Anna G. C. Boef

National Institute for Public Health and the Environment

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Saskia le Cessie

Leiden University Medical Center

Olaf M. Dekkers

Leiden University Medical Center

Jan P. Vandenbroucke

Aarhus University

Fiona van der Klis

National Institute for Public Health and the Environment

Mirjam J. Knol

National Institute for Public Health and the Environment

Hester E. de Melker

National Institute for Public Health and the Environment

David van Bodegom

Leiden University Medical Center

Rudi G. J. Westendorp

University of Copenhagen

Nynke Y. Rots

National Institute for Public Health and the Environment

Linda May

Leiden University Medical Center

Cooperative Institutions

Leiden University Medical Center

National Institute for Public Health and the Environment

Leiden University

University Medical Center Utrecht

Amsterdam University Medical Centers

University of Groningen

University of Amsterdam

University Medical Center Groningen

Utrecht University

University College London

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Parasitic infections and immune function: Effect of helminth infections in a malaria endemic area

Immunobiology (2012)

Anna G. C. Boef Linda May David van Bodegom Lisette van Lieshout Jaco J. Verweij

According to the hygiene hypothesis, reduced exposure to infections could explain the rise of atopic diseases in high-income countries. Helminths are hypothesised to alter the host's immune response in order to avoid elimination and, as a consequence, also reduce the host responsiveness to potential allergens. To elucidate the effect of current helminth infections on immune responsiveness in humans, we measured cytokine production in a rural Ghanaian population in an area with multiple endemic parasites including malaria, intestinal helminths and protozoa. Multiplex real-time PCR in stool samples was used for the detection of four gastrointestinal helminths, of which only Necator americanus was commonly present. A similar assay was used to test for Giardia lamblia in stool samples and malaria infection in venous blood samples. Levels of the cytokines interleukin (IL)-10, tumour necrosis factor (TNF)-α, IL-17, IL-6, IL-13, and interferon (IFN)-γ were determined in whole-blood samples ex vivo-stimulated either with lipopolysaccharide (LPS) and zymosan (for innate cytokine production) or the T-cell mitogen phytohaemagglutinin (PHA). There were no significant differences in either innate or PHA-stimulated cytokine production dependent on current N. americanus infection. Plasmodium falciparum malarial infection was associated with a pro-inflammatory response indicated by increased innate production of TNF-α, IL-17 and IL-6. There was no clear pattern in cytokine responses dependent on G. lamblia-infection. In conclusion, in this rural Ghanaian population current N. americanus infections are not associated with altered immune function, while infection with P. falciparum is associated with pro-inflammatory innate immune responses.

Phytohaemagglutinin

10.1016/j.imbio.2012.08.273

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Citations (22)

Sample size importantly limits the usefulness of instrumental variable methods, depending on instrument strength and level of confounding

Journal of Clinical Epidemiology (2014)

Anna G. C. Boef Olaf M. Dekkers Jan P. Vandenbroucke Saskia le Cessie

Ordinary least squares

Instrumental variable

Omitted-variable bias

Variables

10.1016/j.jclinepi.2014.05.019

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Citations (54)

The influence of genetic variation on innate immune activation in an environment with high infectious pressure

Genes and Immunity (2011)

Anna G. C. Boef L. May David van Bodegom Maris Kuningas Ulf Eriksson

Zymosan

10.1038/gene.2011.57

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Socioeconomic Status Is Associated With Antibody Levels Against Vaccine Preventable Diseases in the Netherlands

Frontiers in Public Health (2018)

Joske Hoes Anna G. C. Boef Mirjam J. Knol Hester E. de Melker Liesbeth Mollema

Background: We investigated whether low socioeconomic status (SES), which is associated with reduced health and life expectancy, might play a role in increased risk for infectious diseases. Therefore, we explored the association between SES and immunoglobulin G (IgG) levels against various pathogens. Methods: We analyzed the association between SES (educational level and net household income (NHI)) and serum IgG concentration against measles, mumps, rubella, varicella, Haemophilus influenzae type B (HiB), pneumococcus, meningococcus serogroup C (MenC), and cytomegalovirus (CMV) collected within a national cross-sectional serosurvey (2006/2007) using linear regression analyses among non-vaccinated individuals. Results: Higher educational level was associated with higher IgG concentrations against measles (GMC ratio 1.34, 95% CI 1.18-1.53) and rubella (1.13, 1.02-1.25) compared to low education level. In contrast, higher education level was associated with lower IgG concentrations against pneumococcus (0.78, 0.70-0.88), MenC (0.54, 0.44-0.68), and CMV (0.23, 0.18-0.31) compared to low education level. This pattern was also evident when NHI was used as SES indicator. Conclusion: Our study suggests that socioeconomic status is associated with antibody levels in a pathogen-dependent manner. The results suggest that differences in serological response upon infection or differences in exposure might be involved in the variation in IgG levels between SES groups.

