• Identification of Requirements for Computer-Supported Matching of Food Consumption Data with Food Composition Data.

      Koroušić Seljak, Barbara; Korošec, Peter; Eftimov, Tome; Ocke, Marga; van der Laan, Jan; Roe, Mark; Berry, Rachel; Crispim, Sandra Patricia; Turrini, Aida; Krems, Carolin; et al. (2018-03-30)
      This paper identifies the requirements for computer-supported food matching, in order to address not only national and European but also international current related needs and represents an integrated research contribution of the FP7 EuroDISH project. The available classification and coding systems and the specific problems of food matching are summarized and a new concept for food matching based on optimization methods and machine-based learning is proposed. To illustrate and test this concept, a study has been conducted in four European countries (i.e., Germany, The Netherlands, Italy and the UK) using different classification and coding systems. This real case study enabled us to evaluate the new food matching concept and provide further recommendations for future work. In the first stage of the study, we prepared subsets of food consumption data described and classified using different systems, that had already been manually matched with national food composition data. Once the food matching algorithm was trained using this data, testing was performed on another subset of food consumption data. Experts from different countries validated food matching between consumption and composition data by selecting best matches from the options given by the matching algorithm without seeing the result of the previously made manual match. The evaluation of study results stressed the importance of the role and quality of the food composition database as compared to the selected classification and/or coding systems and the need to continue compiling national food composition data as eating habits and national dishes still vary between countries. Although some countries managed to collect extensive sets of food consumption data, these cannot be easily matched with food composition data if either food consumption or food composition data are not properly classified and described using any classification and coding systems. The study also showed that the level of human expertise played an important role, at least in the training stage. Both sets of data require continuous development to improve their quality in dietary assessment.
    • Identification of TUB as a novel candidate gene influencing body weight in humans.

      Shiri-Sverdlov, Ronit; Custers, Anne; Vliet-Ostaptchouk, Jana V van; Gorp, Patrick J J van; Lindsey, Patrick J; Tilburg, Jonathan H O van; Zhernakova, Sasha; Feskens, Edith J M; A, Daphne L van der; Dollé, Martijn E T; et al. (2006-02-01)
      Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m(2), P = 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3' end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P = 0.016 and P = 0.010, respectively). Combined analysis confirmed this association (P = 0.005 and P = 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m(2)) from the combined cohort with 289 normal subjects (BMI <25 kg/m(2)) revealed that the protective alleles have a lower frequency in obese subjects (odds ratio 1.32 [95% CI 1.04-1.67], P = 0.022). Altogether, data from the tubby mouse as well as these data suggest that TUB could be an important factor in controlling the central regulation of body weight in humans.
    • Identifying and correcting epigenetics measurements for systematic sources of variation.

      Perrier, Flavie; Novoloaca, Alexei; Ambatipudi, Srikant; Baglietto, Laura; Ghantous, Akram; Perduca, Vittorio; Barrdahl, Myrto; Harlid, Sophia; Ong, Ken K; Cardona, Alexia; et al. (2018)
      Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis.
    • Identifying germ cell mutagens using OECD test guideline 488 (transgenic rodent somatic and germ cell gene mutation assays) and integration with somatic cell testing

      Marchetti, Francesco; Aardema, Marilyn J.; Beevers, Carol; van Benthem, Jan; Godschalk, Roger; Williams, Andrew; Yauk, Carole L.; Young, Robert; Douglas, George R. (2018-08)
    • Identifying the source of food-borne disease outbreaks: An application of Bayesian variable selection.

      Jacobs, Rianne; Lesaffre, Emmanuel; Teunis, Peter Fm; Höhle, Michael; van de Kassteele, Jan (2017-01-01)
      Early identification of contaminated food products is crucial in reducing health burdens of food-borne disease outbreaks. Analytic case-control studies are primarily used in this identification stage by comparing exposures in cases and controls using logistic regression. Standard epidemiological analysis practice is not formally defined and the combination of currently applied methods is subject to issues such as response misclassification, missing values, multiple testing problems and small sample estimation problems resulting in biased and possibly misleading results. In this paper, we develop a formal Bayesian variable selection method to account for misclassified responses and missing covariates, which are common complications in food-borne outbreak investigations. We illustrate the implementation and performance of our method on a Salmonella Thompson outbreak in the Netherlands in 2012. Our method is shown to perform better than the standard logistic regression approach with respect to earlier identification of contaminated food products. It also allows relatively easy implementation of otherwise complex methodological issues.
    • IL-18 reduces ultraviolet radiation-induced DNA damage and thereby affects photoimmunosuppression.

