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Distributed lag models (DLM) are regression models that include multiple lagged exposure variables as covariates. They are frequently used to model the relationship between daily mortality and short-term air pollution exposures. Specifying a maximum lag number is but one of the difficulties in using a DLM for environmental epidemiology. We propose an easily extendible ensemble post-processing approach. The resultant estimates are both more parsimonious, approaching zero with increasing lag, and more efficient. The benefits are shown to be robust under various simulation scenario’s and illustrated with data from the National Morbidity, Mortality and Air Pollution Study.

Distributed lag models (DLM) are attractive methods for dealing with mortality displacement, however their estimates can have substantial bias when the data is generated by a multi-state model. In particular DLMs are not valid for mortality displacement. Alternative methods are scarce and lack feasibility and validation. We investigate the breakdown of DLM in three state models by means of simulation and propose simulation enhanced distributed lag models (SEDLM) to overcome the defects. The new method provides simultaneous estimates of the net effect (entry) and the displacement effect (exit). These have improved performance over the singular estimate from a regular DLM. SEDLM entry estimates have negligible bias and their variance is reduced. The exit estimates are unbiased and their variance is one order of magnitude lower with respect to the entry estimates. Applying SEDLM to the original Chicago data, the 95% highest posterior density intervals for both entry and exit contain 0, providing neither evidence for a ‘displacement effect’ nor for a ‘net effect’. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-3566-6) contains supplementary material, which is available to authorized users.

Introduction The adverse health effects of exposure to air pollution have been well-established and include mortality, hospital admissions, emergency department visits, etc, but also less severe outcomes such as medication use and purchase. The economic impact, an additional motivator for policy, has been studied primarily for the more severe outcomes. Methods Purchase data of reimbursed medications typically prescribed for asthma and chronic obstructive pulmonary disease, were obtained through the mandatory Belgian health insurance system. A time series analyses approach was used to model daily sales on daily air pollution concentrations (NO 2 , PM 10 and PM 2.5 ) for residents of the Brussels Capital Region as a whole. In addition, a higher geographical resolution of both sales and pollutant concentrations allowed for a multi-sector approach. Annual savings were estimated for the scenario of a 10% reduction in each of the pollutants. Results Medication purchase was significantly associated with NO 2 concentrations, leading to an annual cost saving potential of € 107,845 [95%CI: € 71,483–€ 143,823] in R03 sales (WHO classification for drugs of obstructive airway diseases). Saving potentials of PM 10 and PM 2.5 were not significant. Estimates were not sensitive to the geographical resolution, however, higher precision can be obtained with higher resolution data, subject to the condition that the number of sales is sufficiently large.

Introduction The aim of study is comparing the haemostatic properties of conventional monopolar resection (TURP) and bipolar transurethral resection in saline (TURIS) of the prostate in patients under chronic oral anticoagulants. Material and methods Out of a cohort group of 550 endoscopic resections for bladder outlet obstruction, 176 patients on chronic oral anticoagulant therapy required endoscopic resection either by monopolar TURP or bipolar TURIS technology. Changes in haemoglobin, blood transfusion, and clot retention were compared between both groups. Results Mean postoperative change in haemoglobin level was -1.21 ±0.92 mg/dl in the TURP group compared to -1.29 ±0.99 mg/dl in the TURIS group (p = 0.603). The need for blood transfusions and the mean numbers of units transfused did not significantly differ between the 2 groups. Clot retention appeared in 12 patients (15%) in the TURP group compared to 13 patients (13%) in the TURIS group (p = 0.828). Conclusions Despite promising experimental results of better haemostasis and deeper coagulation depth, bipolar technology does not permit one to reduce the amount of blood loss when compared to patients treated by conventional monopolar technology in this study group of patients on oral anticoagulation therapy. Patients on oral anticoagulants suffer more incidents of clot retention, which sometimes results in re-hospitalisation.

