Dynamics of the risk of smoking-induced lung cancer: a compartmental hidden Markov model for longitudinal analysis.

BACKGROUND: To account for the dynamic aspects of carcinogenesis, we propose a compartmental hidden Markov model in which each person is healthy, asymptomatically affected, diagnosed, or deceased. Our model is illustrated using the example of smoking-induced lung cancer. METHODS: The model was fitted on a case-control study nested in the European Prospective Investigation into Cancer and Nutrition study, including 757 incident cases and 1524 matched controls. Estimation was done through a Markov Chain Monte Carlo algorithm, and simulations based on the posterior estimates of the parameters were used to provide measures of model fit. We performed sensitivity analyses to assess robustness of our findings. RESULTS: After adjusting for its impact on exposure duration, age was not found to independently drive the risk of lung carcinogenesis, whereas age at starting smoking in ever-smokers and time since cessation in former smokers were found to be influential. Our data did not support an age-dependent time to diagnosis. The estimated time between onset of malignancy and clinical diagnosis ranged from 2 to 4 years. Our approach yielded good performance in reconstructing individual trajectories in both cases (sensitivity >90%) and controls (sensitivity >80%). CONCLUSION: Our compartmental model enabled us to identify time-varying predictors of risk and provided us with insights into the dynamics of smoking-induced lung carcinogenesis. Its flexible and general formulation enables the future incorporation of disease states, as measured by intermediate markers, into the modeling of the natural history of cancer, suggesting a large range of applications in chronic disease epidemiology.

Environmental triggers of nocturnal dry cough in infancy: new insights about chronic domestic exposure to formaldehyde in the PARIS birth cohort.

Although formaldehyde is a common indoor pollutant, its impact on respiratory symptoms in childhood remains unclear. The aim of this study was to examine the relation between domestic formaldehyde exposure and occurrence of coughing, one of the most prevalent respiratory symptoms during the first year of life of infants from the PARIS birth cohort involving 3840 healthy full-term babies. The presence of respiratory symptoms, including dry cough at night apart from a cold or chest infection in the past 12 months was reported on a standardized health questionnaire. Formaldehyde exposure was estimated for all infants using a predictive model established from data (both repeated measurements and information about determinants of levels) collected in a random sample of infants from the cohort. An unconditional logistic regression was fitted to study the relation between annual domestic formaldehyde exposure and dry cough at night, adjusting for all potential risk factors/confounders. The prevalence of dry cough at night was 14.9%. Parental history of allergy was found to modify the relation between environmental factors and dry cough. Cockroaches, used mattresses, and family stressor events were associated with dry cough in infants with parental allergy history. Conversely, domestic formaldehyde exposure tended to increase occurrence of dry cough at night only among babies without parental history of allergy (adjusted OR per 10 µg/m(3) increase in levels, single imputation approach: 1.45, 95% CI: 1.08-1.96, and Bayesian approach: 1.12, 0.91-1.36). This study suggests that the impact of indoor environmental exposure on dry cough at night in infancy is different depending on the presence or not of parental history of allergy.

Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: a Mechanisms of the Development of Allergy (MeDALL) seminar.

Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human in vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL.

Determinants of serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls among French women in the CECILE study.

BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are persistent organochlorine compounds bioaccumulating in human tissues. Body burden of organochlorines may be influenced by individual characteristics such as age, weight variations, breastfeeding, dietary habits and place of residence. OBJECTIVES: To assess the current serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the main DDT breakdown product, and of PCBs in women from two French administrative areas (Ille-et-Vilaine and Côte d'Or). To identify determinants of the current serum levels among individual characteristics related to intake, metabolism, and excretion of organochlorines. METHODS: We measured serum p,p'-DDE and PCB levels in 1055 general population women who were recruited in 2005-2007 to serve as controls in a case-control study on breast cancer. Associations between organochlorine levels and age, current body mass index (BMI), BMI change during the last 10 years, dietary habits, breastfeeding history, residence area and education were assessed in multivariate analyses. RESULTS: Median concentrations of p,p'-DDE and total PCBs were 85 and 240ng/g lipid, respectively. Based on multivariate analyses, the main predictors of high p,p'-DDE levels included age and frequent consumption of saltwater fish in women below 50 years, and high BMI in older women. Total PCB levels increased markedly with age. Among older women, other important predictors of high PCB levels included frequent consumption of saltwater fish and low BMI. Our results are also suggestive of an inverse association between PCB levels and BMI gain during the last ten years. Women in Côte d'Or had significantly higher PCB levels than women in Ille-et-Vilaine. CONCLUSION: The patterns of associations between determinants and serum organochlorine concentrations suggest that human PCB contamination is still ongoing in France. The most important predictors of serum p,p'-DDE and PCB concentrations among French women include age, body mass index, dietary habits, and place of residence.

Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999).