Cross-sectional study

10.3389/fpubh.2018.00209

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Frontiers in Public Health (2022)

Milou Ohm Anna G. C. Boef Susanne P. Stoof Mariëtte B. van Ravenhorst Fiona van der Klis

Background Immune responses to pediatric vaccinations have been reported to differ according to sex. Such sex-differential responses may become more pronounced during adolescence due to hormonal differences. We investigated whether the vaccine response following primary vaccination against meningococcal serogroup A (MenA), MenW and MenY and booster vaccination against MenC differed between girls and boys using data from two clinical studies. Methods Children aged 10, 12, and 15 years, who had been primed with MenC vaccination between 14 months and 6 years of age, received a booster MenC vaccination or MenACWY vaccination. Polysaccharide-specific IgG concentrations and functional antibody titers [determined with the serum bactericidal antibody (SBA) assay] were measured at baseline, 1 month, 1 year, and 3 years (only MenC group) after vaccination. We calculated geometric mean concentrations and titers (GMC and GMT) ratios for girls vs. boys adjusted for age group. Additionally, we compared the proportion protected individuals between girls and boys at all timepoints. Results This study included 342 girls and 327 boys from two clinical trials. While MenAWY antibody levels did not differ consistently 1 month after vaccination, all GMC- and GMT-ratios were in favor of girls 1 year after vaccination [range: 1.31 (1.02–1.70) for MenA IgG to 1.54 (1.10–2.16) for MenW IgG]. Overall, MenC antibody levels were slightly higher in girls at all postvaccination timepoints (GMC- and GMT-ratios: 1.16/1.17 at 1 month, 1.16/1.22 at 1 year and 1.12/1.15 3 years postvaccination). Higher MenC antibody levels were observed in 12- and 15-year-old girls compared to boys of the same age, whereas 10-year-old boys and girls had similar antibody levels. The percentage of participants protected (SBA titer ≥ 8) was very high (95–100%) at all timepoints, and did not differ significantly between boys and girls. Conclusion Antibody responses were higher in girls than in boys for all serogroups at most timepoints after primary MenAWY vaccination and booster MenC vaccination. The differences in average titers were however small and the percentage participants with protective titers was very high for both sexes.

Meningococcal vaccine

Booster dose

Antibody titer

10.3389/fpubh.2022.871670

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Low C-Reactive Protein Levels in a Traditional West-African Population Living in a Malaria Endemic Area

PLoS ONE (2013)

Ulrika K. Eriksson David van Bodegom Linda May Anna G. C. Boef Rudi G. J. Westendorp

Background C-reactive protein (CRP) levels are reported to be elevated in populations of African descent living in affluent environments compared to populations of European ancestry. However, the natural history of CRP levels in populations of African descent living under adverse environments remains largely unknown. Methods CRP levels were measured with a high sensitivity assay in 624 apparently healthy individuals who contributed blood as part of a study on innate immune responsiveness in a traditional Ghanaian population living under adverse environmental conditions in a malaria endemic area. As a comparison, we included CRP measurements from 2931 apparently healthy individuals from the Dutch population that were included in the same batch of CRP analyses. Associations between CRP and body mass index (BMI), immune responsiveness, and P. falciparum parasitaemia were investigated. Results In an age- and sex-adjusted model, CRP levels were 0.54 mg/L lower in the Ghanaian compared to the Dutch cohort (1.52 vs. 0.98 mg/L, p<0.001). When accounting for the substantially higher average BMI in the Dutch compared to the Ghanaians (25.6 vs. 18.4 kg/m2) the difference in CRP levels disappeared. BMI associated positively with CRP in the Dutch but not in the Ghanaians. In individuals with an acute phase response, CRP levels were higher in the Ghanaian compared to the Dutch cohort (24.6 vs. 17.3 mg/L, p = 0.04). Levels of CRP were positively related to immune responsiveness and P. falciparum parasitaemia (all p<0.001) among Ghanaians. Conclusions Our study demonstrates that West-Africans do not exhibit an inherently high inflammatory state. The role of genes, environment and gene-environment interaction in explaining reports of elevated CRP levels in populations of African ancestry when compared to other ethnicities living in affluent environments thus merits further investigation.

