prevalent chronic lung disease at enrollment (p for interaction < 0.05). There was no association between PM2.5 and mortality from non-malignant respiratory disease. In conclusion, this thesis observed significant positive associations between ecological indicators of residential radon and PM2.5 concentrations and lung cancer mortality. These findings further support efforts to reduce radon concentrations in homes to the lowest possible level and strengthens the evidence that ambient concentrations of PM2.5 measured in recent decades are associated with small but measurable increases in lung cancer mortality. Further research is needed to better understand possible complex inter-relationships between environmental risk factors, chronic lung disease, and lung cancer.

In recent decades there has been a rekindling of academic interest in place, and with the way in which processes associated with modernity, globalisation and individualisation may have diminished place based communities, and weakened the attachment between individuals and the neighbourhoods in which they live. There are also debates about the importance of neighbourhood context, particularly whether neighbourhood level material deprivation and increased ethnic diversity act to reduce individual belonging to neighbourhoods and interactions between neighbours. This thesis aims to contribute towards an understanding of the ways in which individual belonging to neighbourhoods, and interaction with neighbours, may have changed over time, in relation to individual and neighbourhood context. Data from the British Household Panel Survey, for England, for the period 1998 to 2008, measuring the outcomes of individual level belonging to neighbourhoods and the likelihood of talking to neighbours, are combined with neighbourhood level Census data. Longitudinal models are used to test for age and cohort effects, and then extended to consider neighbourhood level context. Specific attention is given to the relationship between the outcomes under study and neighbourhood material deprivation, neighbourhood ethnic diversity, household income and individual mobility between neighbourhoods. Some evidence was found for cohort effects, with younger cohorts, particularly those in higher income households, being less likely to talk to neighbours. There were no apparent cohort effects for the outcome of belonging to the neighbourhood, which is found to be associated with age (generally increasing as individuals get older), and neighbourhood context. In materially deprived neighbourhoods levels of belonging are lower, but only for individuals in households with low incomes. Similarly any effect of individual mobility was found to be conditional on household income and neighbourhood level material deprivation. In general, high or increasing neighbourhood level ethnic diversity was not associated with reduced individual belonging to neighbourhoods or likelihood of talking to neighbours once other contextual variables were considered. Also, increased ethnic diversity had a small positive effect on the outcomes under study for individuals living in neighbourhoods with high levels of material deprivation.