      Schwarz, Agatha; Maeda, Akira; Ständer, Sonja; Steeg, Harry van; Schwarz, Thomas (2006-03-01)
      UV-induced DNA damage has been recognized as the major molecular trigger for photoimmunosuppression. IL-12 prevents UV-induced immunosuppression via its recently discovered capacity to reduce DNA damage presumably via induction of DNA repair. Because IL-18 shares some biological activities with IL-12 we studied the effect of IL-18 on UV-induced DNA damage and immunosuppression. IL-18 reduced UV-induced apoptosis of keratinocytes and supported long-term cell survival on UV exposure. Injection of IL-18 into mice that were exposed to UV radiation significantly lowered the number of apoptotic keratinocytes. Accordingly, radiation immunohistochemistry revealed reduced amounts of DNA damage in epidermal cells upon injection of IL-18. These effects were not observed in DNA repair-deficient (XpaKO) mice, indicating that IL-18 like IL-12 reduces DNA damage via DNA repair. UV-mediated suppression of the induction of contact hypersensitivity, which is known to be primarily triggered by DNA damage, was prevented upon injection of IL-18 before UV exposure in wild-type but not in XpaKO mice. In contrast to IL-12, IL-18 was not able either in wild-type or in XpaKO mice to break UV-induced immunotolerance that is mediated via regulatory T cells rather than in a DNA damage-dependent fashion. This result indicates that IL-12 is still unique in its capacity to restore immune responses because of its effect on regulatory T cells. Together, these data identify IL-18 as a further cytokine that exhibits the capacity to affect DNA repair. Though being primarily a proinflammatory cytokine through this capacity, IL-18 can also foster an immune response that is suppressed by UV radiation.
    • Immune response-eliciting exposure to Campylobacter vastly exceeds the incidence of clinically overt campylobacteriosis but is associated with similar risk factors: A nationwide serosurvey in the Netherlands.

      Monge, Susana; Teunis, Peter; Friesema, Ingrid; Franz, Eelco; Ang, Wim; van Pelt, Wilfrid; Mughini-Gras, Lapo (2018-05-07)
      We aimed to estimate population-level exposure to Campylobacter and associated risk factors, using three approaches for serological data analysis.
    • Immune Responses After 2 Versus 3 Doses of HPV Vaccination up to 4½ Years After Vaccination: An Observational Study Among Dutch Routinely Vaccinated Girls.

      Donken, Robine; Schurink-Van't Klooster, Tessa M; Schepp, Rutger M; van der Klis, Fiona R M; Knol, Mirjam J; Meijer, Chris J L M; de Melker, Hester E (2017-02-01)
      In 2014 the Netherlands switched from 3 to 2 doses for routine vaccination with the prophylactic bivalent human papillomavirus (HPV) vaccine. The current study explored whether antibody responses are noninferior after 2 versus 3 doses in girls.
    • Immunity against measles, mumps, rubella, varicella, diphtheria, tetanus, polio, hepatitis A and hepatitis B among adult asylum seekers in the Netherlands, 2016.