Thyroid cancer incidence in New Caledonia is the highest reported in the world and is approximately 10-fold higher than in most developed countries. We describe the incidence patterns in this country according to histological and sociodemographic characteristics to give clues about potential etiologic factors. Another objective is to see whether the incidence figures are related to enhanced detection of small size carcinomas. The study included all 498 cases of thyroid cancer diagnosed in 1985-1999. Pathology reports were systematically reviewed to determine the histological type of the tumor and the size of the cancerous nodules. The incidence of carcinomas < or =10 mm was taken as an indicator of enhanced detection due to improved screening procedures. The age-standardized incidence rates in 1985-1999 were exceptionally high in Melanesian women (71.4/100,000) and men (10.4/100,000). The incidence increased three-fold in women from 1995 onwards. The increase in incidence was more striking for papillary carcinomas < or =10 mm than for large size carcinomas, but an increased incidence of carcinomas >10 mm was also observed among women. The analysis by municipality of residence in Melanesian women showed that the incidence was twice as high in 1995-1999 in the Loyalty Islands as in the rest of the country. The sharp increase of thyroid cancer incidence in 1985-1999 in New Caledonia was partly related to enhanced detection of small size carcinomas. The elevated incidence of thyroid cancers, as well as the ethnic and geographic disparities, may result from common environmental or lifestyle risk factors that need to be identified.

Robustness of the BYM model in absence of spatial variation in the residuals.

BACKGROUND: In the context of ecological studies, the Bayesian hierarchical Poisson model is of prime interest when studying the association between environmental exposure and rare diseases. However, adding spatially structured extra-variability in the model fitted to the data when such extra-variability does not exist conditionally on the covariates included in the model (over-fitting) may bias the estimation of the ecological association between covariates and relative risks toward the null. In order to investigate that possibility, a simulation study of the impact of introducing unnecessary residual spatial structure in the estimation model was conducted. RESULTS: In the case where no underlying extra-variability from the Poisson process exists, the simulation results show that models accounting for structured and unstructured residuals do not underestimate the ecological association, unless covariates have a very strong autocorrelation structure, i.e., 0.98 at 100 km on a territory of diameter 1000 km."

Increases of SET level and translocation are correlated with tau hyperphosphorylation at ser202/thr205 in CA1 of Ts65Dn mice.

SET is a multifunctional protein, but when present in the cytoplasm, acts as a powerful inhibitor of phosphatase 2A. We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, and SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205. The presence of SET in the cytoplasm in DS brains may play a role in the progression of the disease. Here, we show that in CA1 of 3-month-old Ts65Dn mice modeling DS, SET level is increased, and SET is translocated to the cytoplasm and associated with tau hyperphosphorylations at ser202/thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains. Tau hyperphosphorylation at ser356 and activation of other phosphatase 2A targets such as the mammalian target of rapamycin and adenosine monophosphate protein kinases were also observed, suggesting deleterious mechanisms. We propose Ts65Dn mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation to slow down disease progression.

Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants.

BACKGROUND: The perinatal prophylactic administration of zidovudine is associated with rapidly reversible macrocytic anemia in infants. However, a recent study suggests that there may be more persistent inhibition of hematopoïetic stem cells. OBJECTIVE: To study hematopoiesis in uninfected infants, born to HIV-1 seropositive mothers, including those exposed and those not exposed to perinatal zidovudine alone or in combination. METHODS: Longitudinal study, from 0 to 18 months, of hemoglobin, platelets, polynuclear neutrophils, total lymphocytes, and CD4+ and CD8+ lymphocytes in more than 4000 infants of the French Perinatal Study. Modeling of repeated measures and non-linear evolution with age, with models combining natural cubic B-splines and random effects. RESULTS: The hemoglobin level was transiently reduced in newborns exposed to zidovudine. Multivariate analysis taking into account age, prematurity, geographical origin, maternal drug use and maternal CD4 cell count, indicated that levels of the three other lineages were slightly lower until age 18 months in exposed than not exposed infants (P < 0.0001 for each lineage). There was a negative relationship between the duration of exposure and each hematological variable. Combinations of antiretroviral treatments were associated with larger decreases than monotherapy up to 15 months of age. Similar, but less pronounced, patterns were found for the CD4+ and CD8+ subpopulations of lymphocytes. CONCLUSIONS: Zidovudine administered during the perinatal period may result in a small but significant and durable effect on hematopoïesis up to the age of 18 months.

A model of the spread of the bovine viral-diarrhoea virus within a dairy herd.

