Small area variations in non-affective first-episode psychosis: the role of socioeconomic and environmental factors.

BACKGROUND: There is strong evidence supporting the association between environmental factors and increased risk of non-affective psychotic disorders. However, the use of sound statistical methods to account for spatial variations associated with environmental risk factors, such as urbanicity, migration, or deprivation, is scarce in the literature. METHODS: We studied the geographical distribution of non-affective first-episode psychosis (NA-FEP) in a northern region of Spain (Navarra) during a 54-month period considering area-level socioeconomic indicators as putative explanatory variables. We used several Bayesian hierarchical Poisson models to smooth the standardized incidence ratios (SIR). We included neighborhood-level variables in the spatial models as covariates. RESULTS: We identified 430 NA-FEP cases over a 54-month period for a population at risk of 365,213 inhabitants per year. NA-FEP incidence risks showed spatial patterning and a significant ecological association with the migrant population, unemployment, and consumption of anxiolytics and antidepressants. The high-risk areas corresponded mostly to peripheral urban regions; very few basic health sectors of rural areas emerged as high-risk areas in the spatial models with covariates. DISCUSSION: Increased rates of unemployment, the migrant population, and consumption of anxiolytics and antidepressants showed significant associations linked to the spatial-geographic incidence of NA-FEP. These results may allow targeting geographical areas to provide preventive interventions that potentially address modifiable environmental risk factors for NA-FEP. Further investigation is needed to understand the mechanisms underlying the associations between environmental risk factors and the incidence of NA-FEP.

Multivariate Bayesian spatio-temporal P-spline models to analyze crimes against women.

Univariate spatio-temporal models for areal count data have received great attention in recent years for estimating risks. However, models for studying multivariate responses are less commonly used mainly due to the computational burden. In this article, multivariate spatio-temporal P-spline models are proposed to study different forms of violence against women. Modeling distinct crimes jointly improves the precision of estimates over univariate models and allows to compute correlations among them. The correlation between the spatial and the temporal patterns may suggest connections among the different crimes that will certainly benefit a thorough comprehension of this problem that affects millions of women around the world. The models are fitted using integrated nested Laplace approximations and are used to analyze four distinct crimes against women at district level in the Indian state of Maharashtra during the period 2001-2013.

Using mortality to predict incidence for rare and lethal cancers in very small areas.

Incidence and mortality figures are needed to get a comprehensive overview of cancer burden. In many countries, cancer mortality figures are routinely recorded by statistical offices, whereas incidence depends on regional cancer registries. However, due to the complexity of updating cancer registries, incidence numbers become available 3 or 4 years later than mortality figures. It is, therefore, necessary to develop reliable procedures to predict cancer incidence at least until the period when mortality data are available. Most of the methods proposed in the literature are designed to predict total cancer (except nonmelanoma skin cancer) or major cancer sites. However, less frequent lethal cancers, such as brain cancer, are generally excluded from predictions because the scarce number of cases makes it difficult to use univariate models. Our proposal comes to fill this gap and consists of modeling jointly incidence and mortality data using spatio-temporal models with spatial and age shared components. This approach allows for predicting lethal cancers improving the performance of individual models when data are scarce by taking advantage of the high correlation between incidence and mortality. A fully Bayesian approach based on integrated nested Laplace approximations is considered for model fitting and inference. A validation process is also conducted to assess the performance of alternative models. We use the new proposals to predict brain cancer incidence rates by gender and age groups in the health units of Navarre and Basque Country (Spain) during the period 2005-2008.

Space-time interactions in Bayesian disease mapping with recent tools: Making things easier for practitioners.

Spatio-temporal disease mapping studies the distribution of mortality or incidence risks in space and its evolution in time, and it usually relies on fitting hierarchical Poisson mixed models. These models are complex for practitioners as they generally require adding constraints to correctly identify and interpret the different model terms. However, including constraints may not be straightforward in some recent software packages. This paper focuses on NIMBLE, a library of algorithms that contains among others a configurable system for Markov chain Monte Carlo (MCMC) algorithms. In particular, we show how to fit different spatio-temporal disease mapping models with NIMBLE making emphasis on how to include sum-to-zero constraints to solve identifiability issues when including spatio-temporal interactions. Breast cancer mortality data in Spain during the period 1990-2010 is used for illustration purposes. A simulation study is also conducted to compare NIMBLE with R-INLA in terms of parameter estimates and relative risk estimation. The results are very similar but differences are observed in terms of computing time.

