[Surveillance and detection of unusual events in toxicovigilance: Review of relevant methods]. / Surveillance et détection des événements inhabituels en toxicovigilance : revue des méthodes pertinentes.

BACKGROUND: Declared cases of exposures related to potential toxic agents are reported through a national database, the French Network of Poison Centers, and account on average for 200,000 cases per year, including 75,000 to 80,000 symptomatic cases. These data are currently used to investigate signals from local, national or international institutional partners (such as hospitals, local health authorities, and the Rapid Alert System for Food and Feed). Our objective is to complete this classical toxicovigilance activity through the automated detection of unexpected or unusual events in order to identify precociously signals representing potential threats for public health. To reach this objective, the inventory of surveillance and detection methods of unexpected events is necessary. METHODS: A literature review was conducted via Scopus(®) and Pubmed(®) databases, completed with grey literature and data available on worldwide vigilance systems' websites. RESULTS: The most commonly used methods are disproportional measures in the field of pharmacovigilance, some of which are subject to a routine detection at regular time intervals. Criteria of signal generation differ from one system to another, which have implemented data filtering strategies before or after analysis, in order to decrease the number of generated signals and improve their priority level. These signals are then transmitted to an experts committee for a clinical and epidemiological evaluation, and at times, for informing the patient's medical records. We also notice an interest in other approaches such as surveillance methods of temporal series or symbolic methods for associative rules extraction between one or more drugs and one or more adverse effects, with the possibility to include other types of variables, such a demographic data. The developments of probabilistic-based algorithms have also been recently developed, opening new opportunities. CONCLUSION: These surveillance and detection methods are of high interest for the automated detection of signals from the French toxicovigilance network. The initial step to developing these methods consists in studying the statistical quality of data and targeting the needs and expectations of the toxicovigilance network for what we want and what we can detect.

[Study of self-reported health of people living near point sources of environmental pollution: a review. First part: health indicators]. / Étude de la santé déclarée par les personnes riveraines de sources locales de pollution environnementale : une revue de la littérature. Première partie : les indicateurs de santé déclarée.

BACKGROUND: Epidemiological studies have investigated the health impacts of local sources of environmental pollution using as an outcome variable self-reported health, reflecting the overall perception interviewed people have of their own health. This work aims at analyzing the advantages and the results of this approach. A first step focused on describing the indicators. METHODS: The literature on indicators of self-reported health was reviewed, leading to a discussion on data collection, selection of health effects, data processing, and construction of indicators. RESULTS: The literature review concerned 51 articles. The use of self-reported health indicators allowed the studies to take into account the health concerns and complaints of populations exposed to environmental pollution. Various indicators of self-reported health were used in the studies. They measured physical, psychological and general dimensions of health. Standardized questionnaires were used less often than ad hoc questionnaires (78% of studies) developed to fit the needs of a given study. Three standardized questionnaires were used more frequently: the MOS Short-Form Health Survey (SF-36) to measure general health perceptions, the General Health Questionnaire (GHQ), and the Symptoms Checklist (SCL-90) to measure psychological distress. CONCLUSION: The choice of self-reported health indicators is a compromise between specificity of the studied health issues within a given environment and standardization of the questionnaires used to measure them. Such standardization is necessary to ensure the validity and the reliability of the information collected across time and situations. The psychometric properties of the measuring questionnaires are rarely estimated or verified when they are used.

[Study of self-reported health of people living near point sources of environmental pollution: a review. Second part: analysis of results and perspectives]. / Étude de la santé déclarée par les personnes riveraines de sources locales de pollution environnementale : une revue de la littérature. Seconde partie : analyse des résultats et perspectives.

