Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - part I: which parameters from human studies are most relevant for toxicological assessments?

The 2018 European Food Safety Authority/European Chemicals Agency Guidance on the Identification of Endocrine Disruptors lacks clarity on how the presence or absence of substance-induced maternal thyroid hormone imbalance, or the potential for subsequent deleterious consequences in child neurodevelopment, should be established by toxicological assessments. To address these uncertainties, this narrative review evaluates human evidence on how altered maternal thyroid function may be associated with child neurodevelopmental outcomes; and seeks to identify parameters in human studies that appear most relevant for toxicological assessments. Serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) are most frequently measured when assessing thyroid function in pregnant women, whereas a broad spectrum of neurodevelopmental parameters is used to evaluate child neurodevelopment. The human data confirms an association between altered maternal serum fT4 and/or TSH and increased risk for child neurodevelopmental impairment. Quantitative boundaries of effects indicative of increased risks need to be established. Moreover, it is unknown if altered serum levels of total T4, free or total triiodothyronine, or parameters unrelated to serum thyroid hormones might be more relevant indicators of such effects. None of the human studies established a link between substance-mediated liver enzyme induction and increased serum thyroid hormone clearance, let alone further to child neurodevelopmental impairment. This review identifies research needs to contribute to the development of toxicity testing strategies, to reliably predict whether substances have the potential to impair child neurodevelopment via maternal thyroid hormone imbalance.

Determinants of Citation in Epidemiological Studies on Phthalates: A Citation Analysis.

Citing of previous publications is an important factor in knowledge development. Because of the great amount of publications available, only a selection of studies gets cited, for varying reasons. If the selection of citations is associated with study outcome this is called citation bias. We will study determinants of citation in a broader sense, including e.g. study design, journal impact factor or the funding source of the publication. As a case study we assess which factors drive citation in the human literature on phthalates, specifically the metabolite mono(2-ethylhexyl) phthalate (MEHP). A systematic literature search identified all relevant publications on human health effect of MEHP. Data on potential determinants of citation were extracted in duplo. Specialized software was used to create a citation network, including all potential citation pathways. Random effect logistic regression was used to assess whether these determinants influence the likelihood of citation. 112 Publications on MEHP were identified, with 5684 potential citation pathways of which 551 were actual citations. Reporting of a harmful point estimate, journal impact factor, authority of the author, a male corresponding author, research performed in North America and self-citation were positively associated with the likelihood of being cited. In the literature on MEHP, citation is mostly driven by a number of factors that are not related to study outcome. Although the identified determinants do not necessarily give strong indications of bias, it shows selective use of published literature for a variety of reasons.

Impact of changes in human reproduction on the incidence of endocrine-related diseases.

The incidence rates of a wide range of diseases and conditions have increased over the last decades. There is controversy over the origin of these increases, whether they are caused by exposure to compounds thought to have an effect on the endocrine system, the "endocrine disruption theory", or whether some other factor is responsible. In this analysis, the authors take a closer look at the role that changes in reproductive factors have played in this respect. They apply the relative risks of age at first pregnancy and parity or family size to a set of Dutch demographic data from 1955 and 2015 and calculate the percentage of disease increase explained. The decrease in parity over the last decades explains an increase of 26% in testicular cancer. The combination of decrease in parity and increase in maternal age at first pregnancy explains an increase of 34% in hypospadias prevalence. This combination of decreased parity and increased maternal age at pregnancy explains an increase of 24% in childhood obesity prevalence. The authors further point to a perhaps even more profound effect of the trend toward smaller families. This trend has led to an estimated doubling of the proportion of children born from subfertile couples. Since children born from subfertile couples are more likely to be preterm or of low birth weight, the incidence of these conditions must have increased as well. Low birth weight and preterm delivery are risk factors for a wide range of diseases and conditions. The changes in human reproduction over the last decades have had a profound impact on the incidence of a range of diseases and conditions in the next generation and thus provide a sound explanation for a substantial portion of the reported increases. Key messages The incidence rates of a wide range of diseases and conditions have increased in the Western societies over the last decades. Many have argued that these increases are attributable to compounds thought to have effects on the human endocrine system: the endocrine disruption theory This analysis shows, however, that human reproductive factors such as maternal age at first pregnancy and parity explain substantial proportions of the reported increases.