      Freidl, Gudrun S; Tostmann, Alma; Curvers, Moud; Ruijs, Wilhelmina L M; Smits, Gaby; Schepp, Rutger; Duizer, Erwin; Boland, Greet; de Melker, Hester; van der Klis, Fiona R M; et al. (2018-02-14)
      Asylum seekers are a vulnerable population for contracting infectious diseases. Outbreaks occur among children and adults. In the Netherlands, asylum seeker children are offered vaccination according to the National Immunization Program. Little is known about protection against vaccine-preventable diseases (VPD) in adult asylum seekers. In this 2016 study, we assessed the immunity of adult asylum seekers against nine VPD to identify groups that might benefit from additional vaccinations. We invited asylum seekers from Syria, Iran, Iraq, Afghanistan, Eritrea and Ethiopia to participate in a serosurvey. Participants provided informed consent and a blood sample, and completed a questionnaire. We measured prevalence of protective antibodies to measles, mumps, rubella, varicella, diphtheria, tetanus, polio type 1-3 and hepatitis A and B, stratified them by country of origin and age groups. The median age of the 622 participants was 28 years (interquartile range: 23-35), 81% were male and 48% originated from Syria. Overall, seroprotection was 88% for measles (range between countries: 83-93%), 91% for mumps (81-95%), 94% for rubella (84-98%), 96% for varicella (92-98%), 82% for diphtheria (65-88%), 98% for tetanus (86-100%), 91% (88-94%) for polio type 1, 95% (90-98%) for polio type 2, 82% (76-86%) for polio type 3, 84% (54-100%) for hepatitis A and 27% for hepatitis B (anti-HBs; 8-42%). Our results indicate insufficient protection against certain VPD in some subgroups. For all countries except Eritrea, measles seroprotection was below the 95% threshold required for elimination. Measles seroprevalence was lowest among adults younger than 25 years. In comparison, seroprevalence in the Dutch general population was 96% in 2006/07. The results of this study can help prioritizing vaccination of susceptible subgroups of adult asylum seekers, in general and in outbreak situations.
    • Immunodominance in T cell responses elicited against different domains of detoxified pneumolysin PlyD1

      van Westen, Els; Poelen, Martien C. M.; van den Dobbelsteen, Germie P. J. M.; Oloo, Eliud O.; Ochs, Martina M.; Rots, Nynke Y.; van Els, Cecile A. C. M. (2018-03-06)
    • Immunogenicity of Influenza Vaccines: Evidence for Differential Effect of Secondary Vaccination on Humoral and Cellular Immunity.

      Rosendahl Huber, Sietske K; Hendriks, Marion; Jacobi, Ronald H J; van de Kassteele, Jan; Mandersloot-Oskam, Jolanda C; van Boxtel, Renée A J; Wensing, Anne M J; Rots, Nynke Y; Luytjes, Willem; van Beek, Josine (2018-01-01)
      While currently used influenza vaccines are designed to induce neutralizing antibodies, little is known on T cell responses induced by these vaccines. The 2009 pandemic provided us with the opportunity to evaluate the immune response to vaccination in a unique setting. We evaluated both antibody and T cell responses in a cohort of public health care workers (18-52 years) during two consecutive influenza seasons from 2009 to 2011 and compared the MF59-adjuvanted pandemic vaccine with the unadjuvanted seasonal subunit vaccine that included the pandemic strain [The study was registered in the Netherlands Trial Register (NTR2070)]. Antibody responses were determined in serum by a hemagglutination inhibition assay. Vaccine-specific T cell responses were evaluated by detecting IFN-γ producing peripheral blood mononuclear cells using whole influenza virus or vaccine-specific peptide pools as stimulating antigens. Mixed effects regression models were used to correct the data for influenza-specific pre-existing immunity due to previous infections or vaccinations and for age and sex. We show that one dose of the pandemic vaccine induced antibody responses sufficient for providing seroprotection and that the vaccine induced T cell responses. A second dose further increased antibody responses but not T cell responses. Nonetheless, both could be boosted by the seasonal vaccine in the subsequent season. Furthermore, we show that the seasonal vaccine alone is capable of inducing vaccine-specific T cell responses, despite the fact that the vaccine did not contain an adjuvant. In addition, residual antibody levels remained detectable for over 15 months, while T cell levels in the blood had contracted to baseline levels by that time. Hereby, we show that pandemic as well as seasonal vaccines induce both humoral and cellular responses, however, with a different profile of induction and waning, which has its implications for future vaccine design.
    • The immunomodulatory effects of measles-mumps-rubella (MMR) vaccination on persistence of heterologous vaccine responses.