BACKGROUND: Epidemiological studies have investigated the health impacts of local sources of environmental pollution using as an outcome variable self-reported health, reflecting the overall perception interviewed people have of their own health. This work aims at analyzing the advantages and the results of this approach. This second part presents the results of the studies. METHODS: Based on a literature review (51 papers), this article presents an analysis of the contribution of self-reported health to epidemiological studies investigating local sources of environmental pollution. It discusses the associations between self-reported health and exposure variables, and other risk factors that can influence health reporting. RESULTS: Studies using self-reported health showed that local sources can be associated with a wide range of health outcomes, including an impact on mental health and well-being. The perception of pollution, especially sensory information such as odors, affects self-reported health. Attitudes referring to beliefs, worries and personal behaviors concerning the source of pollution have a striking influence on reported health. Attitudes can be used to estimate the reporting bias in a biomedical approach, and also constitute the main explanatory factors in biopsychosocial studies taking into account not only the biological, physical, and chemical factors but also the psychological and social factors at stake in a situation of environmental exposure. CONCLUSION: Studying self-reported health enables a multifactorial approach to health in a context of environmental exposure. This approach is most relevant when conducted within a multidisciplinary framework involving human and social sciences to better understand psychosocial factors. The relevance of this type of approach used as an epidemiological surveillance tool to monitor local situations should be assessed with regard to needs for public health management of these situations.

["Veille sanitaire": tools, functions, process of healthcare monitoring in France]. / Veille sanitaire : outils, fonctions, processus.

In France, the term "veille sanitaire" is widely used to designate healthcare monitoring. It contains, however, a set of concepts that are not shared equally by the entire scientific community. The same is true for activities that are part of it, even if some (surveillance for example) are already well defined. Concepts such as "observation", "vigilance", "alert" for example are not always clear. Furthermore, the use of these words in everyday language maintains this ambiguity. Thus, it seemed necessary to recall these definitions as already used in the literature or legislation texts and to make alternative suggestions. This formalization cannot be carried out without thinking about the structure of "veille sanitaire" and its components. Proposals are provided bringing out concepts of formated "veille" (monitoring) and non-formatted "veille" (monitoring). Definitions, functions, (methods and tools, processes) of these two components are outlined here as well as the cooperative relationship they sustain. The authors have attempted to provide the scientific community with a reference framework useful for exchanging information to promote research and methodological development dedicated to this public health application of epidemiology.

Main clinical, therapeutic and technical factors related to patient's maximum skin dose in interventional cardiology procedures.

OBJECTIVE: The study aimed to characterise the factors related to the X-ray dose delivered to the patient's skin during interventional cardiology procedures. METHODS: We studied 177 coronary angiographies (CAs) and/or percutaneous transluminal coronary angioplasties (PTCAs) carried out in a French clinic on the same radiography table. The clinical and therapeutic characteristics, and the technical parameters of the procedures, were collected. The dose area product (DAP) and the maximum skin dose (MSD) were measured by an ionisation chamber (Diamentor; Philips, Amsterdam, The Netherlands) and radiosensitive film (Gafchromic; International Specialty Products Advanced Materials Group, Wayne, NJ). Multivariate analyses were used to assess the effects of the factors of interest on dose. RESULTS: The mean MSD and DAP were respectively 389 mGy and 65 Gy cm(-2) for CAs, and 916 mGy and 69 Gy cm(-2) for PTCAs. For 8% of the procedures, the MSD exceeded 2 Gy. Although a linear relationship between the MSD and the DAP was observed for CAs (r=0.93), a simple extrapolation of such a model to PTCAs would lead to an inadequate assessment of the risk, especially for the highest dose values. For PTCAs, the body mass index, the therapeutic complexity, the fluoroscopy time and the number of cine frames were independent explanatory factors of the MSD, whoever the practitioner was. Moreover, the effect of technical factors such as collimation, cinematography settings and X-ray tube orientations on the DAP was shown. CONCLUSION: Optimising the technical options for interventional procedures and training staff on radiation protection might notably reduce the dose and ultimately avoid patient skin lesions.

Modelling the effect of breast cancer screening on related mortality using French data.

