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Rapidly detecting the beginning of influenza outbreaks helps health authorities to reduce their impact. Accounting for the spatial distribution of the data can greatly improve the performance of an outbreak detection method by promptly detecting the first foci of infection. The use of Hidden Markov chains in temporal models has shown to be great tools for classifying the epidemic or endemic state of influenza data, though their use in spatio-temporal models for outbreak detection is scarce. In this work, we present a spatio-temporal Bayesian Markov switching model over the differentiated incidence rates for the rapid detection of influenza outbreaks. This model focuses its attention on the incidence variations to better detect the higher increases of early epidemic rates even when the rates themselves are relatively low. The differentiated rates are modelled by a Gaussian distribution with different mean and variance according to the epidemic or endemic state. A temporal autoregressive term and a spatial conditional autoregressive model are added to capture the spatio-temporal structure of the epidemic mean. The proposed model has been tested over the USA Google Flu Trends database to assess the relevance of the whole structure.

This study was funded by Grants from EU (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1); Spain: ISCIII (Red INMA G03/176, CB06/02/0041; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI09/00090, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI13/02187, PI14/00891, PI14/01687, PI16/1288, PI17/00663, PI18/01142 and PI19/1338; Miguel Servet FEDER MS15/00025, MS20/0006, CPII16/00051, and FIS-FSE: 17/00260); CIBERESP; Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), AICO/2020/285, and Alicia Koplowitz Foundation 2017; Generalitat de Catalunya-CIRIT 1999SGR 00241; Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065); Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221). We acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the "Centro de Excelencia Severo Ochoa 2019-2023" Programme (CEX2018000806-S), and from the Generalitat de Catalunya through the CERCA Programme, as well as the municipalities in the study area., Background: Humans are regularly exposed to metals and metalloids present in air, water, food, soil and domestic materials. Most of them can cross the placental barrier and cause adverse impacts on the developing foetus. Objectives: To describe the prenatal concentrations of metals and metalloids and to study the associated sociodemographic, environmental and dietary factors in pregnant Spanish women. Methods: Subjects were 1346 pregnant women of the INMA Project, for whom the following metals arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), molybdenum (Mo), nickel (Ni), lead (Pb), antimony (Sb), selenium (Se), thallium (Tl) and zinc (Zn) were determined in urine, at both the first and the third trimesters of gestation. Sociodemographic, dietary and environmental information was collected through questionnaires during pregnancy. Multiple linear mixed models were built in order to study the association between each metal and metalloid concentrations and the sociodemographic, environmental and dietary factors. Results: The most detected compounds were As, Co, Mo, Sb, Se and Zn at both trimesters. Zn was the element found in the highest concentrations at both trimesters and Tl was detected in the lowest concentrations. We observed significant associations between As, Cd, Cu, Sb, Tl and Zn concentrations and working situation, social class and age. Seafood, meat, fruits, nuts, vegetables and alcohol intake affected the levels of all the metals but Cd and Cu. Proximity to industrial areas, fields and air pollution were related to all metals except Cd, Sb and Se. Conclusions: This is the first large prospective longitudinal study on the exposure to metals and metalloids during pregnancy and associated factors to include several cohorts in Spain. The present study shows that some modifiable lifestyles, food intakes and environmental factors could be associated with prenatal exposure to metal (loid)s, which may be considered in further studies to assess their relationship with neonatal health outcomes., European Commission 282957 HEALTH.2010.2.4.5-1, Spain: ISCIII Red INMA G03/176 CB06/02/0041 CIBERESP, Generalitat Valenciana: FISABIO UGP 15-230 UGP-15-244 UGP-15-249 AICO/2020/285, Alicia Koplowitz Foundation, Generalitat de Catalunya, General Electric CIRIT 1999SGR 00241, Department of Health of the Basque Government 2005111093 2009111069 2013111089 2015111065, Provincial Government of Gipuzkoa DFG06/002 DFG08/001 DFG15/221, Spanish Ministry of Science, Innovation and Universities CEX2018000806-S, General Electric, Spain (FIS-FEDER) PI03/1615 PI04/1509 PI04/1112 PI04/1931 PI05/1079 PI05/1052 PI06/0867 PI06/1213 PI07/0314 PI09/00090 PI09/02647 PI11/01007 PI11/02591 PI11/02038 PI13/1944 PI13/2032 PI13/02187, Spain (Miguel Servet FEDER) MS15/00025 MS20/0006 CPII16/00051, Spain (FIS-FSE) 17/00260, the Spain (FIS-FEDER) PI14/00891 PI14/01687 PI16/1288 PI17/00663 PI18/01142 PI19/1338