Comments on the opinions published by Bergman et al. (2015) on Critical Comments on the WHO-UNEP State of the Science of Endocrine Disrupting Chemicals (Lamb et al., 2014).

Recently Bergman et al. (2015) took issue with our comments (Lamb et al., 2014) on the WHO-UNEP(1) report entitled the "State of the Science of Endocrine Disrupting Chemicals - 2012" (WHO 2013a). We find several key differences between their view and ours regarding the selection of studies and presentation of data related to endocrine disrupting chemicals (EDCs) under the WHO-IPCS(2) definition (2002). In this response we address the factors that we think are most important: 1. the difference between hazard and risk; 2. the different approaches for hazard identification (weight of the evidence [WOE] vs. emphasizing positive findings over null results); and 3. the lack of a justification for conceptual or practical differences between EDCs and other groups of agents.

Critical comments on the WHO-UNEP State of the Science of Endocrine Disrupting Chemicals - 2012.

Early in 2013, the World Health Organization (WHO) released a 2012 update to the 2002 State of the Science of Endocrine Disrupting Chemicals. Several significant concerns have been identified that raise questions about conclusions reached in this report regarding endocrine disruption. First, the report is not a state-of-the-science review and does not follow the 2002 WHO recommended weight-of-evidence approach. Second, endocrine disruption is often presumed to occur based on exposure or a potential mechanism despite a lack of evidence to show that chemicals are causally established as endocrine disruptors. Additionally, causation is often inferred by the presentation of a series of unrelated facts, which collectively do not demonstrate causation. Third, trends in disease incidence or prevalence are discussed without regard to known causes or risk factors; endocrine disruption is implicated as the reason for such trends in the absence of evidence. Fourth, dose and potency are ignored for most chemicals discussed. Finally, controversial topics (i.e., low dose effects, non-monotonic dose response) are presented in a one-sided manner and these topics are important to understanding endocrine disruption. Overall, the 2012 report does not provide a balanced perspective, nor does it accurately reflect the state of the science on endocrine disruption.

Review of 2,4-dichlorophenoxyacetic acid (2,4-D) biomonitoring and epidemiology.

A qualitative review of the epidemiological literature on the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and health after 2001 is presented. In order to compare the exposure of the general population, bystanders and occupational groups, their urinary levels were also reviewed. In the general population, 2,4-D exposure is at or near the level of detection (LOD). Among individuals with indirect exposure, i.e. bystanders, the urinary 2,4-D levels were also very low except in individuals with opportunity for direct contact with the herbicide. Occupational exposure, where exposure was highest, was positively correlated with behaviors related to the mixing, loading and applying process and use of personal protection. Information from biomonitoring studies increases our understanding of the validity of the exposure estimates used in epidemiology studies. The 2,4-D epidemiology literature after 2001 is broad and includes studies of cancer, reproductive toxicity, genotoxicity, and neurotoxicity. In general, a few publications have reported statistically significant associations. However, most lack precision and the results are not replicated in other independent studies. In the context of biomonitoring, the epidemiology data give no convincing or consistent evidence for any chronic adverse effect of 2,4-D in humans.

Framework for integrating human and animal data in chemical risk assessment.

Although regulatory agencies formally encourage the integration of all available data in chemical risk assessment, consistent implementation of this practice has been constrained by the lack of a clear, systematic method for doing so. In this paper, we describe a methodology for evaluating, classifying and integrating human and animal data into the risk assessment process that incorporates: (1) a balanced appraisal of human and animal data, (2) relevance to different stages of the risk assessment process, and (3) accommodation for different data quality requirements. The proposed framework offers a flexible, step-wise approach for determining which set of available data best support the chemical risk assessment that involves the rating and relative ranking of human and animal data quality. The evaluation of human data incorporates seven data quality elements, nature and specificity of the lead effect; evaluation of animal data incorporates data quality and relevance to humans. Results of simulations with selected chemicals previously evaluated in a formal risk assessment generally agreed with existing regulatory guidance. Application of the proposed framework across a wider range of chemical agents will improve transparency of the risk assessment process and validity of results, while informing continuous refinements to this evolving methodology.

Citation bias and other determinants of citation in biomedical research: findings from six citation networks.