INTRODUCTION: This study aimed at modelling the effect of organized breast cancer screening on mortality in France. It combined results from a Markov model for breast cancer progression, to predict number of cases by node status, and from relative survival analyses, to predict deaths. The method estimated the relative risk of mortality at 8 years, in women aged 50-69, between a population screened every two years and a reference population. METHODS: Analyses concerned cases diagnosed between 1990 and 1996, with a follow-up up to 2004 for the vital status. Markov models analysed data from 3 screening programs (300,000 mammographies) and took into account opportunistic screening among participants to avoid bias in parameter's estimates. We used survival data from cancers in the general population (n=918, 7 cancer registries) and from screened cancers (n=565, 3 cancer registries), after excluding a subgroup of screened cases with a particularly high survival. Sensitivity analyses were performed. RESULTS: Markov model main analysis lacked of fit in two out of three districts. Fit was improved in stratified analyses by age or district, though some lack of fit persisted in two districts. Assuming 10% or 20% overdiagnosed screened cancers, mortality reduction was estimated as 23% (95% CI: 4, 38%) and 19% (CI: -3, 35%) respectively. Results were highly sensitive to the exclusion in the screened cancers survival analysis. Conversely, RR estimates varied moderately according to the Markov model parameters used (stratified by age or district). CONCLUSION: The study aimed at estimating the effect of screening in a screened population compared to an unscreened control group. Such a control group does not exist in France, and we used a general population contaminated by opportunistic screening to provide a conservative estimate. Conservative choices were systematically adopted to avoid favourable estimates. A selection bias might however affect the estimates, though it should be moderate because extreme social classes are under-represented among participants. This modelling provided broad estimates for the effect of organized biennial screening in France in the early nineteen-nineties. Results will be strengthened with longer follow-up.

Multi-state Markov models in cancer screening evaluation: a brief review and case study.

This work presents a brief overview of Markov models in cancer screening evaluation and focuses on two specific models. A three-state model was first proposed to estimate jointly the sensitivity of the screening procedure and the average duration in the preclinical phase, i.e. the period when the cancer is asymptomatic but detectable by screening. A five-state model, incorporating lymph node involvement as a prognostic factor, was later proposed combined with a survival analysis to predict the mortality reduction associated with screening. The strengths and limitations of these two models are illustrated using data from French breast cancer service screening programmes. The three-state model is a useful frame but parameter estimates should be interpreted with caution. They are highly correlated and depend heavily on the parametric assumptions of the model. Our results pointed out a serious limitation to the five-state model, due to implicit assumptions which are not always verified. Although it may still be useful, there is a need for more flexible models. Over-diagnosis is an important issue for both models and induces bias in parameter estimates. It can be addressed by adding a non-progressive state, but this may provide an uncertain estimation of over-diagnosis. When the primary goal is to avoid bias, rather than to estimate over-diagnosis, it may be more appropriate to correct for over-diagnosis assuming different levels in a sensitivity analysis. This would be particularly relevant in a perspective of mortality reduction estimation.

[Prolonged exposure to atmospheric air pollution and mortality from respiratory causes]. / Exposition prolongée à la pollution atmosphérique et mortalité par pathologies respiratoires.

Different designs can be used to analyze the relationships between respiratory mortality and long term exposure to atmospheric pollution: epidemiological studies (cohort, prevalence study) demonstrate the reality of the relationship and toxicological studies explain it. Cohort studies have the advantage of being able to take into account many confounding factors and thus avoid biases (which is not the case with prevalence studies), but require significant human and financial resources. They were first adopted in the US, but are now more often applied in Europe. The results are relatively consistent, as they all show a statistically significant association between an increase in particulate pollution and cardiopulmonary mortality. Mortality from lung cancer is also associated with long term exposition to particles and sometimes to ozone or nitrogen oxides. Cerebrovascular diseases and sudden death of young children have also been associated with particulate pollution. The relationships are more powerful for long term than short term exposure but are also linear and without threshold. In order to explain these effects (today the causality of the relationship is certain) there are many possible factors, particularly regarding particulate exposures: an increase in cardiovascular risk biomarkers (fibrinogen, white blood cells, and platelets), atherosclerosis, chronic inflammation of lung tissues increased by acute exposure, etc. More and more studies address the interaction between gene and environment and even epigenetic phenomena which could be responsible of these effects. Public Health impact could be quantified. The European E&H surveillance program Apheis, for example, estimated that if PM2.5 levels remained below 15 microg/m(3), a 30 year old person could see his life expectancy increased by 1 month to 2 years, depending on the studied city. Finally, mortality is not the only relevant indicator for health effects of air pollution. ISAAC studies address asthma, allergic rhinitis and eczema among children.

[Incidence of lung cancer in Bas-Rhin, France: trends and projection for 2014]. / Incidence du cancer du poumon dans le Bas-Rhin: tendance et projections en 2014.

