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In this paper, we propose a method to cluster multivariate functional data with missing observations. Analysis of functional data often encompasses dimension reduction techniques such as principal component analysis (PCA). These techniques require complete data matrices. In this paper, the data are completed by means of multiple imputation, and subsequently each imputed data set is submitted to a cluster procedure. The final partition of the data, summarizing the partitions obtained for the imputed data sets, is obtained by means of ensemble clustering. The uncertainty in cluster membership, due to missing data, is characterized by means of the agreement between the members of the ensemble and fuzziness of the consensus clustering. The potential of the method was brought out on the heart failure (HF) data. Daily measurement for four biomarkers (heart rate, diastolic, and systolic blood pressure, weight) were used to cluster the patients. To normalize the distributions of the longitudinal outcomes, the data were transformed with a natural logarithm function. A cubic spline base with 69 basis functions was employed to smooth the profiles. The proposed algorithm indicates the existence of a latent structure and divides the HF patients into two clusters, showing a different evolution in blood pressure values and weight. In general, cluster results are sensitive to choices made. Likewise for the proposed approach, alternative choices for the distance measure, procedure to optimize the objective function, choice of the scree-test threshold, or the number of principal components, to be used in the approximation of the surrogate density, could all influence the final partition. For the HF data set, the final partition depends on the number of principal components used in the procedure. ; The authors gratefully acknowledge support from IAP research Network P7/06 of the Belgian government (Belgian Science Policy).

Finite mixture models have been used to model population heterogeneity and to relax distributional assumptions. These models are also convenient tools for clustering and classification of complex data such as, for example, repeated-measurements data. The performance of model-based clustering algorithms is sensitive to influential and outlying observations. Methods for identifying outliers in a finite mixture model have been described in the literature. Approaches to identify influential observations are less common. In this paper, we apply local-influence diagnostics to a finite mixture model with known number of components. The methodology is illustrated on real-life data. ; The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support from the IAP research Network P7/06 of the Belgian government (Belgian Science Policy) is gratefully acknowledged.

Degeneration of the aortic wall becomes life-threatening when the risk of rupture increases. Cluster analysis on repeated measures of the diameter of the artery revealed two subgroups of patients included in a surveillance program. These results were obtained under the assumption of missingness at random. In this article, we study the vulnerability of the cluster analysis results - the estimated trajectories and the posterior membership probabilities - by applying different missing-data models for non-ignorable dropout, as proposed by Muthen et al. (2011) to the growth of the diameter of the artery. ; The authors gratefully acknowledge support from IAP research Network P7/06 of the Belgian Government (Belgian Science Policy). We are grateful to the Department of Clinical Chemistry, Maastricht University Medical Center (MUMC), Maastricht, for kind permission to use the AAA data.

Persistent disturbing behaviour refers to a chronic condition in highly unstable, therapy resistant psychiatric patients. Because these patients are difficult to maintain in their natural living environment and even in hospital wards, purposely designed residential psychiatric facilities need to be established. Therefore, it is important to define and circumscribe the group carefully. Serroyen and co-workers, starting from the longitudinal analysis of a score based on data from the Belgian national psychiatric registry, undertook a discriminant analysis to distinguish persistent disturbing behaviour patients from a control group. They also indicated that there is scope for further subdividing the persistent disturbing behaviour patients into two subgroups, using conventional cluster analysis techniques. We employ a variety of novel longitudinal-data-based cluster analysis techniques. These are based on either conventional growth models, growth-mixture models or latent class growth models. Unlike in earlier analyses, where some evidence for two groups was found, there now is an indication of three groups, which is a finding with high practical and organizational relevance. ; The authors gratefully acknowledge financial support from the Interuniversity Attraction Pole research network P6/03 of the Belgian Government (Belgian Science Policy).