Hepatocellular Carcinoma (HCC) is the fourth most common cause of cancer deaths worldwide, and its early detection is a critical determinant of whether curative treatment is achievable. Early stage HCC is typically asymptomatic. Thus, screening programmes are used for cancer detection in patients at risk of tumour development. Radiological screening methods are limited by imperfect data, cost and associated risks, and additionally are unable to detect lesionsuntil they have grown to a certain size. Therefore, some screening programmes use additional blood/serum biomarkers to help identify individuals in whom to target diagnostic cancer investigations. The GALAD score, combining the levels of several blood biomarkers, age and sex, has been developed to identify patients with early HCC. Here we propose a Bayesian hierarchical model for an individual's longitudinal GALAD scores whilst in HCC surveillance to identify potentially significant changes in the trend of the GALAD score, indicating the development of HCC, aiming to improve early detection compared to standard methods. An absorbent two-state continuous-time hidden Markov model is developed for the individual level longitudinal data where the states correspond to the presence/absence of HCC. The model is additionally informed by the information on the diagnosis by standard clinical practice, taking into account that HCC can be present before the actual diagnosis so that there may be false negatives within the diagnosis data. We fit the model to a Japanese cohort of patients undergoing HCC surveillance and show that the detection capability of this proposal is greater than using a fixed cut-off point.

Background & Aims Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. Methods We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). Results HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. Conclusions We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.

Introduction Manganese (Mn) is an essential element, diet being its main source. Some epidemiological studies have found that a prenatal excess of Mn could negatively affect neuropsychological development during infancy, but the evidence is inconclusive. The aim of this study was to explore the relationship between maternal serum Mn concentrations and child neuropsychological development assessed at 1 year of age. Methods study subjects were 1179 mother–child pairs from two Spanish cohorts (Valencia and Gipuzkoa) of the INMA (Environment and Childhood) Project. Mn was measured in serum samples collected during the first trimester of pregnancy. Child neuropsychological development was assessed using the Bayley Scales of Infant Development, composed of both mental and psychomotor scales. Sociodemographic, lifestyle and dietary information was collected through questionnaires during pregnancy and during the child's first year of life. Serum Mn was log-2 transformed. Multivariable linear regression models were built. Generalized additive models were used to assess the shape of the relation between prenatal exposure to Mn and the neuropsychological test scores. Results geometric mean and 95% confidence interval (95% CI) of maternal serum Mn was 1.50 (1.48–1.53) μg/L. Levels of Mn were higher among non-working mothers and in those with a higher consumption of nuts. The association between maternal Mn levels and child neuropsychological development was negative in the multivariable models for the mental (β [95% CI] = −0.39 [-2.73, 1.95]) and psychomotor scales (β [95% CI] = −0.92 [-3.48, 1.65]), although the coefficients were not statistically significant. The best shape describing the relationship between Mn and the Bayley scales was linear in both cases. Conclusion This study shows a null association between maternal prenatal levels of Mn and neuropsychological development at one year after birth in two cohorts within the INMA study.

We assessed whether prenatal selenium (Se) exposure is associated with anthropometry at birth, placental weight and gestational age. Study subjects were 1249 mother-child pairs from the Valencia and Gipuzkoa cohorts of the Spanish Childhood and Environment Project (INMA, 2003–2008). Se was determined in serum samples taken at the first trimester of pregnancy. Socio-demographic and dietary characteristics were also collected by questionnaires. Mean (SD) serum Se concentration was 79.57 (9.64) μg/L. Se showed weak associations with both head circumference and gestational age. The association between serum Se concentration and birth weight and length was negative, and direct for placental weight and probability of preterm birth, although the coefficients did not reach statistical significance. Individuals with total mercury (THg) levels >15 μg/L reversed the serum Se concentration effect on head circumference. Significant interactions were found between sex and both gestational age and prematurity. Spontaneous birth gestational ages were estimated to be lower for males and their probability of prematurity was higher. In conclusion, prenatal Se exposure may be associated with lower head circumference and lower gestational ages at spontaneous birth. Interactions with THg exposure and gender should be considered when assessing these relationships.