Cytokinins are involved in drought tolerance of Pinus radiata plants originating from embryonal masses induced at high temperatures.

Vegetative propagation through somatic embryogenesis is an effective method to produce elite varieties and can be applied as a tool to study the response of plants to different stresses. Several studies show that environmental changes during embryogenesis could determine future plant development. Moreover, we previously reported that physical and chemical conditions during somatic embryogenesis can determine the protein, hormone and metabolite profiles, as well as the micromorphological and ultrastructural organization of embryonal masses and somatic embryos. In this sense, phytohormones are key players throughout the somatic embryogenesis process as well as during numerous stress-adaptation responses. In this work, we first applied different high-temperature regimes (30 °C, 4 weeks; 40 °C, 4 days; 50 °C, 5 min) during induction of Pinus radiata D. Don somatic embryogenesis, together with control temperature (23 °C). Then, the somatic plants regenerated from initiated embryogenic cell lines and cultivated in greenhouse conditions were subjected to drought stress and control treatments to evaluate survival, growth and several physiological traits (relative water content, water potential, photosynthesis, stomatal conductance and transpiration). Based on those preliminary results, even more extreme high-temperature regimes were applied during induction (40 °C, 4 h; 50 °C, 30 min; 60 °C, 5 min) and the corresponding cytokinin profiles of initiated embryonal masses from different lines were analysed. The results showed that the temperature regime during induction had delayed negative effects on drought resilience of somatic plants as indicated by survival, photosynthetic activity and water- use efficiency. However, high temperatures for extended periods of time enhanced subsequent plant growth in well-watered conditions. High-temperature regime treatments induced significant differences in the profile of total cytokinin bases, N6-isopentenyladenine, cis-zeatin riboside and trans-zeatin riboside. We concluded that phytohormones could be potential regulators of stress-response processes during initial steps of somatic embryogenesis and that they may have delayed implications in further developmental processes, determining the performance of the generated plants.

Induction of Radiata Pine Somatic Embryogenesis at High Temperatures Provokes a Long-Term Decrease in DNA Methylation/Hydroxymethylation and Differential Expression of Stress-Related Genes.

Based on the hypothesis that embryo development is a crucial stage for the formation of stable epigenetic marks that could modulate the behaviour of the resulting plants, in this study, radiata pine somatic embryogenesis was induced at high temperatures (23 °C, eight weeks, control; 40 °C, 4 h; 60 °C, 5 min) and the global methylation and hydroxymethylation levels of emerging embryonal masses and somatic plants were analysed using LC-ESI-MS/ MS-MRM. In this context, the expression pattern of six genes previously described as stress-mediators was studied throughout the embryogenic process until plant level to assess whether the observed epigenetic changes could have provoked a sustained alteration of the transcriptome. Results indicated that the highest temperatures led to hypomethylation of both embryonal masses and somatic plants. Moreover, we detected for the first time in a pine species the presence of 5-hydroxymethylcytosine, and revealed its tissue specificity and potential involvement in heat-stress responses. Additionally, a heat shock protein-coding gene showed a down-regulation tendency along the process, with a special emphasis given to embryonal masses at first subculture and ex vitro somatic plants. Likewise, the transcripts of several proteins related with translation, oxidative stress response, and drought resilience were differentially expressed.

Online relative risks/rates estimation in spatial and spatio-temporal disease mapping.

BACKGROUND AND OBJECTIVE: Spatial and spatio-temporal analyses of count data are crucial in epidemiology and other fields to unveil spatial and spatio-temporal patterns of incidence and/or mortality risks. However, fitting spatial and spatio-temporal models is not easy for non-expert users. The objective of this paper is to present an interactive and user-friendly web application (named SSTCDapp) for the analysis of spatial and spatio-temporal mortality or incidence data. Although SSTCDapp is simple to use, the underlying statistical theory is well founded and all key issues such as model identifiability, model selection, and several spatial priors and hyperpriors for sensitivity analyses are properly addressed. METHODS: The web application is designed to fit an extensive range of fairly complex spatio-temporal models to smooth the very often extremely variable standardized incidence/mortality risks or crude rates. The application is built with the R package shiny and relies on the well founded integrated nested Laplace approximation technique for model fitting and inference. RESULTS: The use of the web application is shown through the analysis of Spanish spatio-temporal breast cancer data. Different possibilities for the analysis regarding the type of model, model selection criteria, and a range of graphical as well as numerical outputs are provided. CONCLUSIONS: Unlike other software used in disease mapping, SSTCDapp facilitates the fit of complex statistical models to non-experts users without the need of installing any software in their own computers, since all the analyses and computations are made in a powerful remote server. In addition, a desktop version is also available to run the application locally in those cases in which data confidentiality is a serious issue.