Background Patients infected with severe acute respiratory syndrome coronavirus (SARS-CoV-2) can develop severe illness necessitating intensive care admission. Critically ill patients are susceptible for the development of secondary bacterial infections. Due to a combination of virus- and drug-induced immunosuppression, critically ill patients with corona virus disease 2019 (COVID-19) may even have a higher risk of developing a secondary infection. These secondary infections can aggravate the severity of illness and increase the risk of death. Further research on secondary infections in COVID-19 patients is essential. Therefore, the objective of this study was to investigate the incidence and associated risk factors of secondary bacterial infections and to identify the most common groups of pathogens in critically ill COVID-19 patients. Methods This mono-center, retrospective observational cohort study was performed at the intensive care unit (ICU) of the Jessa Hospital, Hasselt, Belgium. All adult COVID-19 patients admitted to the ICU from 13th March 2020 until 17th October 2020, were eligible for inclusion in the study. Data from the resulting 116 patients were prospectively entered into a customized database. The resulting database was retrospectively reviewed to investigate three types of secondary bacterial infections (secondary pneumonia, bloodstream infections of unknown origin, catheter-related sepsis). Results Of 94 included patients, 68% acquired at least one of the studied secondary bacterial infections during their ICU stay. Almost two thirds of patients (65.96%, n = 62) acquired a secondary pneumonia, whereas 29.79% (n = 28) acquired a bacteremia of unknown origin and a smaller proportion of patients (14.89%, n = 14) acquired a catheter-related sepsis. Male gender (P = 0.05), diabetes mellitus (P = 0.03) and the cumulative dose of corticosteroids (P = 0.004) were associated with increased risk of secondary bacterial infection. The most common pathogens detected in the cultures of patients with secondary pneumonia were Gram-negative bacilli. Bacteremia of unknown origin and catheter-related sepsis were mostly caused by Gram-positive cocci. Conclusion This study confirms that the incidence of secondary bacterial infections is very high in critically ill COVID-19 patients. These patients are at highest risk of developing secondary pneumonia. Male gender, a history of diabetes mellitus and the administration of corticosteroids were associated with increased risk of secondary bacterial infection. ; This study is part of the Limburg Clinical Research Program (LCRP) UHasseltZOL-Jessa, supported by the foundation Limburg Sterk Merk, province of Limburg, Flemish government, Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital.

The Centre of Expertise for Health and Environment started biomonitoring campaign at the end of 2001, in Flanders (Belgium). The main purpose of this project, funded by the Flemish government, is to investigate the relationship between environmental pollution and human health. This is done by measuring pollutants and health effects in human beings. Social scientists cooperating with the environmental and health experts proposed to include a questionnaire on risk perception related to environment and health. Taking into account, risk perception is important with regard to risk communication, risk assessment and the management of complex issues such as health and environment. We present the results of our survey of 1165 mothers of newborn babies, who participated in the first campaign of the biomonitoring. The perception research discussed in this paper can be evaluated as a succesful experiment, with potential for further development and use.

Background:The Sequential Organ Failure Assessment (SOFA) score has been developed to score the severity of organ dysfunction in critically ill sepsis patients and has been proven to have a high predictive value for intensive care unit (ICU) mortality in severely ill patients. Our goal was to evaluate the prognostic value of the SOFA score as well as trends in SOFA score for ICU mortality in COVID-19 patients. Methods: All consecutive patients with confirmed COVID-19 pneumonia admitted to the ICU between March 13th, 2020, and October 17th, 2020 were included in this retrospective cohort study. The worst SOFA score was evaluated daily. Multiple logistic regression models were used to evaluate the predictive value of SOFA in ICU mortality. Results: 103 patients were included in this study. 30 patients (29%) died during their ICU stay and 73 (71%) patients were discharged alive. The ICU admission SOFA score was 5.2 +/- 3.3 in ICU non-survivors vs. 4.3 +/- 2.9 in ICU survivors (P = 0.15). The maximum SOFA score in ICU non-survivors was 11.7 +/- 4.7 vs. 7.4 +/- 4.3 in ICU survivors. SOFA scores increased the first week in both survivors and non-survivors, but the increase was less pronounced in survivors. In the multiple logistic regression models, neither admission SOFA score nor combination with delta SOFA in the first 48 hours was statistically significantly related to ICU mortality. Only the maximum SOFA score remained significant (OR = 1.23, 95% CI: 1.11-1.37, P < 0.001) in the multiple logistic models with an AUC of 0.91. Conclusions: Evaluation of SOFA scores in the first 48 hours after ICU admission is not a good prognostic indicator in COVID-19 patients. Only the maximum SOFA score was predictive for ICU mortality. ; 1. Assistance with the article: This study is part of the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk, province of Limburg, Flemish government, Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. 2. Financial support ...

Background: Environmental justice research suggests that inequalities in the distribution of environmental exposure to chemical pollution systematically disadvantage the lower social strata of society. The effects of these inequalities on the human exposure to pollution are however to a large extend unknown. The purpose of this study is to assess social gradients in human biomonitoring results of a representative sample of Flemish adolescents. Methods: We investigate the associations between individual socioeconomic status (SES), measured by parental educational attainments, and internal body concentration of seven chemical compounds in biological samples of 1642 adolescents aged 14–15 in Flanders (Belgium): PCBs, HCB, DDE, lead, cadmium, benzene and PAHs. Social gradients in average and high exposure to these biomarkers were examined with geometric means and odds ratios (with 95% confidence intervals), using multiple regression models, controlling for covariates and confounders. Results: Depending on the (type of) pollutant, adolescents with a lower SES either have higher or lower internal concentrations. Chlorinated compounds (PCBs and pesticides HCB and DDE) are positively associated with SES (higher exposures for higher SES), while heavy metals (lead and cadmium) are negatively associated (higher exposures for lower SES). For metabolites of organic compounds (benzene and PAHs) we find no association with SES. Socially constructed factors, such as dietary and lifestyle habits, play an important role in these relations. Conclusions: Our study suggests that the association between individual SES and the internal body concentration of exposure to environmental pollutants in Flemish adolescents is more complex than can be assumed on the basis of the environmental justice hypothesis. ; Flemish Government (Department of Science, Department of Public Health and Environment, Nature and Energy Department)