INTRODUCTION: The aim was to evaluate the postoperative morbidity and outcome of palliative endoscopic resections for relief of infravesical obstruction in prostate cancer patients with hormone deprivation therapy, and to investigate the added value of bipolar technology over conventional monopolar resections. MATERIAL AND METHODS: A retrospective study was performed on 70 patients with prostate cancer under hormone deprivation therapy undergoing 75 endoscopic procedures, by either monopolar or bipolar technology, between August 2005 and March 2009 at a single institution. The analysis used outpatient, inpatient, and operative records, and observations of electrolyte changes in the serum, postoperative morbidity, and the overall results of palliative endoscopic resections. Preoperative cancer stages and grades were compared with the pathological findings after surgery. Postoperative outcome and complications of conventional monopolar and bipolar technology were compared. RESULTS: Over a period of 44months, 34 conventional monopolar resections were performed in 32 patients and 41 bipolar resections in 38 patients. Patients' profiles regarding age, initial cancer stage and grade, resection weight, resection speed, catheterization time, and hospital stay were similar in both groups. No statistically significant difference was observed in sodium drop (p = 0.802), clot retention (p = 0.565), or urinary retention (p = 0.292). The overall success rate in relieving obstruction leading to spontaneous voiding was 77%. While 38% of the patients had a high grade tumour at diagnosis, 79% were found to be high grade after the endoscopic resection (p

Objective: To investigate early changes in leukocyte subsets and autonomic function as predictors of the development of poststroke infections.Methods: We assessed the time course of leukocyte subsets in the blood of 59 patients with acute ischemic stroke. We divided the patients into 2 groups: those who developed infections during the first 7 days after stroke onset and those who did not. We measured urinary norepinephrine and epinephrine concentrations and pulse rate variability indices within 24 hours of admission.Results: We found that the number of circulating natural killer (NK) cells within the first hours after stroke was higher in stroke patients who developed infections (mean 435 cells/mL; 95% confidence interval [CI] 321-588) than in stroke patients who did not develop infections (mean 236 cells/mL; 95% CI 186-300; p = 0.001). This was followed by a decrease in all lymphocyte subsets from admission to day 1, varying between 22% and 40%, which was not seen in patients without poststroke infection (mean increase varied between 2% and 23%; all p Conclusions: High circulating NK cell count within the first hours after ischemic stroke onset followed by a drop in all lymphocyte subsets identified patients who developed infections and may be caused by a sympathovagal imbalance with sympathetic overweight. These findings need to be validated in larger studies.

PURPOSE: To investigate a computed tomographic (CT) protocol with iterative reconstruction at conventional radiography dose levels for the assessment of structural lung abnormalities in patients with cystic fibrosis ( CF cystic fibrosis ). MATERIALS AND METHODS: In this institutional review board-approved study, 38 patients with CF cystic fibrosis (age range, 6-58 years; 21 patients 18 years) underwent investigative CT (at minimal exposure settings combined with iterative reconstruction) as a replacement of yearly follow-up posteroanterior chest radiography. Verbal informed consent was obtained from all patients or their parents. CT images were randomized and rated independently by two radiologists with use of the Bhalla scoring system. In addition, mosaic perfusion was evaluated. As reference, the previous available conventional chest CT scan was used. Differences in Bhalla scores were assessed with the χ(2) test and intraclass correlation coefficients ( ICC intraclass correlationcoefficient s). Radiation doses for CT and radiography were assessed for adults (>18 years) and children (

OBJECTIVE: To investigate the differences in exposure to medications in a cohort of multi-ethnic pregnant women. METHODS: Six hundred and forty-one pregnant women of Western, Arab/Turkish and "other origins" participated in this cross-sectional study using a questionnaire in a university hospital in Brussels, Belgium. Assessment of the drug safety was done using the food and drug administration (FDA) risk classification system. Data analysis was performed using SPSS (Chicago, IL). RESULTS: In overall cohort, 83.8% used at least one preparation (including multivitamins) during pregnancy and 37.0% of women used at least one drug (excluding multivitamins). Significantly more Western women (43.7%) used one or more medications compared to Arab/Turkish women (28.7%; p = 0.000). This difference in exposure was most pronounced for over-the-counter (OTC) drugs for occasional and pregnancy-related complaints, and was observed for potentially unsafe drugs or drugs with unknown safety. None of the womenreported use of FDA X category drugs. CONCLUSIONS: The use of drugs known to be harmful was not observed, but a higher prevalence of exposure to potentially harmful drugs (FDA C/D) was found among Western women who also consumed more OTC drugs. This highlights the need for cautious prescribing for women in the fertile age in general and for continuous monitoring of medication use during pregnancy.