Temperature and Water Availability During Maturation Affect the Cytokinins and Auxins Profile of Radiata Pine Somatic Embryos.

Somatic embryogenesis (SE) provides us a potent biotechnological tool to manipulate the physical and chemical conditions (water availability) along the process and to study their effect in the final success in terms of quantity of somatic embryos produced. In the last years, our research team has been focused on the study of different aspects of the SE in Pinus spp. One of the main aspects affecting SE is the composition of culture media; in this sense, phytohormones play one of the most crucial roles in this propagation system. Many studies in conifers have shown that different stages of SE and somatic embryo development are correlated with distinct endogenous phytohormone profiles under the stress conditions needed for the process (i.e., cytokinins play a regulatory role in stress signaling, which it is essential for radiata pine SE). Based on this knowledge, the aim of this study was to test the effect of different temperatures (18, 23, and 28°C) and gelling agent concentrations (8, 9, and 10 gL-1) during the maturation stage of Pinus radiata SE in maturation and germination rates. Parallel, phytohormone profile of somatic embryos developed was evaluated. In this sense, the highest gellan gum concentration led to significantly lower water availability. At this gellan gum concentration and 23°C a significantly higher number of somatic embryos was obtained and the overall success of the process increased with respect to other treatments assayed. The somatic embryos produced in these conditions showed the highest concentration of iP-type cytokinins and total ribosides. Although, the different conditions applied during maturation of somatic embryos led to different hormonal profiles, they did not affect the ex vitro survival of the resulting somatic plants, where no significant differences were observed.

Effect of Thermal Stress on Tissue Ultrastructure and Metabolite Profiles During Initiation of Radiata Pine Somatic Embryogenesis.

Climate change will inevitably lead to environmental variations, thus plant drought tolerance will be a determinant factor in the success of plantations and natural forestry recovery. Some metabolites, such as soluble carbohydrates and amino acids, have been described as being the key to both embryogenesis efficiency and abiotic stress response, contributing to phenotypic plasticity and the adaptive capacity of plants. For this reason, our main objectives were to evaluate if the temperature during embryonal mass initiation in radiata pine was critical to the success of somatic embryogenesis, to alter the morphological and ultrastructural organization of embryonal masses at cellular level and to modify the carbohydrate, protein, or amino acid contents. The first SE initiation experiments were carried out at moderate and high temperatures for periods of different durations prior to transfer to the control temperature of 23°C. Cultures initiated at moderate temperatures (30°C, 4 weeks and 40°C, 4 days) showed significantly lower initiation and proliferation rates than those at the control temperature or pulse treatment at high temperatures (50°C, 5 min). No significant differences were observed either for the percentage of embryogenic cell lines that produced somatic embryos, or for the number of somatic embryos per gram of embryonal mass. Based on the results from the first experiments, initiation was carried out at 40°C 4 h; 50°C, 30 min; and a pulse treatment of 60°C, 5 min. No significant differences were found for the initiation or number of established lines or for the maturation of somatic embryos. However, large morphological differences were observed in the mature somatic embryos. At the same time, changes observed at cellular level suggested that strong heat shock treatments may trigger the programmed cell death of embryogenic cells, leading to an early loss of embryogenic potential, and the formation of supernumerary suspensor cells. Finally, among all the differences observed in the metabolic profile, it is worth highlighting the accumulation of tyrosine and isoleucine, both amino acids involved in the synthesis of abiotic stress response-related secondary metabolites.

Spatial gender-age-period-cohort analysis of pancreatic cancer mortality in Spain (1990-2013).

Recently, the interest in studying pancreatic cancer mortality has increased due to its high lethality. In this work a detailed analysis of pancreatic cancer mortality in Spanish provinces was performed using recent data. A set of multivariate spatial gender-age-period-cohort models was considered to look for potential candidates to analyze pancreatic cancer mortality rates. The selected model combines features of APC (age-period-cohort) models with disease mapping approaches. To ensure model identifiability sum-to-zero constraints were applied. A fully Bayesian approach based on integrated nested Laplace approximations (INLA) was considered for model fitting and inference. Sensitivity analyses were also conducted. In general, estimated average rates by age, cohort, and period are higher in males than in females. The higher differences according to age between males and females correspond to the age groups [65, 70), [70, 75), and [75, 80). Regarding the cohort, the greatest difference between men and women is observed for those born between the forties and the sixties. From there on, the younger the birth cohort is, the smaller the difference becomes. Some cohort differences are also identified by regions and age-groups. The spatial pattern indicates a North-South gradient of pancreatic cancer mortality in Spain, the provinces in the North being the ones with the highest effects on mortality during the studied period. Finally, the space-time evolution shows that the space pattern has changed little over time.