Introduction: Previous studies suggested that green space is beneficial for the cognitive development in children. However, evidence in adolescents is limited. Therefore, we aim to investigate green space exposure in association with attention and behaviour in adolescents. Methods: This study includes 596 Flemish adolescents between 13 and 17 years old. Attention was assessed with Stroop Test (selective attention) and Continuous Performance Test (sustained and selective attention). Behaviour was determined based on the Strengths and Difficulties Questionnaire. Green space was estimated in several radius distances around their current residence and school based on high-resolution land cover data. Multilevel regression analyses were used adjusting for participant's age, sex, education level of the mother, and area deprivation index. Results: Surrounding green space in a 2000 m radius is associated with a faster reaction time in adolescents. An IQR (13%) increment in total green space within 2000 m of the residence and school combined, is associated with a 32.7 ms (95% CI: -58.9 to -6.5; p = 0.02) and a 7.28 ms (95% CI: -11.7 to -2.8; p = 0.001) shorter mean reaction time between the presentation of a stimulus and the response based on the Stroop Test and the Continuous Performance Test. Subdividing green space based on vegetation height, shows that green space higher than 3 m is associated with a faster reaction time of the Continuous Performance Test (-6.50 ms; 95% CI: -10.9 to -2.2; p = 0.004), while low green is not. We did not find an association between green space and behavioural development in adolescents. Conclusions: Our study shows that green space, especially trees, surrounding the residence and school combined is associated with better sustained and selected attention in adolescents. These findings indicate that the availability of green is important for adolescents that are growing up in a rapidly urbanizing world. ; Government of Flanders, Department of Environment & Spatial Development;

Background : Hepatitis C is a viral infection caused by the hepatitis C virus (HCV) with people who inject drugs as the main group at risk worldwide.Aim : This study investigated the differences in uptake for HCV screening and treatment between persons in opioid substitution therapy (OST) and the other members of the Christian Health Insurance Fund in Belgium.Methods : Invoice data were retrospectively collected from the Christian Health Insurance Fund, representing 42% of the healthcare users. Information on demographics, screening, diagnostic tests, treatment and disease progression was obtained from 2008 till 2013. All people in this study were aged 20-65 year. Persons in the OST group were identified as having at least one prescription reimbursed for methadone. This group was compared to the other members of the Insurance Fund not on OST (NOST).Results : The Insurance Fund registered 8,409 unique OST and 3,525,190 members in the general group. HCV RNA screening rate was higher in the OST group after correction for age and gender (4.3% vs. 0.2%). Ribavirin reimbursement, did not differ between the OST and NOST group screened for HCV RNA (16.9% vs. 14.4%), though the probability of having ribavirin reimbursed was smaller for females than for males. Procedures concerning disease progression were reimbursed less frequently in the HCV RNA screened OST group compared to the NOST group (0.3% vs. 1.2%).Conclusion : People on OST were screened more often for HCV RNA. However, the general uptake for HRA screening and treatment in both populations remained suboptimal. ; This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements This study is part of the 'Limburg Clinical Research Center (LCRC), supported by the foundation Limburg Sterk Merk, province of Limburg, Flemish government, Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. D.B., N.H. and G.R. are part of the FWO project G0B2317N.

Abstract
Background
PFAS are persistent, bioaccumulative compounds repelling water, oil and stains which are widely used. There is mounting evidence linking exposure to a range of adverse health outcomes including renal, hepatic, immunotoxic, reproductive, endocrine disrupting and carcinogenic effects. PFAS possibly also induce neurobehavioral and developmental effects. Within Flanders Environment and Health Studies (FLEHS) internal exposure to PFAS and relevant health effects are assessed since 2008.