INTRODUCTION: In France lung cancer is the second most common cancer in men and the fourth most common in women. In the department of Bas-Rhin the incidence is increasing by 0.1% per annum in men and by 4.4% in women. The aim is to analyse and predict the trend of lung cancer incidence in Bas-Rhin from 1975 to 2014. METHODS: The incidence data from 1975 to 1999 were extracted from the Bas-Rhin cancer registry. Population estimates (2594 years) were made for the period 1975-2014. Predictions were based on a Bayesian age-period-cohort model. RESULTS: Between 1975 and 1999 the incidence of lung cancer increased by 4.5% p.a. in women. In men it increased by 1.6% p.a. between 1975 and 1989 and then diminished. For the periods 2000-2004, 2005-2009 and 2010-2014 respectively the rates should reach 25.6, 32.9 and 42.8 per 100,000 in women and 117.5, 111.6 and 110.1 per 100,000 in men. CONCLUSIONS: Increasing tobacco smoking among women and a reduction among men could be one of the reasons for the respective increasing and decreasing incidences.

Deaths from chronic obstructive pulmonary disease in France, 1979-2002: a multiple cause analysis.

BACKGROUND: A study was undertaken of deaths with an underlying or associated cause of chronic obstructive pulmonary disease (COPD), and trends in COPD mortality from 1979 to 2002 in France were analysed. METHODS: Data were obtained from the Centre of Epidemiology on the Medical Causes of Death (CépiDc) for individuals aged 45 years and over. Owing to implementation of ICD-10 in 2000 for recording causes of death, two separate periods were analysed (1979-99 and 2000-2). RESULTS: In 2000-2, COPD was the underlying cause of 1.4% of deaths (deaths from COPD) and was mentioned on the death certificate in 3.0% (deaths with COPD). The other main underlying causes in these cases were cardiovascular diseases (32.0%) and cancers (24.5%). In 1979-99, age standardised rates of death with COPD remained stable in men (-0.01%/year) and increased in women (+1.7%/year). The mean annual rates of death with COPD per 100 000 were 84 for men and 19 for women in 2000-2. CONCLUSION: Multiple cause analysis improved the estimate of COPD related mortality. In 1979-99, COPD related mortality rates in France were stable in men but increased in women. Implementation of ICD-10 in 2000 introduced substantial discontinuities in mortality trends.

[Estimating mortality attribuable to PM10 particles in 9 French cities participating in the European programme Apheis]. / Estimation de la mortalité attribuable aux particules (PM10) dans les 9 villes françaises participant au programme européen Apheis.

The relationship between air pollution and mortality is now admissible with a sufficiently high level of causality proven. This link allows for health impact assessment to be carried out with a significant degree of accuracy, such as the case for the results which are presented here from the nine French cities involved in the Apheis programme. This health impact assessment is based on the methodology developed by the World Health Organization. The number of avoidable deaths is contained between categories ranging from 2.0 to 4.3, 4.0 to 8.9, and from 15.0 to 31.5 per 100,000 inhabitants according to very short term effects, short term effects and long term effects, respectively. There are two scenarios which can be envisioned for the reduction of fine particles levels which are capable of obtaining similar results for both very short term and short term effects. The first involves diminishing the daily concentrations which are above 20 microg/m3 until they reach this value, and the second entails systematically decreasing the daily levels by 5 microg/m3. The first strategy of reducing values to stabilize at 20 microg/m3 has been shown to be the one most favourable and promising for the long term effects. This strategy therefore confirms the reliability and strength of the recommendation formulated at the national level.

[Lung cancer mortality among women in France. Trend analysis and projection between 1975 and 2014, with a bayesian age-cohort model]. / Mortalité par cancer du poumon chez les femmes françaises. Analyse de tendance et projection à l'aide d'un modèle âge-cohorte bayésien, de 1975 à 2014.

