We propose to examine the association between pet ownership, allergic sensitization and asthma, within a cohort of children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). On the basis of the findings of previous studies, we hypothesise that childhood household pet ownership will be associated with childhood asthma and asthma/atopy symptoms, and that these associations will be moderated by a number of factors including child genotype, time and duration of exposure, species of exposure (cats, dogs, other pets), and associated parental behaviours (domestic hygiene practices). By making use of an existing large-scale database, which has detailed records of pet keeping in the prenatal and early-to-middle childhood period, as well as extensive information concerning potential confounding factors, we propose to conduct the most rigorous study to date of the relationship between pet keeping and childhood asthma morbidity.

5.2. Hypotheses

We hypothesise that household ownership of cats, dogs and other pets, prenatally, in infancy and in early-to-middle childhood will be associated with:

1. Sensitisation to aeroallergens at 84 months (7 years);

2. Wheezing illnesses during early childhood up to 81 months of age (6 years 9 months);

3. Doctor-diagnosed asthma by 96 months(8 years);

4. Lung function and bronchial responsiveness at age 96 months (8 years).

We additionally hypothesise:

1. that pet ownership effects on sensitisation to aeroallergens, wheezing illness and asthma are independent of other social and lifestyle variables;

2. age and duration of pet exposure, number and types of pets owned (e.g. cats & dogs, cats only, dogs only, other furry pets., etc.) will moderate these associations;

3. parental hygiene practices (e.g. cleaning frequency and use of household cleaning products) will moderate these associations.

5.3. The study population - The Avon Longitudinal Study of Parents and Children (ALSPAC):

Child health questionnaires: Maternal reports of their children's health were collected using questionnaires issued six months after birth and at annual intervals thereafter. Mothers were asked if, during the preceding 12 months (6 months for the initial questionnaire), their child had 'wheeze with whistling on his/her chest when s/he breathed'. If they answered, "Yes," they were asked to complete a number of supplementary questions detailing the frequency of wheezing episodes, duration of wheezing, associated symptoms of breathlessness or fever, and what (if anything) provoked the wheezing. At 91 & 103 months of age (7 1/2 & 8 1/2 years approximately) they were also asked to report if a 'doctor had ever diagnosed (their) child as having asthma'. From responses to these questions, we reported differences in the epidemiological associations of wheezing illnesses in young children (Sherriff et al., 2001) and we have been able to map these symptoms to early wheezing phenotypes reported from the Tucson Children's Respiratory Study (Martinez et al., 1995).

Household pet ownership questionnaires: Details of pets kept in the household of the child were reported by mothers within the same questionnaires used to obtain details concerning child and maternal health. Respondents were asked "Do you have any pets?" and "How many of the following pets do you have?". Pet types listed included cats, dogs, rabbits, rodents (mice, hamster gerbil, etc.), birds (budgerigar, parrot etc.) and 'other' pets. Two additional categories of pet type (fish and turtles/tortoises/terrapins) were added when the cohort children were 2 years of age and onwards. Pet questions were asked prenatally (when the mother was between 8 and 32 weeks pregnant), at 8 months, and at 21, 33, 47, 85 and 97 months (approximately 2, 3, 4, 7 and 8 years).

Additional Questionnaire information: Measures of numerous potential confounds and moderators of pet ownership-asthma associations were collected using the same and additional maternal questionnaires administered both before birth and at yearly intervals thereafter. ALSPAC variables that have previously been found to be associated with variations in pet ownership include: gender of child, number of people in household, presence of older sibling, type of dwelling, maternal age, maternal and paternal social class, presence of other species of pet and maternal and paternal education (Westgarth et al 2010). ALSPAC variables that have previously been found or are thought to be to be associated with childhood asthma include: maternal and paternal smoking (including total number of hours of exposure to tobacco smoke per week in home), environmental pollution, use of household cleaning products, maternal anxiety during pregnancy, maternal and child diet, child activity levels (Shaheen et al 2002, 2004, 2005; Sherriff et al 2005, 2010; Cookson et al 2009).

Child clinic assessments: A range of clinical and behavioural data were collected between 91 and 103 months of age (approx. 7-8 years), including skin prick test responses to cat (felis domesticus), house dust mite (Dermatophagoides pteronyssinus), and mixed grass pollen. A subsample of the clinic population (approx 2500 children) was also assessed by skin prick test responses to other animals commonly kept as domestic pets (dog, horse, mouse, rabbit, guinea pig and hamster). For genetic analyses, DNA was extracted from maternal blood and from infant cord blood samples at birth, and later supplemented by blood samples drawn at approx. 91 months; such samples are currently available for approximately 10,000 mothers and 10,000 children.

The ALSPAC population is broadly representative of the rest of the British population based on 1991 census data, although participants in the study were more likely to live in owner-occupied accommodation and less likely to have a non-white mother (ALSPAC 2.6%; population of Avon 1970 4.1%; UK census 1991 7.6%). In common with all population-based longitudinal studies, there has been incomplete retention of the cohort with attrition biased towards the more socially disadvantaged groups. However, over 11,000 children actively participated in the study to age 96 months (8 years), providing a large dataset with which to assess antenatal and early life effects on the development of childhood asthma and wheeze.

5.4. Health outcomes (see Hypotheses):

1. Sensitisation to aeroallergens was assessed by skin prick test responses to cat (felis domesticus), house dust mite (Dermatophagoides pteronyssinus) and mixed grass pollen at the age of 91 months (approx. 7 years). A positive skin prick test response (greater than 2mm weal) to any of these three allergens identifies over 95% of atopic children in our population (i.e., positive skin test to any allergen).

2. Doctor diagnosed asthma at approx. 96 months (8 years) was assessed from response to questionnaires completed by the mother.

3. Wheezing illness during early childhood is based on a novel approach to wheezing phenotype characterisation developed by our group from longitudinal analyses of wheeze data using latent class models (Henderson et al 2008). This analytical approach defines the minimum number of wheezing trajectories (classes) that best describe the data and is robust to missing data, providing wheeze phenotype classifications for 11,625 of the study population from birth through 81 months. The best fitting model to our data suggested the presence of 6 classes (5 wheezing classes plus non-wheezers). We have named these five wheezing trajectories Transient Early, Prolonged Early, Intermediate-onset, Late-onset and Persistent Wheezing as shown in the legend. These include classes that have been suggested to be associated with abnormalities of early (including intrauterine) airway development (Stocks and Dezateux, 2003). Our analyses showed strong associations between intermediate and late onset wheezing with bronchial hyper-responsiveness and of intermediate onset and persistent wheezing with allergy to cat and house dust mite. Therefore, it appears that these classes are representative of discrete wheezing phenotypes in early childhood that may have differing natural histories and aetiology (Henderson et al 2008).

4. Lung function and bronchial responsiveness were assessed at a research clinic at approximately 103 months. Spirometry was performed according to American Thoracic Society criteria for acceptability and reproducibility (American Thoracic Society, 1995). Measurements were quality controlled to ensure appropriate selection of the optimal curve from which lung function variables (FEV1, FVC, MMEF, FEF50, FEF75) were derived. Each variable was converted to a scale of gender- age- and height-adjusted standard deviation units based on log-linear regression against age and height, for boys and girls separately and then combined across genders (Chin and Rona, 1992). After completion of satisfactory baseline lung function measurements, bronchial responsiveness to methacholine was measured in consenting children (n=5000) according to the rapid method of Yan et al, (1983) using hand-operated glass nebulisers. For each participant, we measured forced expiratory volume (FEV1) post-saline inhalation (baseline) and 1 minute after each of a sequence of cumulative doses of methacholine.