The objective of this study was to describe the postnatal exposure to Hg and to evaluate its association with neuropsychological development among preschool children. The study population are 4–5 years old children (n = 1252) participant in the Spanish INMA Project. Total Hg was measured in cord blood and in hair samples taken at 4 years of age (2008–2012). Neuropsychological development was assessed using the McCarthy Scales of Children’s Abilities (MSCA). Information on covariates and possible confounders was obtained by questionnaires during pregnancy and childhood. Generalized additive and linear regression models were built in order to assess the relationship between MSCA scores and Hg exposure. We also evaluated the magnitude of the possible bias generated from measurement error in seafood intake estimate from questionnaire and Hg determination. The geometric mean of hair Hg was 0.98 μg/g [95% confidence interval (CI) 0.94, 1.03]. In the regression analysis, the association between Hg and the MSCA scores was positive for all the scales and statistically significant for the verbal (β = 0.89; 95%CI 0.38, 1.39), memory (β = 0.42; 95%CI 0.09, 0.76) and general cognitive scales (β = 1.35; 95%CI 0.45, 2.25). However, these associations were clearly attenuated when we adjusted by the children’s fish intake variables or when took into account theoretical scenarios of low precision in fish intake and Hg measurements. Hg levels in this Spanish population were high in comparison with other European countries; however, we did not observe adverse effects on child neuropsychological development associated with this postnatal exposure to Hg.

En este trabajo proponemos un esquema de variables para el análisis de las resoluciones de los problemas de probabilidad condicional. Se consideran tres variables principales: las variables del enfoque, del proceso y del producto o resultado, las cuales describen aquello que el resolutor hace desde que lee el enunciado del problema hasta que produce un resultado. Estas tres variables principales pueden ser explicadas por medio de no menos de 15 variables secundarias, la mayoría de ellas dicotómicas.

Background: The relationship between maternal selenium (Se) status and child neurodevelopment has been scarcely assessed. In a previous study we observed an inverse U-shaped association between maternal Se concentrations and infant neurodevelopment at 12 months of age. In this study, this non-linear association was explored at preschool age. The effect modification by breastfeeding, child's sex and cord blood mercury was also evaluated.Methods: Study subjects were 490 mother-child pairs from the Spanish Childhood and Environment Project (INMA, 2003–2012). Child neuropsychological development was assessed at around 5 years of age by theMcCarthy Scales of Children's Abilities (MSCA). Sociodemographic and dietary characteristics were collected by questionnaire at the first and third trimester of gestation and at 5 years of age. Se was measured in serum samples by ICP-MS at the end of the first trimester of pregnancy (mean ± standard deviation(SD)=12.4 ± 0.6 weeks of gestation).Results: The mean ± SD of maternal serum Se concentrations was 79.9 ± 8.1 μg/L. In multivariate analysis, no linear association was found between Se concentrations and the nine MSCA scales. Generalized additive models indicated inverted U-shaped relationships between Se concentrations and the verbal and global memory scales. When assessing the influence of effect modifiers, breastfeeding played a role: the association between Se and neuropsychological development was inverted U-shaped for the quantitative, general cognitive, working memory, fine motor, global motor and executive function scales only for non-breastfed children.Conclusion: Low and high maternal Se concentrations seem to be harmful for child neuropsychological development, however further studies should explore this non-linear relationship.