This chapter focuses on cluster analysis in the context of unsupervised data mining. Various facets of cluster analysis, including proximities, are discussed in detail. Techniques of determining the natural number of clusters are described. Finally, techniques of assessing cluster accuracy and reproducibility are detailed. Techniques mentioned in this chapter are expanded upon in the following chapters.

PURPOSE: To compare the incidence of urethral strictures after monopolar transurethral resection of the prostate (TURP) and bipolar transurethral resection in saline (TURIS) for symptomatic benign prostatic hyperplasia. PATIENTS AND METHODS: Between January 2005 and January 2009, 518 patients with symptomatic benign prostate hyperplasia underwent either monopolar or bipolar resection. In a randomized trial, the incidence of urethral strictures after both treatment modalities was analyzed. RESULTS: Over 48 months, 255 patients were treated with conventional TURP and 263 patients with TURIS. Patient related, operation, and hospitalization characteristics were similar in both groups. After a mean follow-up of 32.1 months (range 50-7 months), the incidence of urethral strictures was 2.4% in the TURP group. After a comparable period of 31.4 months (range 50-7 months), the incidence in the TURIS group was 1.5%. No statistically significant difference was obtained (P = 0.539). These values were compared with the results of other randomized controlled trials with the same or other bipolar technology. No statistically significant difference in urethral structures was noticed between monopolar and bipolar resections (P = 0.739). CONCLUSIONS: With a stricture incidence of 1.5%, bipolar transurethral prostate resection has a low stricture rate, comparable with monopolar TURP (2.4%).

A free beta computer program is demonstrated for simulation and design of composite control charts that have overall performance specifications. Composite control charts that can be designed by the software include those based on moving average, exponentially weighted moving average, and cumulative sum control charts. the software package, algorithms contained within the software, and an example of using the software to design a four-component composite cumulative sum control chart are described. Keywords: average difference relative to the average; composite cumulative sum control charts; optimisation; program; stead-state average time-to-signal

A new variable selection wrapper method named the Monte Carlo variable selection (MCVS) method was developed utilizing the framework of the Monte Carlo cross-validation (MCCV) approach. The MCVS method reports the variable selection results in the most conventional and common measure of statistical hypothesis testing, the P-values, thus allowing for a clear and simple statistical interpretation of the results. The MCVS method is equally applicable to the multiple-linear-regression (MLR)-based or non-MLR-based quantitative structure-activity relationship (QSAR) models. The method was applied to blood-brain barrier (BBB) permeation and human intestinal absorption (HIA) QSAR problems using MLR to demonstrate the workings of the new approach. Starting from more than 1600 molecular descriptors, only two (TPSA(NO) and ALOGP) yielded acceptably low P-values for the BBB and HIA problems, respectively. The new method has been implemented in the QSAR-BENCH v2 program, which is freely available (including its Java source code) from www.dmitrykonovalov.org for academic use.

In general, linear modelling techniques such as multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS), are used to model QSAR data. This type of data can be very complex and linear modelling techniques often model only a limited part of the information captured in the data. In this study, it was tried to combine linear techniques with the flexible non-linear technique multivariate adaptive regression splines (MARS). Models were built using an MLR model, combined with either a stepwise procedure or a genetic algorithm for variable selection, a PCR model or a PLS model as starting points for the MARS algorithm. The descriptive and predictive power of the models was evaluated in a QSAR context and compared to the performances of the individual linear models and the single MARS model. In general, the combined methods resulted in significant improvements compared to the linear models and can be considered valuable techniques in modelling complex QSAR data. For the used data set the best model was obtained using a combination of PLS and MARS. This combination resulted in a model with a Pearson correlation coefficient of 0.90 and a cross-validation error, evaluated with 10-fold cross-validation of 9.9%, pointing at good descriptive and high predictive properties.

The use of classification trees for modeling and predicting the passage of molecules through the blood−brain barrier was evaluated. The models were built and evaluated using a data set of 147 molecules extracted from the literature. In the first step, single classification trees were built and evaluated for their predictive abilities. In the second step, attempts were made to improve the predictive abilities using a set of 150 classification trees in a boosting approach. Two boosting algorithms, discrete and real adaptive boosting, were used and compared. High-predictive classification trees were obtained for the data set used, and the models could be improved with boosting. In the context of this research, discrete adaptive boosting gives slightly better results than real adaptive boosting.