Introduction : Le trouble dépressif majeur (TDM) représente un enjeu de Santé Publique. Aujourd’hui, il existe différents médicaments antidépresseurs (AD), mais 60% des patients déprimés ne répondent pas suffisamment à ce type de traitement. La pharmacogénétique (PG) se définit comme l’étude de la variabilité de la réponse aux médicaments associée à des variations génétiques des gènes de la pharmacodynamie ou de la pharmacocinétique. La médecine personnalisée utilise la PG pour améliorer la prise en charge des patients. La venlafaxine (VEN), AD fréquemment utilisé en psychiatrie, est métabolisée par les enzymes du Cytochrome P450 (CYP) 2D6 et 2C19. Elle augmente le turnover des monoamines cérébrales, qui sont catabolisées par la catechol-O-méthyltransférase (COMT). L'objectif de ce travail est d'identifier des biomarqueurs génétiques de réponse à la VEN qui pourraient être utilisés dans la pratique clinique psychiatrique. Ce travail présente deux études de gènes candidats, et une étude de panel de gènes basée sur une revue de la littérature. Méthodes : Deux cent six patients caucasiens souffrant d’un épisode dépressif majeur unipolaire (DSM-IVTR), nécessitant un nouveau traitement AD, issus de la cohorte METADAP et traités par VEN ont été étudiés. METADAP est une cohorte prospective d’une durée de 6 mois, multicentrique, naturaliste, en conditions réelles de prescription en psychiatrie. La dépression a été mesurée avec l’échelle de dépression de Hamilton à l’inclusion et après 1, 3 et 6 mois de traitement antidépresseur, permettant d’évaluer le pourcentage d’amélioration, la réponse et la rémission. Les patients ont été génotypés pour les polymorphismes génétiques ou Single Nucleotide Polymorphisms (SNP) majeurs du CYP2D6 et du CYP2C19 : allèles défectueux entraînant une déficience enzymatique complète (CYP2D6 *3 rs35742686, *4 rs3892097, *6 rs5030655, délétion du gène *5); (CYP2C19 *2 rs4244285, *3 rs4986893, *4 rs28399504, *5 rs56337013), allèles entraînant une diminution de l'activité enzymatique (CYP2D6 *10 rs1065852, CYP2D6*41 rs28371725), allèles associés à un métabolisme accéléré (duplication du gène CYP2D6*2xN) ; (CYP2C19 *17 rs12248560) et pour le polymorphisme de la COMT Val(108/158)Met, rs4680. La technique de discrimination allélique TaqMan a été utilisée. Les patients ont été classés selon le phénotype CYP2D6 et CYP2C19 en métaboliseurs lents, normaux, rapides, intermédiaires et ultrarapides et en 3 génotypes COMT Val(108/158)Met: Val/Val, Val/Met, Met/Met. Par ailleurs, 70 patients ont été séquencés en utilisant les technologies de séquençage à haut débit ou Next Generation Sequencing (NGS) MiSeq Illumina pour un panel de 70 gènes. Résultats : Dans cet échantillon, il n’existe pas d’association entre l’évolution de la dépression sous VEN et les SNPs que nous avons étudiés du CYP2D6, du CYP2C19 et de la COMT. Les données NGS sont en cours d’analyse. D’ores et déjà, la qualité des données a été validée par comparaison aux résultats de la discrimination allélique TaqMan des CYP. Suite à une revue de la littérature mettant en évidence l’importance des transporteurs OCTs (Organic Cation Transporter) et PMATs (Plasma Membrane Monoamine Transporter) dans le transport des monoamines et leur rôle dans la réponse aux AD, ces gènes seront intégrés dans la sélection du panel de gènes pour le NGS. Conclusion : Ce travail ne permet pas de recommander le génotypage des SNPs du CYP2D6, du CYP2C19 et de la COMT Val(108/158)Met en routine clinique psychiatrique chez les patients déprimés traités par VEN. Ce travail se poursuivra par l’analyse NGS qui tentera d’identifier des variants rares ou ultra-rares et pertinents, notamment pour des gènes qui n'ont pas été étudiés dans le TDM comme ceux des OCTs et PMATs. / Introduction: Major Depressive Disorder (MDD) represents an issue of Public Health. Currently, different antidepressant (AD) treatments exist, but 60% of depressed patients do not respond sufficiently to this type of treatment. Pharmacogenetics (PG) represents the study of the variability of response to a treatment associated to genetic variations identified in pharmacokinetic and pharmacodynamic genes. Personalized medicine is using PG to make the best therapeutic choice for a depressed patient. Venlafaxine (VEN), AD frequently used in psychiatry, is metabolized by the enzymes of Cytochromes P450 (CYP) 2D6 and 2C19. VEN increases the turnover of cerebral monoamines, which are catabolized by the cathecol-O-methyltransferase (COMT). The aim of this study is to identify genetic biomarkers of response to VEN that may be used in clinical practice in psychiatry. This work presents two candidate gene studies and a study of panel of genes based on a review of the literature. Methods : Two hundred and six Caucasian patients suffering from a unipolar major depressive episode (DSM-IVTR), requiring a new AD treatment, selected from METADAP cohort, treated by VEN have been studied. The METADAP cohort is a 6-month prospective, multicenter, real-world setting, treatment study in psychiatry. Depression was assessed by the Hamilton scale at the baseline and after 1, 3 and 6 months of AD treatment allowing the evaluation of the percentage of improvement, the response and the remission. Patients were genotyped for the major SNPs (Single Nucleotide Polymorphisms) of CYP2D6 and CYP2C19: loss of function alleles (CYP2D6 *3 rs35742686, *4 rs3892097, *6 rs5030655, the complete gene deletion *5); (CYP2C19 *2 rs4244285, *3 rs4986893, *4 rs28399504, *5 rs56337013); increased function alleles (gene duplication CYP2D6*2xN); (CYP2C19 *17 rs12248560); decreased function alleles (CYP2D6 *10 rs1065852, CYP2D6*41 rs28371725) and COMT Val(108/158)Met, rs4680. The TaqMan allelic discrimination technology was used. Accordingly to the CYP2D6 and CYP2C19 phenotype, the patients were classified in: poor, normal, extensive, intermediate, and ultra-rapid metabolizers and respectively 3 COMT Val(108/158)Met genotypes : Val/Val, Val/Met, Met/Met. Furthermore, 70 patients were sequenced using Next Generation Sequencing (NGS) technologies of MiSeq Illumina for a panel of 70 genes. Results : No association between the evolution of depression of patients treated by VEN and the SNPs of CYP2D6, of CYP2C19 and of COMT was showed in this sample. The NGS data is being analyzed. Le quality of the NGS data has been validated by comparing the results to the TaqMan allelic discrimination of the CYP. Following the review of the literature showing the importance of the OCTs (Organic Cation Transporter) and PMATs (Plasma Membrane Monoamine Transporter) transporters in the transport of monoamines and their role in the AD response, these genes will be integrated in the selection of the panel of genes for the NGS study. Conclusion: This work shows that routine genotyping of the SNPs of CYP2D6, of CYP2C19 and of COMT Val(108/158) Met cannot be recommended in clinical practice in psychiatry for depressed patients treated by VEN. This work will continue with the NGS analyses that will attempt to identify relevant, rare and very rare variants, in particular for genes that have not been studied in a context of MDD such as OCTs and PMATs.