Results
Adolescents 14–15 y (2010–2011) living in an industrially contaminated area (without known PFAS contamination) and adults 50–65 y (2014) randomly sampled from the general Flemish population using a stratified clustered multi-stage design, were recruited. For the adolescents perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were measured in serum, for the adults PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) and perfluorobutane sulfonate (PFBS). In adolescents the Neurobehavioral Evaluation System (NES3) computerized battery of tests developed to study the neurological effects of an exposure to environmental agents was applied. The adults did the Stroop test, the NES3 Continuous Performance Test and the NES3 Digit Span Test. In adolescents sleepiness, masculinity and femininity were assessed via the Epworth Sleepiness Scale and Personal Attributes Questionnaires, respectively. In adolescents PFOA was associated with significantly increased somnolence, and PFOS with a significant inverse association with boys' femininity and with girls' masculinity. In adolescents, PFAS were also associated with a marginal decrease in sustained attention (PFOS) and cognitive performance (PFOA) and a significant decrease in short-term memory (PFOS). However, in older adults PFOS was associated with a significant increase in the capacity to pay attention and PFHxS with a significant increase in sustained attention.

Conclusion
Our observations point to neurobehavioral and cognitive effects of PFAS. The neurobehavioral effects might in part result from the changes in sex hormone levels that have been reported to be associated with internal exposure to PFAS. Interestingly, whereas in relation to cognition some adverse effects were recorded for adolescents, for elderly persons our observations rather suggest possible weak positive effects with respect to cognition. Our observations might be in line with the view that PFAS have many, sometimes contrasting health effects.

Lipophilic contaminants are present in the environment and bioaccumulate in the food chain. Therefore, their intake via animal fat of various sources was assessed for three age groups of the Flemish population, participating in a large biomonitoring program of the Flemish government. In total, 1636 adolescents (14-15 years), I 186 mothers (18-44 years), and 1586 adults (50-65 years) participated in the study and completed a semi quantitative food frequency questionnaire. Individual consumption data were combined, via a so-called simple distribution approach, with recent data on polychlorinated dibenzo-p-dioxins/furans and dioxin-like polychlorinated biphenyls, measured via the chemical-activated luciferase gene expression (CALUX) bio-assay in food items available on the Flemish market. The median (95th percentile) estimated intakes of dioxin-like contaminants were 2.24 (4.61), 2.09 (4.26), and 1.74 (3.53) pg CALUX-TEQ kg(-1) bw d(-1) for, respectively adolescents, mothers and adults. These data are in the same range as those found in other European studies. The CALUX-TEQ results of respectively 59.8%, 53.7% and 36.2% of the adolescent, mother and adult population exceed the tolerable weekly intake (TWI) of 14 pg WHO-TEQ kg(-1) bw w(-1), as derived by the Scientific Committee on Food [Scientific Committee on Food, 2001. Opinion of the Scientific Committee on Food on the Risk Assessment of Dioxins and Dioxin-like PCBs in Food, CS/CNTM/DIOXIN/20 final Brussels, Belgium]. The main contributors of dioxin-like substances are fish and seafood (25-43% of the total intake), added fats (22-25% of the total intake) and dairy products (17-20% of the total intake). (c) 2007 Elsevier Ltd. All rights reserved.

Abstract
Background
The successive FLEHS campaigns assess internal exposure to pollutants and associated early biological and health effects in participants of different age groups.

Materials and methods
Mother–newborn pairs (N = 220 in 2008–2009, age 18–42 years; N = 269 in 2013–2014, age 18–44 years), 197 adolescents 14–15 years (2010–2011), 201 adults 20–40 years (2008–2009) and 205 adults 50–65 years (2014) were recruited. For the various groups of subjects different sets of PFAS were assessed. Perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorobutane sulfonate (PFBS) were determined in cord plasma and peripheral serum as these were the PFAS compounds for which we had access to high quality measurements and which were expected to be present in the highest concentrations. Participants filled out a questionnaire based on the European Community Respiratory Health Survey questionnaire on asthma and allergy. In these cross-sectional studies associations were assessed using stepwise multiple logistic regression, with confounders (including smoking and familial occurrence of the disease) and potential covariates selected on the basis of experience in our previous studies and a literature search. Forest plots of odds ratios summarize the associations between the various PFAS on the one hand and the different immune outcomes on the other hand.

Results
For several self-reported immune system-related diseases inverse associations with PFAS serum concentrations were observed. These inverse associations were more pronounced in mothers and adults than in adolescents. A significant inverse association was observed in adults and mothers (for mothers based on measurements on cord plasma) between PFNA, PFOS, and PFHxS and asthma (for mothers also for PFOA), in mothers between PFHxS, PFNA and PFOS and allergic rhinitis, in mothers and adults between PFHxS and PFOS and some forms of allergy (for mothers also for PFOA), in adults between PFOA and eczema, and in adolescents between PFOS and systemic allergy.

Conclusion
Internal exposure to PFAS was associated with changes in immunological processes consistent with what has been reported in the literature. Whereas these changes were observed in many publications to be associated with adverse health effects, our findings suggest that they can also lead to inverse associations with certain immune system-related diseases.