BACKGROUND: With 4,500 deaths in year 2000, female lung cancer mortality rates increased by 3% every year over the last two decades in France. This trend, not observed among males, is attributed to the regular increase of female smoking. In order to answer French Health decider's concerns, we estimated the future female lung cancer mortality rates and numbers of deaths for the next fifteen years, in France and its regions. METHODS: Analyses were based on numbers of female deaths from lung cancer observed between 1975 and 1999, and on past and future population estimates for 1975-2014, at national and regional levels. Mortality rates and numbers of deaths in France and its regions by 5-year periods and 5-year age groups were given in the 1975-1999 death certificate data base, and were projected for 2000-2014. The analysis used a bayesian approach of the age-cohort model with auto-regressive constraints on parameters. Estimated mortality rates were standardized on truncated 20-85 + world population. RESULTS: French female lung cancer mortality increased by 3% every year between 1975 and 1999. In period 1995-1999, truncated 20-85 + mortality rates, and number of deaths per year were respectively 11.4 per 100,000 and 4,000. Mortality rates increased in all regions but variations were maximum in Corsica (+ 314%) and minimum in Auvergne (+ 37%). For the whole of France, the estimated truncated 20-85 + standardized rate, was respectively, 14.1 and 22.5 per 100,000 in period 2000-04 and period 2010-14, which represents a 60% increase between these two time periods. At the regional level, the maximum variation was found in Languedoc-Roussillon (107%), the minimum in Nord-Pas-de-Calais (40%). CONCLUSIONS: The bayesian approach of the age-cohort model is increasingly used because it produces stable projections, without having to include other cancer parameters. Nevertheless, it would be interesting to extend this model by incorporating a tobacco consumption component, in order to assess scenarios based on consumption decreases.

[The impact of air pollution on health. The "Programme de Surveillance Air et Santé 9 villes" (Air and Health surveillance program in 9 cities)]. / Retentissement de la pollution atmosphérique sur la santé. Le Programme de Surveillance Air et Santé 9 villes.

OBJECTIVES: To quantify the short term effects of air pollution on mortality and hospitalisation for cardiovascular or respiratory disorders in the nine French cities (Bordeaux, Le Havre, Lille, Lyon, Marseille, Paris, Rouen, Strasbourg and Toulouse) of the Surveillance Air et Santé program. METHODS: Data were available on mortality and hospitalisation were available, respectively, from 1990 to 1997 and 1995 to 1999. Exposure data were the concentrations of sulphur dioxide, particles with a diameter of less than or equal to 10 mm, black smoke, nitrogen dioxide, ozone, and carbon monoxide. The analysis assessed the relationships, in each of the cities, between the daily numbers of deaths and hospitalisations and the daily levels of polluting agents, taking into account confounding factors. A combined relative risk was calculated for all the cities. The number of deaths and hospitalisations attributable to air pollution was then estimated for each of the cities, based on the relative risk. RESULTS: Significant relationships were found for mortality, from whatever cause, and for hospitalisations for respiratory disorders in children aged under 15. If the levels of air pollution were reduced to 10 microg/m3 in the nine cities, 2800 premature deaths and 750 hospitalisations for respiratory disorders in children would be avoided, every year. CONCLUSION: Today, it is possible to assess the benefits of reducing air pollution in terms of health in the short term. These analyses would provide a sanitary dimension to the strategies for the reduction of urban pollution on local and European level.

[Air pollution and cardiovascular toxicity: known risks]. / Particules atmosphériques urbaines et toxicité cardiovasculaire: des risques de mieux en mieux connus.

SUBJECT: Review of studies about epidemiological and physiopathological knowledge of ambient air particles short-term cardio-vascular effects. CURRENTS AND STRONG POINTS: Many studies, in contrasted countries for pollution's sources, meteorological conditions or socio-demographical characteristics, have shown health effects due to ambient air particles. After having studied mainly the respiratory effects of particulate air pollution, epidemiologists are now interested in the cardio-vascular effects of ambient air particles. In fact, serious effects seem to exist in fragile people which can get to emergency department visits, hospitalisation and even death. In addition, studies have shown less serious effects, but likely to be frequent (cardiac symptoms, and stoppages for cardio-vascular causes, notably). The exact mechanism by which particles have cardio-vascular adverse health effects is unknown, but experimental and epidemiological studies have led to several hypotheses: local pulmonary effects seem to be followed by systemic effects, which would be responsible for effects on the electrical activity of the heart through cardiac autonomic dysfunction and effects on the blood supply to the heart. The objective of this work is to summarise epidemiological and physiopathological knowledge about the cardio-vascular effects of ambient air particles. PROSPECTS AND PROJECTS: To evaluate the real importance of cardio-vascular effects due to particulate air pollution and to identify their exact mechanism, a more precise knowledge of detailed causes of deaths and hospitalisations and a better knowledge of less serious effects, but likely to be frequent, is necessary. Equally, a detailed identification of fragile people is essential for developing preventive actions.