京都大学 / 0048 / 新制・論文博士 / 博士(社会健康医学) / 乙第13293号 / 論社医博第14号 / 新制||社医||10(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 松田 秀一, 教授 今中 雄一, 教授 古川 壽亮 / 学位規則第4条第2項該当 / Doctor of Public Health / Kyoto University / DFAM

No description available.

No description available.

博士（経済学） / 甲第457号 / 124p / Hitotsubashi University

Objective: The Paducah Gaseous Diffusion Plant (PGDP) became operational in 1952; it is located in the western part of Kentucky. We conducted a mortality study for adverse health effects that workers may have suffered while working at the plant, including exposures to chemicals. Materials and Methods: We studied a cohort of 6820 workers at the PGDP for the period 1953 to 2003; there were a total of 1672 deaths to cohort members. Trichloroethylene (TCE) is a specific concern for this workforce; exposure to TCE occurred primarily in departments that clean the process equipment. The Life Table Analysis System (LTAS) program developed by NIOSH was used to calculate the standardized mortality ratios for the worker cohort and standardized rate ratio relative to exposure to TCE (the U.S. population is the referent for age-adjustment). LTAS calculated a significantly low overall SMR for these workers of 0.76 (95% CI: 0.72-0.79). A further review of three major cancers of interest to Kentucky produced significantly low SMR for trachea, bronchus, lung cancer (0.75, 95% CI: 0.72-0.79) and high SMR for Non-Hodgkin's lymphoma (NHL) (1.49, 95% CI: 1.02-2.10). Results: No significant SMR was observed for leukemia and no significant SRRs were observed for any disease. Both the leukemia and lung cancer results were examined and determined to refect regional mortality patterns. However, the Non-Hodgkin's Lymphoma finding suggests a curious amplification when living cases are included with the mortality experience. Conclusions: Further examination is recommended of this recurrent finding from all three U.S. Gaseous Diffusion plants.