10.1371/journal.pone.0070076

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Citations (18)

CHOOSING BETWEEN INSTRUMENTAL VARIABLE ANALYSES AND CONVENTIONAL ANALYSES : THE ROLE OF SAMPLE SIZE.

American Journal of Epidemiology (2013)

Anna G. C. Boef Olaf M. Dekkers J.P. Vandenbroucke Saskia le Cessie

Instrumental variable

Sample (material)

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Citations (0)

Physician’s prescribing preference as an instrumental variable

Epidemiology (2015)

Anna G. C. Boef Saskia le Cessie Olaf M. Dekkers Pascal Frey Patricia M. Kearney

Background: Physician's prescribing preference is increasingly used as an instrumental variable in studies of therapeutic effects.However, differences in prescribing patterns among physicians may reflect differences in preferences or in case-mix.Furthermore, there is debate regarding the possible assumptions for point estimation using physician's preference as an instrument.Methods: a survey was sent to general practitioners (gPs) in the netherlands, the United Kingdom, new Zealand, ireland, Switzerland, and germany, asking whether they would prescribe levothyroxine to eight fictitious patients with subclinical hypothyroidism.We investigated (1) whether variation in physician's preference was observable and to what extent it was explained by characteristics of gPs and their patient populations and (2) whether the data were compatible with deterministic and stochastic monotonicity assumptions.Results: levothyroxine prescriptions varied substantially among the 526 responding gPs.Between-gP variance in levothyroxine prescriptions (logit scale) was 9.9 (95% confidence interval: 8.0, 12) in the initial mixed effects logistic model, 8.3 (6.7, 10) after adding a fixed effect for country and 8.2 (6.6, 10) after adding gP characteristics.the occurring prescription patterns falsified the deterministic monotonicity assumption.all cases in all countries were more likely to receive levothyroxine if a different case of the same gP received levothyroxine, which is compatible with the stochastic monotonicity assumption.the data were incompatible with this assumption for a different definition of the instrument.Conclusions: Our study supports the existence of physician's preference as a determinant in treatment decisions.Deterministic monotonicity will generally not be plausible for physician's preference as an instrument.Depending on the definition of the instrument, stochastic monotonicity may be plausible.

Levothyroxine

Instrumental variable

Mixed logit

10.1097/ede.0000000000000425

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Citations (10)

DO YOU BELIEVE IN GHOST POPULATIONS? PRESENTATION AND ILLUSTRATION OF A SIMPLE ADJUSTMENT FACTOR FOR INVERSE-PROBABILITY WEIGHTING

American Journal of Epidemiology (2013)

Anna G. C. Boef Olaf M. Dekkers Jan P. Vandenbroucke Saskia le Cessie

Presentation (obstetrics)

Inverse probability weighting

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Instrumental variable analysis as a complementary analysis in studies of adverse effects: venous thromboembolism and second‐generation versus third‐generation oral contraceptives

Pharmacoepidemiology and Drug Safety (2016)

Anna G. C. Boef Patrick C. Souverein Jan P. Vandenbroucke Astrid van Hylckama Vlieg Anthonius de Boer

Abstract Purpose A potentially useful role for instrumental variable (IV) analysis may be as a complementary analysis to assess the presence of confounding when studying adverse drug effects. There has been discussion on whether the observed increased risk of venous thromboembolism (VTE) for third‐generation oral contraceptives versus second‐generation oral contraceptives could be (partially) attributed to confounding. We investigated how prescribing preference IV estimates compare with conventional estimates. Methods Women in the Clinical Practice Research Database who started a second‐generation or third‐generation oral contraceptive from 1989 to 2013 were included. Ordinary least squares and two‐stage least squares regression were used to estimate risk differences in VTE. Cox regression and IV for Cox proportional hazards regression were used to calculate hazard ratios (HR). The instrument used was the proportion of prescriptions for third‐generation oral contraceptives by the general practitioner in the year preceding the current prescription. Results All analyses pointed in the direction of an increased VTE risk for third‐generation oral contraceptives. The adjusted HR from the conventional Cox regression was 1.62 (95% confidence interval 1.16–2.27) and the fully adjusted HR from the IV Cox regression was 3.45 (95% confidence interval; 0.97–11.7), showing a larger risk and wider confidence intervals in the IV analysis. Conclusions The similarity in direction of results from the IV analyses and conventional analyses suggests that major confounding is unlikely. IV analysis can be a useful complementary analysis to assess the presence of confounding in studies of adverse drug effects in very large databases. Copyright © 2016 John Wiley & Sons, Ltd.

First generation

Instrumental variable

Pharmacoepidemiology

10.1002/pds.3956

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Citations (11)