Introduction: Copper (Cu) is an essential element involved in biological processes; however, excessive Cu could be harmful because of its reactive nature. Very few studies have evaluated its potential neurotoxic effects. We aimed to evaluate the association between maternal Cu levels and children's neuropsychological development. Methods: Study subjects were mother-child pairs from the Spanish INMA (i.e. Childhood and Environment) Project. Cu was measured by inductively coupled plasma mass spectrometry in serum samples taken at the first trimester of pregnancy (2003-2005). Neuropsychological development was assessed using the Bayley Scales of Infant Development (BSID) at 12 months (n = 651) and the McCarthy Scales of Children's Abilities (MSCA) at 5 years of age (n = 490). Covariates were obtained by questionnaires during pregnancy and childhood. Multivariate linear and non-linear models were built in order to study the association between maternal Cu and child neuropsychological development.Results: The mean ± standard deviation of maternal Cu concentrations was 1606 ± 272 μg/L. In the multivariate analysis, a negative linear association was found between maternal Cu concentrations and both the BSID mental scale (beta = −0.051; 95% confidence intervals [CI]: −0.102, −0.001) and the MSCA verbal scale (beta = −0.044; 95%CI:-0.094, 0.006). Boys obtained poorer scores than girls, with increasing Cu at 12 months (interaction p-value = 0.040 for the mental scale and 0.074 for the psychomotor scale). This effect modification disappeared at 5 years of age. The association between Cu and the MSCA scores (verbal, perceptive performance, global memory and motor, general cognitive, and executive function scales) was negative for those children with lowest maternal iron concentrations (< 938μg/L).Conclusion: The Cu concentrations observed in our study were within the reference range established for healthy pregnant women in previous studies. The results of this study contribute to the body of scientific knowledge with important information on the possible neurotoxic capability of Cu during pregnancy.

Background/Aim: Selenium (Se) is an essential nutrient for humans. However, at high exposures, it has been linked to neurotoxicity during early development. Very few studies have evaluated the pote...

Selenium(Se) has been positively associated with neurodevelopment in early life. However, its margin of safety is rather narrow, and few prospective studies have evaluated its potential neurotoxic effects at intermediate levels. We aimed to explore the association between maternal Se concentrations and child neuropsychological development, including the genetic effect modification of the Se metabolizing gene INMT. Study subjects were 650 mother-child pairs from the Spanish Childhood and Environment Project (INMA, 2003-2005). Infant neuropsychological development was assessed around 12 months of age by the Bayley Scales of Infant Development. Sociodemographic and dietary characteristics were collected by questionnaire at the first and third trimester of gestation. Se was measured in serum samples at the first trimester. The mean serum Se concentration was 79.7 (standard deviation=7.9) mu g/L. In multivariate analysis, nonsignificant inverse linear associations were found between Se concentrations and standardized mental and psychomotor development scores (beta (95% CI) = -0.13 (-0.29, 0.03) and beta (95% CI) = -0.08 (-0.24, 0.07), respectively). Generalized additive models indicated inverted U-shaped relationships between Se concentrations and both scales. Using segmented regression, the turning point for the associations was estimated at 86 mu g/L for both scales. The association between Se and neuropsychological development was inverted U-shaped for children with the AG+AA genotype for rs6970396 INMT but a descending curve was suggested for the GG genotype. Further studies would be necessary in order to disentangle the complex equilibrium between the toxicity and benefits of Se exposure during the prenatal period. (C) 2017 Elsevier B.V. All rights reserved.

Inorganic arsenic (i-As) has been related to wide-ranging health effects in children, leading to lifelong concerns. Proportionally, dietary i-As exposure dominates in regions with low arsenic drinking water. This study aims to investigate the relation between rice and seafood consumption and urinary arsenic species during childhood and to assess the proportion of urinary i-As metabolites. Urinary arsenic species concentration in 400 4-year-old children living in four geographical areas of Spain, in addition to repeated measures from 100 children at 7 years of age are included in this study. Rice and seafood products intake was collected from children's parents using a validated food frequency questionnaire (FFQ). At 4 years of age, children's urine i-As and monomethylarsonic acid (MMA) concentrations increased with rice product consumption (p-value = 0.010 and 0.018, respectively), and urinary arsenobetaine (AsB) with seafood consumption (p = 0.002). Four-year-old children had a higher consumption of both rice and seafood per body weight and a higher urinary %MMA (p-value = 0.001) and lower % dimethylarsinic acid (DMA) (p-value = 0.017). This study suggests increased dietary i-As exposure related to rice product consumption among children living in Spain, and the younger ones may be especially vulnerable to the health impacts of this exposure also considering that they might have a lower i-As methylation capacity than older children. In contrast, seafood consumption did not appear to influence the presence of potentially toxic arsenic species in this population of children.