Two-level spatially structured models in spatio-temporal disease mapping.

This work focuses on extending some classical spatio-temporal models in disease mapping. The objective is to present a family of flexible models to analyze real data naturally organized in two different levels of spatial aggregation like municipalities within health areas or provinces, or counties within states. Model fitting and inference will be carried out using integrated nested Laplace approximations. The performance of the new models compared to models including a single spatial random effect is assessed by simulation. Results show good behavior of the proposed two-level spatially structured models in terms of several criteria. Brain cancer mortality data in the municipalities of two regions in Spain will be analyzed using the new model proposals. It will be shown that a model with two-level spatial random effects overcomes the usual single-level models.

Temporal evolution of brain cancer incidence in the municipalities of Navarre and the Basque Country, Spain.

BACKGROUND: Brain cancer incidence rates in Spain are below the European's average. However, there are two regions in the north of the country, Navarre and the Basque Country, ranked among the European regions with the highest incidence rates for both males and females. Our objective here was two-fold. Firstly, to describe the temporal evolution of the geographical pattern of brain cancer incidence in Navarre and the Basque Country, and secondly, to look for specific high risk areas (municipalities) within these two regions in the study period (1986-2008). METHODS: A mixed Poisson model with two levels of spatial effects is used. The model also included two levels of spatial effects (municipalities and local health areas). Model fitting was carried out using penalized quasi-likelihood. High risk regions were detected using upper one-sided confidence intervals. RESULTS: Results revealed a group of high risk areas surrounding Pamplona, the capital city of Navarre, and a few municipalities with significant high risks in the northern part of the region, specifically in the border between Navarre and the Basque Country (Gipuzkoa). The global temporal trend was found to be increasing. Differences were also observed among specific risk evolutions in certain municipalities. CONCLUSIONS: Brain cancer incidence in Navarre and the Basque Country (Spain) is still increasing with time. The number of high risk areas within those two regions is also increasing. Our study highlights the need of continuous surveillance of this cancer in the areas of high risk. However, due to the low percentage of cases explained by the known risk factors, primary prevention should be applied as a general recommendation in these populations.

Age- and sex-specific spatio-temporal patterns of colorectal cancer mortality in Spain (1975-2008).

In this paper, space-time patterns of colorectal cancer (CRC) mortality risks are studied by sex and age group (50-69, ≥70) in Spanish provinces during the period 1975-2008. Space-time conditional autoregressive models are used to perform the statistical analyses. A pronounced increase in mortality risk has been observed in males for both age-groups. For males between 50 and 69 years of age, trends seem to stabilize from 2001 onward. In females, trends reflect a more stable pattern during the period in both age groups. However, for the 50-69 years group, risks take an upward trend in the period 2006-2008 after the slight decline observed in the second half of the period. This study offers interesting information regarding CRC mortality distribution among different Spanish provinces that could be used to improve prevention policies and resource allocation in different regions.

On fitting spatio-temporal disease mapping models using approximate Bayesian inference.

Spatio-temporal disease mapping comprises a wide range of models used to describe the distribution of a disease in space and its evolution in time. These models have been commonly formulated within a hierarchical Bayesian framework with two main approaches: an empirical Bayes (EB) and a fully Bayes (FB) approach. The EB approach provides point estimates of the parameters relying on the well-known penalized quasi-likelihood (PQL) technique. The FB approach provides the posterior distribution of the target parameters. These marginal distributions are not usually available in closed form and common estimation procedures are based on Markov chain Monte Carlo (MCMC) methods. However, the spatio-temporal models used in disease mapping are often very complex and MCMC methods may lead to large Monte Carlo errors and a huge computation time if the dimension of the data at hand is large. To circumvent these potential inconveniences, a new technique called integrated nested Laplace approximations (INLA), based on nested Laplace approximations, has been proposed for Bayesian inference in latent Gaussian models. In this paper, we show how to fit different spatio-temporal models for disease mapping with INLA using the Leroux CAR prior for the spatial component, and we compare it with PQL via a simulation study. The spatio-temporal distribution of male brain cancer mortality in Spain during the period 1986-2010 is also analysed.