Wet BVDSim (a stochastic simulation model) was developed to study the dynamics of the spread of the bovine viral-diarrhoea virus (BVDV) within a dairy herd. This model took into account herd-management factors (common in several countries), which influence BVDV spread. BVDSim was designed as a discrete-entity and discrete-event simulation model. It relied on two processes defined at the individual-animal level, with interactions. The first process was a semi-Markov process and modelled the herd structure and dynamics (demography, herd management). The second process was a Markov process and modelled horizontal and vertical virus transmission. Because the horizontal transmission occurs by contacts (nose-to-nose) and indirectly, transmission varied with the separation of animals into subgroups. Vertical transmission resulted in birth of persistently infected (PI) calves. Other possible consequences of a BVDV infection during the pregnancy period were considered (pregnancy loss, immunity of calves). The outcomes of infection were modelled according to the stage of pregnancy at time of infection. BVDV pregnancy loss was followed either by culling or by a new artificial insemination depending on the modelled farmer's decision. Consistency of the herd dynamics in the absence of any BVDV infection was verified. To explore the model behaviour, the virus spread was simulated over 10 years after the introduction of a near-calving PI heifer into a susceptible 38 cow herd. Different dynamics of the virus spread were simulated, from early clearance to persistence of the virus 10 years after its introduction. Sensitivity of the model to the uncertainty on transmission coefficient was analysed. Qualitative validation consisted in comparing the bulk-milk ELISA results over time in a sample of herds detected with a new infection with the ones derived from simulations.

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients.

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.

Citrulline diet supplementation improves specific age-related raft changes in wild-type rodent hippocampus.

The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high-density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging.

Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer.

OBJECTIVE: Different treatments have been investigated in head and neck cancers (HNCs) but not all of them have been appraised using pairwise comparison. This has resulted in failure to directly identify the best treatment with standard methods. Mixed treatment comparison (MTC) meta-analysis allows one to perform simultaneous inference regarding all treatments and select the best among them. STUDY DESIGN AND SETTING: We applied MTC models to the Meta-Analyses of Chemotherapy and Radiotherapy in HNC, which pooled individual patient data concerning more than 24,000 patients involved in 102 trials. Fixed- and random-effects models, models with or without consistency factors, possibly adapted to multiarm trials are discussed. RESULTS: Altered fractionated concomitant chemoradiotherapy (AF-CRT) leads to the highest probability of survival in nonmetastatic HNC. The probability that AF-CRT is the best treatment is 94% with random-effects models. There was no relevant inconsistency. When only the most recent trials were selected, AF-CRT and concomitant chemoradiotherapy (CRT) were the two best treatments. AF-CRT remains better than CRT but with a lower posterior probability. CONCLUSION: MTC is a powerful method for investigating networks of randomized trials. Homogeneity, similarity of trial designs, populations, and the consistency of the network should be thoroughly checked.

Formaldehyde exposure and lower respiratory infections in infants: findings from the PARIS cohort study.

BACKGROUND: Certain chemical pollutants can exacerbate lower respiratory tract infections (LRIs), a common childhood ailment. Although formaldehyde (FA) is one of the most common air pollutants found in indoor environments, its impact on infant health is uncertain. OBJECTIVE: Our aim was to determine the impact of FA exposure on the LRI incidence during the first year of life of infants from the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort. METHODS: FA was measured in a random sample of 196 infants' dwellings, and exposure to this pollutant was estimated for 2,940 infants using predictive models based on measurements and data about potential determinants of FA levels. Health data were collected from parents by regular self-administered questionnaires. We used multivariate logistic regressions to estimate associations between FA exposure and the occurrence of LRI and wheezy LRI (wLRI), adjusting for potential confounders/risk factors. RESULTS: During the first year of life, 45.8% of infants had at least one LRI, and LRI occurred simultaneously with wheezing in 48.7% of cases. The FA predictive models correctly classified 70% of dwellings as having high or low exposure, and we estimated that 43.3% of infants were exposed throughout the first year to levels of FA > 19.5 µg/m3. FA exposure was significantly associated with LRI and wLRI before and after adjustment for known LRI risk factors/confounders. For an interquartile increase in FA levels (12.4 µg/m3), we estimated a 32% [95% confidence interval (CI): 11, 55] and 41% (95% CI: 14, 74) increase in the incidence of LRI and wLRI, respectively. CONCLUSION: The findings of this study suggest that infants exposed to FA at an early age have an increased incidence of LRI.

Approach for qualitative validation using aggregated data for a stochastic simulation model of the spread of the bovine viral-diarrhoea virus in a dairy cattle herd.

Qualitative validation consists in showing that a model is able to mimic available observed data. In population level biological models, the available data frequently represent a group status, such as pool testing, rather than the individual statuses. They are aggregated. Our objective was to explore an approach for qualitative validation of a model with aggregated data and to apply it to validate a stochastic model simulating the bovine viral-diarrhoea virus (BVDV) spread within a dairy cattle herd. Repeated measures of the level of BVDV-specific antibodies in the bulk-tank milk (total milk production of a herd) were used to summarise the BVDV herd status. First, a domain of validation was defined to ensure a comparison restricted to dynamics of pathogen spread well identified among observed aggregated data (new herd infection with a wide BVDV spread). For simulations, scenarios were defined and simulation outputs at the individual animal level were aggregated at the herd level using an aggregation function. Comparison was done only for observed data and simulated aggregated outputs that were in the domain of validation. The validity of our BVDV model was not rejected. Drawbacks and ways of improvement of the approach are discussed.