      Zimmermann, Petra; Perrett, Kirsten P; van der Klis, Fiona R M; Curtis, Nigel (2019-02-21)
      It is proposed that measles-containing vaccines (MCV) have immunomodulatory effects which include a reduction in all-cause childhood mortality. The antibody response to heterologous vaccines provides a means to explore these immunomodulatory effects. This is the first study to investigate the influence of measles-mumps-rubella (MMR) vaccine on the persistence of antibodies to a broad range of heterologous infant vaccinations given in the first year of life. In total, 319 children were included in the study. All infants received routine vaccinations at 6 weeks, 4 and 6 months of age. At 12 months of age, 212 children were vaccinated with measles-mumps-rubella (MMR) and Haemophilus influenzae type b-meningococcus C (Hib-MenC) vaccine while the remaining 99 children had not yet received this vaccine. In the MMR/Hib-MenC-vaccinated group, blood was taken 28 ± 14 days after receiving these vaccines. Antibodies against diphtheria, tetanus, pertussis (pertussis toxin, filamentous haemagglutinin, pertactin), poliomyelitis (type 1, 2, 3) and 13 pneumococcal serotypes were measured. Geometric mean antibody concentrations (GMC) and seroprotection rates were compared between MMR/MenC-Hib-vaccinated and MMR/MenC-Hib-naïve participants. In the final analysis, 311 children were included. Seroprotection rates were lower in MMR/Hib-MenC-vaccinated children against pertussis toxin and pneumococcus serotype 19A. After adjustment for pre-specified factors, MMR/Hib-MenC-vaccinated infants had significantly higher antibody concentrations against tetanus (likely explained by a boosting effect of the carrier protein, a tetanus toxoid), while for the other vaccine antigens there was no difference in antibody concentrations between the two groups. This article is protected by copyright. All rights reserved.
    • Immunotoxic effects of chemicals: A matrix for occupational and environmental epidemiological studies.

      Veraldi, Angela; Costantini, Adele Seniori; Bolejack, Vanessa; Miligi, Lucia; Vineis, Paolo; Loveren, Henk van (2006-12-01)
      BACKGROUND: Many biological and chemical agents have the capacity to alter the way the immune system functions in human and animals. This study evaluates the immunotoxicity of 20 substances used widely in work environments. METHODS: A systematic literature search on the immunotoxicity of 20 chemicals was performed. The first step was to review literature on immunotoxicity testing and testing schemes adopted for establishing immunotoxicity in humans. The second step consisted of providing a documentation on immunotoxicity of substances that are widely used in work environment, by building tables for each chemical of interest (benzene, trichloroethylene, PAHs, crystalline silica, diesel exhausts, welding fumes, asbestos, styrene, formaldehyde, toluene, vinyl chloride monomer, tetrachloroethylene, chlorophenols, 1,3-butadiene, mineral oils, P-dichlorobenzene, dichloromethane, xylene, 1,1,1-trichloroethane, ethylene oxide). The third step was the classification of substances; an index (strong, intermediate, weak, nil) was assigned on the basis of the evidence of toxicity and type of immunotoxic effects (immunosuppression, autoimmunity, hypersensitivity) on the basis of the immune responses. Finally substances were assigned a score of immunotoxic power. RESULTS: Tables have been produced that include information for the 20 substances of interest, based on 227 animal studies and 94 human studies. Each substance was assigned an index of immunotoxic evidence, a score of immunotoxic power and type of immunotoxic effect. CONCLUSIONS: This matrix can represent a tool to identify chemicals with similar properties concerning the toxicity for the immune system, and to interpret epidemiological studies on immune-related diseases.
    • Immunotoxicity Testing of Nanomedicinal Products: Possible Pitfalls in Endotoxin Determination

      Giannakou, Christina; E. Geertsma, Robert; H. de Jong, Wim; van Loveren, Henk; J. Vandebriel, Rob; VDZ Park, Margriet (2017-01-05)
    • Immunotoxicology: A brief history, current status and strategies for future immunotoxicity assessment.

      Germolec, Dori; Luebke, Robert; Rooney, Andrew; Shipkowski, Kelly; Vandebriel, Rob; van Loveren, Henk (2017-08)
    • Impact and cost-effectiveness of different vaccination strategies to reduce the burden of pneumococcal disease among elderly in the Netherlands.

      Thorrington, Dominic; van Rossum, Leo; Knol, Mirjam; de Melker, Hester; Rümke, Hans; Hak, Eelko; van Hoek, Albert Jan (2018)
      Streptococcus pneumoniae causes morbidity and mortality among all ages in The Netherlands. To reduce this burden, infants in The Netherlands receive the 10-valent pneumococcal conjugated vaccine (PCV10), but older persons are not targeted. We assessed the impact and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23) or 13-valent PCV (PCV13) among all those aged 60, 65 or 70 and/or in combination with replacing PCV10 with PCV13 in the infant vaccination programme.
    • Impact of a proposed revision of the IESTI equation on the acute risk assessment conducted when setting maximum residue levels (MRLs) in the European Union (EU): A case study.