Feature selection is a valuable technique in data analysis for information-preserving data reduction. This paper describes Classification and Regression Trees (CART) and Multivariate Regression Trees (MRT)-based approaches for both supervised and unsupervised feature selection. The well-known CART method allows to perform supervised feature selection by modeling one response variable (y) by some explanatory variables (x). The recently proposed CART extension, MRT can handle more than one response variable (y). This allows to perform a supervised feature selection in the presence of more than one response variable. For unsupervised feature selection, where no response variables are available, we propose Auto-Associative Multivariate Regression Trees (AAMRT) where the original variables (x) are not only used as explanatory variables (x), but also as response variables (y=x). Since (AA)MRT is grouping the objects into groups with similar response values by using explanatory variables, this means that the variables are found which are most responsible for the cluster structure in the data. We will demonstrate how these approaches can improve (the detection of) the cluster structure in data and bow they can be used for knowledge discovery.

Classification and regression trees (CART) were evaluated for their potential use in a quantitative structure-activity relationship (QSAR) context. Models were build using the published absorption values for 141 drug-like molecules as response variable and over 1400 molecular descriptors as potential explanatory variables. Both the role of two- and three-dimensional descriptors and their relative importance were evaluated. For the used dataset, CART models showed high descriptive and predictive abilities. The predictive abilities were evaluated based on both cross-validation and an external test set. Application of the variable ranking method to the models showed high importances for the n-octanol/water partition coefficient (log P) and polar surface area (PSA). This shows that CART is capable of selecting the most important descriptors, as known from the literature, for the absorption process in the intestinal tract.

The present study is a follow-up of the research conducted by Jason, Fennell et al. (1995, 1999, 2000) on a multistage theory for chronic fatigue syndrome (CFS). This multistage model is a very promising method for the evaluation of patients suffering from CFS and could facilitate the appropriate selection of various psychosocial therapies that improve the patient's ability to cope with their illness. Four predictive factors emerged with moderate to excellent reliability. A Spearman's rank correlation revealed positive correlations between our four-factor model and the three-factor model identified by Jason et al. (1999). A correlation matrix between the dimensional psychological investigation and the Fennell Phases revealed characteristics as suggested by previous research. Biological parameters varied over the different phases suggesting an important interaction between body and psyche.

The present study is a follow-up of the research conducted by Jason, Fennell et al. (1995,1999, 2000) on a multistage theory for chronic fatigue syndrome (CFS). This multistage model is a very promising method for the evaluation of patients suffering from CFS and could facilitate the appropriate selection of various psychosocial therapies that improve the patient's ability to cope with their illness. Four predictive factors emerged with moderate to excellent reliability. A Spearman's rank correlation revealed positive correlations between our four-factor model and the three-factor model identified by Jason et al. (1999). A correlation matrix between the dimensional psychological investigation and the Fennell Phases revealed characteristics as suggested by previous research. Biological parameters varied over the different phases suggesting an important interaction between body and psyche.

The use of non-linear mixed effects models to describe dissolution data has been evaluated. A theoretical part is included to introduce this approach to scientists who are not familiar with this type of statistics. The standard settings of the statistical software package (S-plus) are used as much as possible. Several mathematical functions like the Weibull, logistic, first-order and Gompertz are employed as basis for the non-linear mixed effects models. Examples are given using dissolution data of immediate and extended release tablets. The results are compared with those obtained using linear mixed effects models.

The performance of linear mixed effects models for the comparison of dissolution profiles is examined. This type of model is frequently used by statisticians, but is rather unknown to people that work in dissolution laboratories. Hence, an extensive theoretical part was introduced to make the methodology more accessible. Firstly, repeated measures ANOVA is discussed, followed by the ‘real’ linear mixed effects models. The theory is applied to two types of dissolution data: one corresponding to an immediate and another to a slow release formulation. We tried to use as much as possible the standard settings of the statistical software (S-plus). Suggestions are given to solve problems encountered during model fitting. It was found that the statistical limits are much more discriminative than the similarity factor.