Background Marfan syndrome is a rare disease of connective tissue characterized by a variable combination of cardiovascular, musculoskeletal, ophthalmic and pulmonary manifestations. Apart from the support of patients' associations, there isn’t a Spanish registry of patients with Marfan syndrome. The objective is to identify the prevalence and incidence, determine the mortality distribution, study the quality of regional registries and analyze the mortality associated with aortic …

Background Patient registries (PRs) are important tools for public-health surveillance and rare-disease research. The purpose of this study is to identify the most important criteria for the creation of a rare-disease PR that could be used by public-health authorities to develop health policies. Methods A consensus-development Delphi study was used, with participants selected for their expertize in rare diseases and registries. Participants were asked to complete a questionnaire on the most important criteria for creating PRs. Three rounds were performed. Results Agreement was reached on half the questions in the first round and on 89% of questions in the final round, with a total expert participation rate of around 60% by the final stage. This study made it possible to reach a broader consensus starting from experts' initial assessment of the features that should be considered for the creation of a rare-disease PR. Conclusion The consensus method used made it possible to define the characteristics of a PR based on expert opinion within a rare-disease framework. This study may serve as a guide for helping other researchers plan and build a rare-disease PR.

SUMMARYThe aim of this study was to monitor the spatio-temporal spread of influenza incidence in Spain during the 2009 pandemic and the following two influenza seasons 2010–2011 and 2011–2012 using a Bayesian Poisson mixed regression model; and implement this model of geographical analysis in the Spanish Influenza Surveillance System to obtain maps of influenza incidence for every week. In the pandemic wave the maps showed influenza activity spreading from west to east. The 2010–2011 influenza epidemic wave plotted a north-west/south-east pattern of spread. During the 2011–2012 season the spread of influenza was geographically heterogeneous. The most important source of variability in the model is the temporal term. The model of spatio-temporal spread of influenza incidence is a supplementary tool of influenza surveillance in Spain.

Objectives Scant evidence is available on effects of air pollution on longitudinally measured fetal biometry, and thus it remains unclear as to whether there are critical windows of exposure or specificity of effects. Our objective was to examine the association between exposure to nitrogen dioxide (NO2) during pregnancy and fetal and neonatal anthropometry in a cohort of Spanish women. Methods Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses. Biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) were evaluated in each trimester by ultrasound. As neonatal outcomes, weight, length and head circumference were analysed. SD scores adjusted by gestational age, mother characteristics and fetus sex were calculated at 12, 20 and 32 weeks of gestation as well as at birth. The association between fetal growth and average exposure to NO2 in the relevant windows was investigated using regression models, adjusted for socio-demographic and lifestyle-related variables. Results Exposure to NO2 was inversely associated with BPD, AC and EFW at week 32 and with growth in these parameters in weeks 20-32. BPD and FL were also affected earlier, at week 20. NO2 levels above the median (38 mu g/m(3)) reduced size at week 32 by around 9% in all parameters except for FL (6%). The critical windows of exposure were in early pregnancy, before 20 weeks. Exposure in this period was also inversely associated with neonatal length and head circumference. Conclusions Maternal exposure to NO2 is associated with impaired fetal growth from mid-gestation onwards.

Background In utero tobacco exposure has been associated with adverse pregnancy outcomes but few studies have used longitudinal ultrasound measurements to asses the effects on fetal growth. The aim of this study was to examine the impact of active and passive smoking during pregnancy on fetal biometry in a cohort of Spanish women. Methods Biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) were evaluated in each trimester of pregnancy. Detailed information on smoking and potential confounders was assessed by questionnaire. SD scores were calculated from longitudinal growth curves adjusted for gestational age and potential determinants of growth. Size was assessed by means of unconditional SD scores at 12, 20, 32 and 38 weeks of pregnancy, while growth between these points was assessed by means of conditional SD scores. The association between smoking and fetal growth was investigated by regression models and adjusted for sociodemographic and lifestyle-related variables. Results Maternal smoking was inversely associated with size of all parameters at weeks 32 and 38 and with growth in 20-32, 12-32 and 12-38 week intervals. In 32-38 weeks the effect was significant for AC and EFW. Environmental tobacco smoke (ETS) exposure was inversely associated with growth in BPD in all the intervals except 32-38 weeks. Conclusions Active smoking during pregnancy was associated with a reduction in BPD, AC, FL and EFW from mid-gestation. ETS adversely affected BPD from early pregnancy.