      Breysse, Nicolas; Vial, Gaelle; Pattingre, Lauriane; Ossendorp, Bernadette C; Mahieu, Karin; Reich, Hermine; Rietveld, Anton; Sieke, Christian; van der Velde-Koerts, Trijntje; Sarda, Xavier (2018-06-03)
      Proposals to update the methodology for the international estimated short-term intake (IESTI) equations were made during an international workshop held in Geneva in 2015. Changes to several parameters of the current four IESTI equations (cases 1, 2a, 2b, and 3) were proposed. In this study, the overall impact of these proposed changes on estimates of short-term exposure was studied using the large portion data available in the European Food Safety Authority PRIMo model and the residue data submitted in the framework of the European Maximum Residue Levels (MRL) review under Article 12 of Regulation (EC) No 396/2005. Evaluation of consumer exposure using the current and proposed equations resulted in substantial differences in the exposure estimates; however, there were no significant changes regarding the number of accepted MRLs. For the different IESTI cases, the median ratio of the new versus the current equation is 1.1 for case 1, 1.4 for case 2a, 0.75 for case 2b, and 1 for case 3. The impact, expressed as a shift in the IESTI distribution profile, indicated that the 95th percentile IESTI shifted from 50% of the acute reference dose (ARfD) with the current equations to 65% of the ARfD with the proposed equations. This IESTI increase resulted in the loss of 1.2% of the MRLs (37 out of 3110) tested within this study. At the same time, the proposed equations would have allowed 0.4% of the MRLs (14 out of 3110) that were rejected with the current equations to be accepted. The commodity groups that were most impacted by these modifications are solanacea (e.g., potato, eggplant), lettuces, pulses (dry), leafy brassica (e.g., kale, Chinese cabbage), and pome fruits. The active substances that were most affected were fluazifop-p-butyl, deltamethrin, and lambda-cyhalothrin.
    • The impact of ambient air pollution on the human blood metabolome.

      Vlaanderen, J J; Janssen, N A; Hoek, G; Keski-Rahkonen, P; Barupal, D K; Cassee, F R; Gosens, I; Strak, M; Steenhof, M; Lan, Q; et al. (2017-07)
      Biological perturbations caused by air pollution might be reflected in the compounds present in blood originating from air pollutants and endogenous metabolites influenced by air pollution (defined here as part of the blood metabolome). We aimed to assess the perturbation of the blood metabolome in response to short term exposure to air pollution.
    • Impact of an Outdoor Smoking Ban at Secondary Schools on Cigarettes, E-Cigarettes and Water Pipe Use among Adolescents: An 18-Month Follow-Up.

      Rozema, Andrea D; Hiemstra, Marieke; Mathijssen, Jolanda J P; Jansen, Maria W J; van Oers, Hans J A M (2018-01-25)
      Abstract: The effectiveness of outdoor smoking bans on smoking behavior among adolescents remains inconclusive. This study evaluates the long-term impact of outdoor school ground smoking bans among adolescents at secondary schools on the use of conventional cigarettes, e-cigarettes (with/without nicotine) and water pipes. Outdoor smoking bans at 19 Dutch secondary schools were evaluated using a quasi-experimental design. Data on 7733 adolescents were obtained at baseline, and at 6 and 18-month follow-up. The impact of outdoor smoking bans on 'ever use of conventional cigarettes', 'smoking onset', 'ever use of e-cigarette with nicotine', 'e-cigarette without nicotine', and 'water pipe' was measured. Multilevel logistic regression analysis was used. At schools with a ban, implementation fidelity was checked. At schools where a ban was implemented, at 18-month follow-up more adolescents had started smoking compared to the control condition. No effect of implementation of the ban was found for smoking prevalence, e-cigarettes with/without nicotine, and water pipe use. Implementation fidelity was sufficient. No long-term effects were found of an outdoor smoking ban, except for smoking onset. The ban might cause a reversal effect when schools encounter difficulties with its enforcement or when adolescents still see others smoking. Additional research is required with a longer follow-up than 18 months.