[Cervical cancer in Bas-Rhin: trend and prediction of the incidence in 2014]. / Cancer du col de l'utérus dans le Bas-Rhin: tendance et projection de l'incidence jusqu'en 2014.

BACKGROUND: In the world, the cervix cancer is the second commonest cancer in women. Its incidence is decreasing but it is still too frequent. The aim of this study was to predict the incidence of cervix cancer among women in the Department of Bas-Rhin. METHODS: Incidence data were provided by the Bas-Rhin Tumor Registry. The incidence of in situ tumors and invasive cancers was predicted in 2010-2014 by using an age - period - cohort model and a Bayesian approach. RESULTS: The incidence rates predicted by the model, standardized to the European population, were 99.7 per 10(5)population in 2000-2004 (CI 95%: [82.7-118.5]) and 177.1 per 10(5) population in 2010-2014 (CI 95%: [103.7-288.5]) for in situ and 13.0 per 10(5) population (CI 95%: [9.5-17.2]) in 2000-2004 and 11.1 per 10(5)population (CI 95%: [4.5-22.7]) in 2010-2014 for invasive tumors. CONCLUSIONS: The decrease of invasive tumors is due to screening. The improvement of the quality of the screening and treatment of in situ tumors would allow the number of incident cases of cervix cancer to decrease.

[Short-term relationships between urban atmospheric pollution and respiratory mortality: time series studies]. / Relations à court terme entre la pollution atmosphérique urbaine et la mortalité respiratoire: la place des études temporelles.

Time series studies conducted in the field of air pollution aim at testing and quantifying short-term relations which can exist between daily air pollution levels and daily health effects. The method used for this type of survey has sometimes been misunderstood mainly because individual factors and indoor exposure to air pollutants were not taken into account. The adjustment on these individual confounding factors commonly used in classic epidemiologic studies (case-control studies, cohort studies) is not adequate to times series studies which are based on aggregate data. This is different for those factors that change over time according to the levels of air pollution (meteorological conditions, influenza epidemics, trend of health cases) which, when being analysed, must be taken into account either indirectly through time modelling or directly through non-linear modelling processes. During this last decade, numerous studies using the time series method have been published and have found short-term associations between daily levels of air pollution commonly observed and daily respiratory mortality. The consistency of the numerous results published in the international literature are more arguments in favour of non-confounding short-term relations between air pollution and respiratory mortality.

[Surveillance of short-term effects of urban air pollution on mortality. Results of a feasibility study in 9 French cities]. / Surveillance des effets à court terme de la pollution atmosphérique sur la mortalité en milieu urbain. Résultats d'une étude de faisabilité dans 9 villes françaises.

BACKGROUND: This study aims at quantifying air pollution effects on mortality and at evaluating the feasibility of a standardized epidemiological surveillance system of air pollution in 9 French cities. METHODS: Data collection and analysis followed a standardized protocol. Data pollution depended on the development of local air quality surveillance networks (number of indicators, number of stations.). The Generalised Additive Models (GAM) were used to quantify the association between air pollution and mortality. RESULTS: In the 9 studied areas, associations between all causes, cardiovascular and respiratory mortality, and air pollution indicators were observed. These associations were linear without threshold. Depending on the pollutants, excess in mortality related to an interquartile increase in acid-particulate pollution varied between 0.3 and 3.5% for total mortality, 0.5 and 6.3% for cardiovascular mortality, and between 0.1 and 12% for respiratory mortality. Photochemical air pollution varied between 0.4 and 7.3% for total mortality, 1.4 and 6.7% for cardiovascular mortality, and between 1.7 and 30.4% for respiratory mortality. CONCLUSION: In spite of a standardized common protocol, some disparities, inherent to the local characteristics, were noted (length of time series, numbers of ambient urban stations selected and pollutants available.). Nevertheless, this pilot study showed that multicentric epidemiological monitoring of air pollution effects on health was feasible. Yet, this requires to validate the results obtained through a re-analysis of the mortality data on a longer period of study. It also requires to study the feasibility and the relevance of the use of other health indicators, such as hospital admissions.