The application and the analytical aspects of an acid etch microbiopsy method for the in vitro and in vivo determination of trace elements in the surface enamel of human teeth were reassessed. The method, based on the use of 1.6 N hydrochloric acid in 70% glycerol as the etching agent, provided adequate material for trace element analysis. Optimal standardization of the method required the selection of one tooth type and the analysis of calcium and phosphorus in the etching solutions. In order to reach an acceptable level of reproducibility for the in vivo biopsy method, the etch depths should not exceed 4.5-mu-m. Moreover, the reproducibility of the biopsy was increased by increasing the sampling area.

The bioadhesive characteristics of tablets for oral use made from modified starch, polyacrylic acid (PAA), polyethylene glycol (PEG) and sodium carboxymethylcellulose (CMC) were investigated. Adhesion force and energy were determined in-vitro and maximal adhesion time was evaluated in-vivo in human subjects. In-vitro, PAA showed the best bioadhesive properties, followed by modified maize starch and PEG with a mol. wt of 300 000–400 000 daltons. The presence of 0·1 mg of fluoride as NaF did not lead to significant differences in adhesion force and energy for the same formulation. The in-vivo bioadhesion was not strongly correlated to the in-vitro data. PAA, despite its excellent adhesion, proved to be irritating to the mucosa. PEG with a mol. wt of 200000 daltons was subject to erosion. CMC showed good bioadhesive properties but the mechanical strength of the tablets was low. Modified maize starch tablets containing 5% (w/w) PAA and PEG with a mol. wt of 300 000 daltons proved to be the most suitable formulations for a fluoride-slow-release tablet with bioadhesive properties. In-vitro, the tablets released all of the fluoride within the 8 h period, with a high initial release. The release rate was related to the water absorption rate of the tablets. The PAA-containing formulations and the CMC formulations had the fastest release. In-vivo, fluoride levels with a minimum of 150 and a maximum of 1000 μg mL−1 were maintained for 8 h in the oral cavity. These fluoride levels were sustained significantly longer than those obtained with the administration of fourfold the amount of fluoride in the form of a fluoride-containing toothpaste. The release characteristics in-vivo exhibited a high variation. The use of bioadhesive polymers in oral pharmacotherapy seems promising.

Acid etch surface enamel microbiopsies were taken in vitro and in vivo and analyzed for lead using electrothermal atomic absorption spectrometry. The in vitro samples were obtained from subjects resident in an urbanized region in Belgium or from a region close to a nonferrometal industrial plant. The smaller set of in vivo samples were all from subjects resident in an urbanized region. Using a regression tree approach it was possible to identify in a stepwise manner factors that contributed to the variation of lead in the samples. For the in vitro as well as in vivo samples, the etch depth, tooth type, and age of the subjects were identified as significant factors but sex and dental arch quadrant were not. The residual lead levels obtained after regression with the significant factors were better distributed with much lesser variance. Moreover, a significant higher lead concentration could be demonstrated in the in vitro samples from the region close to the nonferrometal industrial plant.

Belgium is among the European countries that are the most affected by allergic rhinitis. Pollen grains and fungal spores represent important triggers of symptoms. However, few studies have investigated their real link with disease morbidity over several years. Based on aeroallergen counts and health insurance datasets, the relationship between daily changes in pollen, fungal spore concentrations and daily changes in reimbursable systemic antihistamine sales has been investigated between 2005 and 2011 in the Brussels-Capital Region. A Generalized Linear Model was used and adjusted for air pollution, meteorological conditions, flu, seasonal component and day of the week. We observed an augmentation in drug sales despite no significant increase in allergen levels in the long term. The relative risk of buying allergy medications associated with an interquartile augmentation in pollen distributions increased significantly for Poaceae, Betula, Carpinus, Fraxinus and Quercus. Poaceae affected the widest age group and led to the highest increase of risk which reached 1.13 (95% CI [1.11-1.14]) among the 19- to 39-year-old men. Betula showed the second most consistent relationship across age groups. Clear identification of the provoking agents may improve disease management by customizing prevention programmes. This work also opens several research perspectives related to impact of climate modification or subpopulation sensitivity.

The intrathyroidal stable iodine (ITI) determined in 776 patients chosen at random. Ninety % of these patients presented with nontoxic goiter. Curve-filtering analysis techniques showed a seasonal variation in ITI: an acrophase was found in April/May, a nadir in September/October. The possible relationship of this seasonal variation with the intake of iodine or alimentary antithyroid substances are discussed, as well as possible relationship with variation in chronic TSH stimulation related to ambient temperature.