Background: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence of symptoms of asthma in children. We undertook comprehensive analyses addressing risk factors for asthma symptoms in combination, at both the individual and the school level, to explore the potential role of reverse causation due to selective avoidance or confounding by indication. Objective: To explore the role of reverse causation in risk factors of asthma symptoms. Methods: We compared two sets of multilevel logistic regression analyses, using (a) individual level exposure data and (b) school level average exposure (ie prevalence), in two different age groups. In individual level analyses, reverse causation is a possible concern if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. School level analyses may suffer from ecologic confounding, but reverse causation is less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels. Results: There were 131 924 children aged 6-7 years (2428 schools, 25 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (odds ratio = 2.06; 95% confidence interval 1.97-2.16), early life antibiotic use (1.65; 1.58-1.73) and open fire cooking (1.44; 1.26-1.65). In school level analyses, these risk factors again showed increased risks. There were 238 586 adolescents aged 13-14 years (2072 schools, 42 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (1.80; 1.75-1.86), cooking on an open fire (1.32; 1.22-1.43) and maternal tobacco use (1.23; 1.18-1.27). In school level analyses, these risk factors again showed increased risks. Conclusions & clinical relevance: These analyses strengthen the potentially causal interpretation of previously reported individual level findings, by providing evidence against reverse causation. / Revisión por pares

Due to the intrauterine environment required to maintain pregnancy it may be that neonatal animals are born type-2 immune response (IR) biased, which consequently may increase susceptibility to certain infectious and immune mediated diseases, such as allergy. Recently, the prevalence of both allergic and autoimmune diseases has increased, leading to the development of the hygiene hypothesis. The hypothesis states that lack of early environmental stimulus leading to inappropriate development and bias in IR, may contribute to this increase. The objectives of this thesis, therefore, were to: (a) Determine the IR bias of neonatal pigs. (b) Investigate the effect of heat-killed Escherichia coli, lipopolysaccharide (LPS) and muramyl dipeptide (MDP) on the IR phenotype and the frequency of allergy in pigs sensitized to the egg white allergen ovomucoid (Ovm). (c) Establish IR phenotypes of pigs allergic or clinically tolerant to Ovm. Immune response bias was determined using an established phenotyping protocol and compared between two groups of pigs, (A) and (B). A difference in IR bias was observed. Bias in IR was not consistently towards type-2. Increase in indicators of type-1 IR, were greater in A and the frequency of type-2 IR correlates were greater in B. It’s likely that unidentified environmental variables may have induced this change, although etiology was not pursued. Treatment with heat-killed Escherichia coli, LPS and MDP had an effect on IR bias and frequency of allergy. Muramyl dipeptide-treatments promoted type-2 bias and were associated with increased frequency of allergy. Pre-treatment with E. coli did not affect allergic frequency, but did elicit the production of a relatively balanced allergen-specific IR phenotype. Lipopolysaccharide-pre-treatment was associated with decreased frequency of allergy. Correlates of an allergic IR phenotype in pigs were also established. The measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase intradermal skin tests were proposed to be useful in identifying allergic IR phenotypes. This thesis emphasizes the importance of considering the potential for variation in IR in terms of pig health and experimental reproducibility. Further, given the physiological similarities of pigs and humans, these findings may be extended to studies of food allergy in humans. / NSERC, OMAFRA, Ontario Pork, AllerGen NCE