OBJECTIVES: When the probability of being cited depends on the outcome of that study, this is called citation bias. The aim of this study is to assess the determinants of citation and how these compare across six different biomedical research fields. STUDY DESIGN AND SETTING: Citation network analyses were performed for six biomedical research questions. After identifying all relevant publications, all potential citations were mapped together with the actually performed citations in each network. As determinants of citation we assessed the following: study outcome, study design, sample size, journal impact factor, gender, affiliation, authority and continent of the corresponding author, funding source, title of the publication, number of references, and self-citation. Random effect logistic regression analysis was used to assess these factors. RESULTS: Four out of six networks showed evidence for citation bias. Self-citation, authority of the author, and journal impact factor were also positively associated with the probability of citation in all networks. CONCLUSION: The probability of being cited seems associated with positive study outcomes, the authority of its authors, and the journal in which that article is published. In addition, each network showed specific characteristics that impact the citation dynamics and that need to be considered when performing and interpreting citation analyses.

Determinants of citation in the literature on diesel exhaust exposure and lung cancer: a citation analysis.

OBJECTIVES: Epidemiological research on the association between diesel exhaust exposure and lung cancer risk has some methodological challenges that give rise to different conclusions and intense debates. This raises the question about the role of selective citation and of citation bias in particular. Our aim was to investigate the occurrence and prevalence of selective citation in this field. DESIGN: Citation analysis. SETTING: Web of Science Core Collection. PARTICIPANTS: We identified 96 publications in this network, with 4317 potential citations. For each publication, we extracted characteristics such as study conclusion and funding source. Some of these characteristics are related to the study content: study design, sample size, method of diesel exposure assessment, type of diesel technology under investigation, and whether smoking had been adjusted for. PRIMARY AND SECONDARY OUTCOME MEASURES: Whether a citation occurs or not, measured and analysed according to the preregistered protocol. Exploratively we analysed the association between funding source and study conclusion. RESULTS: Methodological content of a study was clearly related to citation, studies using more sophisticated methods were more likely to be cited. There was some evidence for citation bias: supportive publications had a higher chance of being cited than non-supportive ones, but after adjustment for study quality, this effect decreased substantially (adjusted OR 1.3, 95% CI 1.0 to 1.7). Explorative analyses indicated that three quarters of non-profit funded publications had a supportive study conclusion against only one quarter of the industry-funded publications. CONCLUSIONS: There is evidence for selective citation within this field, but the evidence for citation bias was weak. It seems that factors related to the methodology had more impact on citation than the conclusion of a study. Interestingly, publications that were funded by industry were more skeptical about a causal relationship between diesel exhaust and lung cancer compared to non-profit-funded publications.

The strong focus on positive results in abstracts may cause bias in systematic reviews: a case study on abstract reporting bias.

BACKGROUND: Research articles tend to focus on positive findings in their abstract, especially if multiple outcomes have been studied. At the same time, search queries in databases are generally limited to the abstract, title and keywords fields of an article. Negative findings are therefore less likely to be detected by systematic searches and to appear in systematic reviews. We aim to assess the occurrence of this 'abstract reporting bias' and quantify its impact in the literature on the association between diesel exhaust exposure (DEE) and bladder cancer. METHODS: We set up a broad search query related to DEE and cancer in general. Full-texts of the articles identified in the search output were manually scanned. Articles were included if they reported, anywhere in the full-text, the association between DEE and bladder cancer. We assume that the use of a broad search query and manual full-text scanning allowed us to catch all the relevant articles, including those in which bladder cancer was not mentioned in the abstract, title or keywords. RESULTS: We identified 28 articles. Only 12 of these (43%) had mentioned bladder in their abstract, title or keywords. A meta-analysis based on these 12 detectable articles yielded a pooled risk estimate of 1.10 (95% confidence interval [CI] 0.97-1.25), whereas the meta-analysis based on all 28 articles yielded a pooled estimate of 1.03 (95% CI 0.96-1.11). CONCLUSIONS: This case study on abstract reporting bias shows that (a) more than half of all relevant articles were missed by a conventional search query and (b) this led to an overestimation of the pooled effect. Detection of articles will be improved if all studied exposure and outcome variables are reported in the keywords. The restriction on the maximum number of keywords should be lifted.

Citation bias in the literature on dietary trans fatty acids and serum cholesterol.