Evaluating space-time models for short-term cancer mortality risk predictions in small areas.

Current cancer mortality data are available with a delay of roughly three years due to the administrative procedure necessary to create the registries. Therefore, health agencies rely on forecast cancer deaths. In this context, statistical procedures providing mortality/incidence risk predictions for different regions or health areas are very useful. These predictions are essential for defining priorities for cancer prevention and treatment. The main objective of this work is to evaluate the predictive performance of alternative spatio-temporal models for short-term cancer risk/counts prediction in small areas. All the models analyzed here are presented under a general-mixed model framework, providing a unified structure of presentation and facilitating the use of similar tools for computing the prediction mean squared error. Prostate cancer mortality data are used to illustrate the behavior of the different models in Spanish provinces.

Spatio-temporal trends in gastric cancer mortality in Spain: 1975-2008.

AIM OF THE STUDY: There has been a downward trend in gastric cancer mortality worldwide. In Spain, a marked spatial aggregation of areas with excess mortality due to this cause has long been reported. This paper sought to analyse the evolution of gastric cancer mortality risk in Spanish provinces and explore the possible attenuation of the geographical pattern. METHODS: We studied a series of gastric cancer mortality data by province, year of death, sex and age group using a conditional autoregressive (CAR) model that incorporated space, time and spatio-temporal interactions. RESULTS: Gastric cancer mortality risk decreased in all Spanish provinces in both males and females. Overall, decreasing trends were more pronounced during the first years of the study period, largely due to a sharper fall in gastric cancer mortality risk among the older population. Recent decades have witnessed a slowing in the rate of decrease, especially among the younger age groups. In most areas, risk declined at a similar rate, thus serving to maintain interprovincial differences and the persistence of the geographical pattern, though with some differences. The north and northwest provinces were the areas with higher mortality risks in both sexes and age groups over the entire study period. CONCLUDING STATEMENT: Despite the decline in gastric cancer mortality risk observed for the 50 Spanish provinces studied, geographical differences still persist in Spain, and the cluster of excess mortality in the north-west of the country remains in evidence.

Age-specific spatio-temporal patterns of female breast cancer mortality in Spain (1975-2005).

PURPOSE: In recent decades, a decline in breast cancer mortality has been observed across Europe, and also in Spain. Our objective is to assess the spatio-temporal pattern during the period 1975-2005 by specific age groups (<45, 45-64, ≥65) in the Spanish provinces. METHODS: For each age group, a spatio-temporal P-spline model with a B-spline basis is used to smooth the mortality risks. Smoothing is carried out in three dimensions: longitude, latitude, and time, allowing for a different time evolution of both spatial components. The age-specific decline is calculated as the maximum of the estimated curve in each province. A confidence band for each curve is also provided. RESULTS: For the first age group (<45), the decline in the different provinces is observed between 1986 and 1991. For women aged between 45 to 64 years, the change occurs between 1990 and 1993. For the third age group (≥65), change points range from 1992 to 2000, unlike Malaga and Cadiz where the change has not been observed in the studied period. Northern and some Mediterranean provinces are the areas with higher mortality risks for all the age groups. CONCLUSIONS: A different behavior for breast cancer mortality risks is observed for different provinces among the age specific groups. The decline of mortality is delayed for the oldest age group. Province differences in the implementation of screening programs could explain some of the observed differences.

A taxometric analysis of schizophrenia symptoms.

Specific disorders within the psychosis syndrome have been proposed although no definitive validation of subtypes has been achieved. If there are subtypes of psychosis, latent discontinuity between clinical descriptors should be found. We applied for the first time taxometric analysis on characteristic schizophrenia symptoms. The sample consisted of 660 inpatients with an acute psychotic episode. Computed scores of the clinical dimensions included in the three-syndrome model of schizophrenia symptomatology were used as clinical descriptors or latent variables to be analyzed. Two taxometric analyses were used (MAXCOV and MAMBAC). Discrepancies between observed covariance curves and between the estimated base rates of indicators did not support a taxonic conjecture within psychosis based on the severity of 'Psychosis', 'Negative' and 'Disorganization' dimensions scores, which were used as indicators. However, no appropriate solution could be reached because the three clinical indicators of schizophrenia symptomatology used in this study showed a lack of consistency. The lack of a taxonic structure with symptomatological domains of psychosis suggested the existence of a dimensional solution for schizophrenia symptomatology within psychoses.