OBJECTIVE: Balanced citations are a necessary condition for a sound development of scientific knowledge, whereas selective citations may bias scientific consensus. In this study, we assess which determinants influenced the likelihood of being cited in the literature on trans fatty acids and cholesterol. STUDY DESIGN AND SETTING: We conducted a citation network analysis of the literature concerning trans fats and low density cholesterol and high density cholesterol. Each publication was scored on various potential determinants of citation, such as study outcome, study design, sample size, journal impact factor, and funding source. We applied random effect logistic regression to identify determinants of citation. RESULTS: A network of 108 publications was identified, containing 5,041 potential citation paths and 669 utilized citation paths. Reporting statistically significant results was found to be a strong predictor of citation, together with sample size, journal impact factor, and the authority of the authors. CONCLUSION: Within the literature on trans fat intake and cholesterol, selective citations are based on several grounds. Especially the effect of reporting significant results on citation requires special attention because disproportionate attention is paid to publications suggesting a harmful effect of trans fat on cholesterol.

Selective citation in the literature on the hygiene hypothesis: a citation analysis on the association between infections and rhinitis.

OBJECTIVE: Our objective was to assess the occurrence and determinants of selective citation in scientific publications on Strachan's original hygiene hypothesis. His hypothesis states that lack of exposure to infections in early childhood increases the risk of rhinitis. SETTING: Web of Science Core Collection. PARTICIPANTS: We identified 110 publications in this network, consisting of 5551 potential citations. PRIMARY AND SECONDARY OUTCOME MEASURES: Whether a citation occurs or not, measured and analysed according to the preregistered protocol. RESULTS: We found evidence for citation bias in this field: publications supportive of the hypothesis were cited more often than non-supportive publications (OR adjusted for study design [adjOR] 2.2, 95% CI 1.6 to 3.1), and the same was the case for publications with mixed findings (adjOR 3.1, 95% CI 2.2 to 4.5). Other relevant determinants for citation were type of exposure, specificity, journal impact factor, authority and self-citation. Surprisingly, prospective cohort studies were cited less often than other empirical studies. CONCLUSIONS: There is clear evidence for selective citation in this research field, and particularly for citation bias.

Psychometrics and validation of a screening instrument for sickness absence.

BACKGROUND: Absence from work due to psychosocial health complaints has considerable negative effects for employees, employers and society. A better and more effective strategy would be early identification of employees at risk for psychosocial sickness absence and early intervention to prevent sickness absence as far as possible. AIMS: To assess psychometric characteristics and the external validation of a recently developed screening instrument, called 'Werkwijzer', for the identification of employees at risk for sickness absence due to psychosocial health complaints. METHODS: Exploratory factor analysis was applied on items of the instrument. Cronbach's alpha coefficient was used to determine internal consistency of the subscales. Sum scores on the screening instrument were correlated to absenteeism data to determine their potential for predicting sickness absence. Predictive value was investigated, using objective sickness absence data as criterion measure. Sensitivity and specificity rates were calculated for external validation. RESULTS: For both men and women, three interpretable factors were found. Sum scores on the instrument showed low correlations with sickness absence. The association between 'being at risk' (yes/no) and sickness absence (yes/no) was odds ratio (OR) 3.1 (95% CI 1.5-6.5) for men and OR 2.0 (95% CI 1.4-2.7) for women. Sensitivity scores were rather low, whereas specificity scores were remarkably high. CONCLUSIONS: The results of this study provide the screening instrument a theoretic and scientific basis. Predictive value is promising, when absence is treated as a dichotomous measure. Sensitivity and specificity were unvarying during the development and validation phases of the instrument.

Responsible Epidemiologic Research Practice: a guideline developed by a working group of the Netherlands Epidemiological Society.

OBJECTIVES: To develop a guideline on Responsible Epidemiologic Research Practice that will increase value and transparency, increase the accountability of the epidemiologists, and reduce research waste. SETTING: A working group of the Netherland Epidemiological Society was given the task of developing a guideline that would meet these objectives. Several publications about the need to prevent Detrimental Research Practices triggered this work. Among these were a series in the Lancet on research waste and a subsequent series on transparency in the Journal of Clinical Epidemiology. The reputation and trust in epidemiologic research is still high, and the Netherlands Epidemiological Society wishes to keep it that way. The guideline deals with how epidemiologic research should be conducted, archived, and disclosed. It does not deal with the more technical aspects, such as required sample size, choice of study design, and so forth. The guideline describes each step in the process of conducting an epidemiologic study, from the first idea to the ultimate publication and beyond. METHODS: The working group reviewed the literature on responsible research conduct, including the various existing codes of conduct. It applied the general principles from these codes to the elements of an epidemiologic study and formulated specific recommendations for each of these. Next step was to draft the guideline. Preceding the 2016 annual national epidemiology conference in Wageningen, a preconference was organized to discuss the draft guideline and to assess support. Support was clearly present, and the provided recommendations were incorporated into the draft guideline. In March 2017, a draft version of the guideline was sent to all 1,100 members of the society with the request to review and provide comments. All received responses were positive, and some minor additions were made. The Responsible Epidemiologic Research Practice guideline has now been approved by the board of the Netherlands Epidemiological Society. CONCLUSION: With the Responsible Epidemiologic Research Practice guideline, we hope to contribute to better research practices in epidemiology but perhaps also in adjacent disciplines.

A meta-analysis of observational studies identifies predictors of sickness absence.

OBJECTIVE: About one in every three employees seen by their occupational physician is absent from work because of psychosocial health complaints. To implement preventive measures, it is necessary to identify predictors for this type of sickness absence. STUDY DESIGN AND SETTING: A meta-analysis was carried out to quantify the association between predictive factors and psychosocial sickness absence and to assess clinical outcomes and heterogeneity. Eligible for inclusion were prospective studies that examined this association and provided sufficient information to estimate summary odds ratios (SORs). RESULTS: Twenty prospective studies were included. Significant SORs for sick leave >3 days were found for being unmarried, 1.37 (95% confidence interval [CI]=1.15-1.64), experiencing psychosomatic complaints, 1.79 (95% CI=1.54-2.07), using medication, 3.13 (95% CI=1.71-5.72), having a burnout, 2.34 (95% CI=1.59-3.45), suffering from psychological problems, 1.97 (95% CI=1.37-2.85), having low job control, 1.28 (95% CI=1.23-1.33), having low decision latitude, 1.33 (95% CI=1.16-1.56), and experiencing no fairness at work, 1.30 (95% CI=1.18-1.45). CONCLUSION: This study shows that predictors of sickness absence can be identified in a homogeneous manner. The results provide leads to public health interventions to successfully improve psychosocial health and to reduce sickness absence.

Mortality study update of acrylamide workers.

OBJECTIVE: The authors examined the long-term health effects of occupational exposure to acrylamide among production and polymerisation workers. METHODS: An earlier study of 371 acrylamide workers was expanded to include employees hired since 1979. In this updated study, 696 acrylamide workers were followed from 1955 through 2001 to ascertain vital status and cause of death. Exposure to acrylamide was retrospectively assessed based on personal samples from the 1970s onwards and area samples over the whole study period. RESULTS: Fewer of the acrylamide workers died (n = 141) compared to an expected number of 172.1 (SMR 81.9, 95% CI 69.0 to 96.6). No cause-specific SMR for any of the investigated types of cancer was exposure related. The authors did, however, find more pancreatic cancer deaths than expected (SMR 222.2, 95% CI 72.1 to 518.5). With respect to non-malignant disease, more diabetes deaths were observed than expected (SMR 288.7, 95% CI 138.4 to 531.0). To assess the influence of regional factors, the analysis was repeated with an internal reference population. The elevated SMR for diabetes persisted. CONCLUSION: This study provides little evidence for a cancer risk from occupational exposure to acrylamide at production facilities. However, the increased rates of pancreatic cancer in this study and another larger study of acrylamide production workers indicate that caution is needed to rule out a cancer risk. The authors believe that the excess of diabetes mortality in this study is most likely not related to acrylamide exposure, because a larger study of acrylamide workers reported a deficit in this cause of death. The authors conclude that the increased SMR for diabetes mortality is probably not related to regional influences.

Mortality patterns among workers exposed to acrylamide: updated follow up.

OBJECTIVE: The objective of this study was to update the mortality experience of a cohort of workers with and without potential exposure to acrylamide (AMD) at three U.S. plants (n = 8508) and one plant in The Netherlands (n = 344). METHODS: We computed standardized mortality ratios (SMRs) using national and local rates and modeled internal cohort rates to assess site-specific cancer risks by demographic and work history factors and several exposure indicators for AMD. RESULTS: For the 1925-2002 study period, we observed both deficit and excess overall mortality risks among the U.S. cohort for cancer sites implicated in experimental animal studies: brain and other central nervous system (SMR = 0.67, confidence interval [CI] = 0.40-1.05), thyroid gland (SMR = 1.38, CI = 0.28-4.02), testis and other male genital organs (SMR = 0.64, CI = 0.08-2.30); and for sites selected in earlier exploratory analyses of this cohort: respiratory system cancer (RSC) (SMR = 1.17, CI = 1.06-1.27), esophagus (SMR = 1.20, CI = 0.86-1.63), rectum (SMR = 1.25, CI = 0.84-1.78), pancreas (SMR = 0.94, CI = 0.70-1.22), and kidney (SMR = 1.01, CI = 0.66-1.46). Except for RSC, attributed earlier to muriatic acid exposure, none of the mortality excesses was statistically significant. In the Dutch cohort, we observed deficits in deaths for all sites of a priori interest. An updated analysis of our previous exploratory findings for pancreatic cancer in the U.S. cohort revealed much less evidence of a possible exposure-response relationship with AMD. CONCLUSION: AMD exposure at the levels present in our study sites was not associated with elevated cancer mortality risks.

Advantages and disadvantages of an objective selection process for early intervention in employees at risk for sickness absence.

BACKGROUND: It is unclear if objective selection of employees, for an intervention to prevent sickness absence, is more effective than subjective 'personal enlistment'. We hypothesize that objectively selected employees are 'at risk' for sickness absence and eligible to participate in the intervention program. METHODS: The dispatch of 8603 screening instruments forms the starting point of the objective selection process. Different stages of this process, throughout which employees either dropped out or were excluded, were described and compared with the subjective selection process. Characteristics of ineligible and ultimately selected employees, for a randomized trial, were described and quantified using sickness absence data. RESULTS: Overall response rate on the screening instrument was 42.0%. Response bias was found for the parameters sex and age, but not for sickness absence. Sickness absence was higher in the 'at risk' (N = 212) group (42%) compared to the 'not at risk' (N = 2503) group (25%) (OR 2.17 CI 1.63-2.89; p = 0.000). The selection process ended with the successful inclusion of 151 eligible, i.e. 2% of the approached employees in the trial. CONCLUSION: The study shows that objective selection of employees for early intervention is effective. Despite methodological and practical problems, selected employees are actually those at risk for sickness absence, who will probably benefit more from the intervention program than others.

Selective citation in the literature on swimming in chlorinated water and childhood asthma: a network analysis.

BACKGROUND: Knowledge development depends on an unbiased representation of the available evidence. Selective citation may distort this representation. Recently, some controversy emerged regarding the possible impact of swimming on childhood asthma, raising the question about the role of selective citation in this field. Our objective was to assess the occurrence and determinants of selective citation in scientific publications on the relationship between swimming in chlorinated pools and childhood asthma. METHODS: We identified scientific journal articles on this relationship via a systematic literature search. The following factors were taken into account: study outcome (authors' conclusion, data-based conclusion), other content-related article characteristics (article type, sample size, research quality, specificity), content-unrelated article characteristics (language, publication title, funding source, number of authors, number of affiliations, number of references, journal impact factor), author characteristics (gender, country, affiliation), and citation characteristics (time to citation, authority, self-citation). To assess the impact of these factors on citation, we performed a series of univariate and adjusted random-effects logistic regressions, with potential citation path as unit of analysis. RESULTS: Thirty-six articles were identified in this network, consisting of 570 potential citation paths of which 191 (34%) were realized. There was strong evidence that articles with at least one author in common, cited each other more often than articles that had no common authors (odds ratio (OR) 5.2, 95% confidence interval (CI) 3.1-8.8). Similarly, the chance of being cited was higher for articles that were empirical rather than narrative (OR 4.2, CI 2.6-6.7), that reported a large sample size (OR 5.8, CI 2.9-11.6), and that were written by authors with a high authority within the network (OR 4.1, CI 2.1-8.0). Further, there was some evidence for citation bias: articles that confirmed the relation between swimming and asthma were cited more often (OR 1.8, CI 1.1-2.9), but this finding was not robust. CONCLUSIONS: There is clear evidence of selective citation in this research field, but the evidence for citation bias is not very strong.